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1.  CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer 
Thompson, Deborah J | O’Mara, Tracy A | Glubb, Dylan M | Painter, Jodie N | Cheng, Timothy | Folkerd, Elizabeth | Doody, Deborah | Dennis, Joe | Webb, Penelope M | Gorman, Maggie | Martin, Lynn | Hodgson, Shirley | Michailidou, Kyriaki | Tyrer, Jonathan P | Maranian, Mel J | Hall, Per | Czene, Kamila | Darabi, Hatef | Li, Jingmei | Fasching, Peter A | Hein, Alexander | Beckmann, Matthias W | Ekici, Arif B | Dörk, Thilo | Hillemanns, Peter | Dürst, Matthias | Runnebaum, Ingo | Zhao, Hui | Depreeuw, Jeroen | Schrauwen, Stefanie | Amant, Frederic | Goode, Ellen L | Fridley, Brooke L | Dowdy, Sean C | Winham, Stacey J | Salvesen, Helga B | Trovik, Jone | Njolstad, Tormund S | Werner, Henrica MJ | Ashton, Katie | Proietto, Tony | Otton, Geoffrey | Carvajal-Carmona, Luis | Tham, Emma | Liu, Tao | Mints, Miriam | Scott, Rodney J | McEvoy, Mark | Attia, John | Holliday, Elizabeth G | Montgomery, Grant W | Martin, Nicholas G | Nyholt, Dale R | Henders, Anjali K | Hopper, John L | Traficante, Nadia | Ruebner, Matthias | Swerdlow, Anthony J | Burwinkel, Barbara | Brenner, Hermann | Meindl, Alfons | Brauch, Hiltrud | Lindblom, Annika | Lambrechts, Diether | Chang-Claude, Jenny | Couch, Fergus J | Giles, Graham G | Kristensen, Vessela N | Cox, Angela | Bolla, Manjeet K | Wang, Qin | Bojesen, Stig E | Shah, Mitul | Luben, Robert | Khaw, Kay-Tee | Pharoah, Paul DP | Dunning, Alison M | Tomlinson, Ian | Dowsett, Mitch | Easton, Douglas F | Spurdle, Amanda B
Endocrine-related cancer  2015;23(2):77-91.
Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol concentrations. We analysed 2,937 SNPs in 6,608 endometrial cancer cases and 37,925 controls and report the first genome wide-significant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P=4.8×10−11). SNP rs727479 was also among those most strongly associated with circulating estradiol concentrations in 2,767 post-menopausal controls (P=7.4×10−8). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11–1.21) is compatible with that predicted by the observed effect on estradiol concentrations (1.09, CI=1.03–1.21), consistent with the hypothesis that endometrial cancer risk is driven by estradiol. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associations with rs727479 were stronger among women with a higher BMI (Pinteraction=0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction.
doi:10.1530/ERC-15-0386
PMCID: PMC4697192  PMID: 26574572
Endometrial cancer; CYP19A1; estradiol
2.  Genetic predisposition to ductal carcinoma in situ of the breast 
Petridis, Christos | Brook, Mark N. | Shah, Vandna | Kohut, Kelly | Gorman, Patricia | Caneppele, Michele | Levi, Dina | Papouli, Efterpi | Orr, Nick | Cox, Angela | Cross, Simon S. | dos-Santos-Silva, Isabel | Peto, Julian | Swerdlow, Anthony | Schoemaker, Minouk J. | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Michailidou, Kyriaki | Benitez, Javier | González-Neira, Anna | Tessier, Daniel C. | Vincent, Daniel | Li, Jingmei | Figueroa, Jonine | Kristensen, Vessela | Borresen-Dale, Anne-Lise | Soucy, Penny | Simard, Jacques | Milne, Roger L. | Giles, Graham G. | Margolin, Sara | Lindblom, Annika | Brüning, Thomas | Brauch, Hiltrud | Southey, Melissa C. | Hopper, John L. | Dörk, Thilo | Bogdanova, Natalia V. | Kabisch, Maria | Hamann, Ute | Schmutzler, Rita K. | Meindl, Alfons | Brenner, Hermann | Arndt, Volker | Winqvist, Robert | Pylkäs, Katri | Fasching, Peter A. | Beckmann, Matthias W. | Lubinski, Jan | Jakubowska, Anna | Mulligan, Anna Marie | Andrulis, Irene L. | Tollenaar, Rob A. E. M. | Devilee, Peter | Le Marchand, Loic | Haiman, Christopher A. | Mannermaa, Arto | Kosma, Veli-Matti | Radice, Paolo | Peterlongo, Paolo | Marme, Frederik | Burwinkel, Barbara | van Deurzen, Carolien H. M. | Hollestelle, Antoinette | Miller, Nicola | Kerin, Michael J. | Lambrechts, Diether | Floris, Giuseppe | Wesseling, Jelle | Flyger, Henrik | Bojesen, Stig E. | Yao, Song | Ambrosone, Christine B. | Chenevix-Trench, Georgia | Truong, Thérèse | Guénel, Pascal | Rudolph, Anja | Chang-Claude, Jenny | Nevanlinna, Heli | Blomqvist, Carl | Czene, Kamila | Brand, Judith S. | Olson, Janet E. | Couch, Fergus J. | Dunning, Alison M. | Hall, Per | Easton, Douglas F. | Pharoah, Paul D. P. | Pinder, Sarah E. | Schmidt, Marjanka K | Tomlinson, Ian | Roylance, Rebecca | García-Closas, Montserrat | Sawyer, Elinor J.
Background
Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer. It is often associated with invasive ductal carcinoma (IDC), and is considered to be a non-obligate precursor of IDC. It is not clear to what extent these two forms of cancer share low-risk susceptibility loci, or whether there are differences in the strength of association for shared loci.
Methods
To identify genetic polymorphisms that predispose to DCIS, we pooled data from 38 studies comprising 5,067 cases of DCIS, 24,584 cases of IDC and 37,467 controls, all genotyped using the iCOGS chip.
Results
Most (67 %) of the 76 known breast cancer predisposition loci showed an association with DCIS in the same direction as previously reported for invasive breast cancer. Case-only analysis showed no evidence for differences between associations for IDC and DCIS after considering multiple testing.
Analysis by estrogen receptor (ER) status confirmed that loci associated with ER positive IDC were also associated with ER positive DCIS. Analysis of DCIS by grade suggested that two independent SNPs at 11q13.3 near CCND1 were specific to low/intermediate grade DCIS (rs75915166, rs554219). These associations with grade remained after adjusting for ER status and were also found in IDC.
We found no novel DCIS-specific loci at a genome wide significance level of P < 5.0x10-8.
Conclusion
In conclusion, this study provides the strongest evidence to date of a shared genetic susceptibility for IDC and DCIS. Studies with larger numbers of DCIS are needed to determine if IDC or DCIS specific loci exist.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-016-0675-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-016-0675-7
PMCID: PMC4756509  PMID: 26884359
Ductal carcinoma in situ; Association study; Genetic predisposition; Common variants
3.  Inherited variants in the inner centromere protein (INCENP) gene of the chromosomal passenger complex contribute to the susceptibility of ER-negative breast cancer 
Kabisch, Maria | Lorenzo Bermejo, Justo | Dünnebier, Thomas | Ying, Shibo | Michailidou, Kyriaki | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Shah, Mitul | Perkins, Barbara J. | Czene, Kamila | Darabi, Hatef | Eriksson, Mikael | Bojesen, Stig E. | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Lambrechts, Diether | Neven, Patrick | Peeters, Stephanie | Weltens, Caroline | Couch, Fergus J. | Olson, Janet E. | Wang, Xianshu | Purrington, Kristen | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Peto, Julian | dos-Santos-Silva, Isabel | Johnson, Nichola | Fletcher, Olivia | Nevanlinna, Heli | Muranen, Taru A. | Aittomäki, Kristiina | Blomqvist, Carl | Schmidt, Marjanka K. | Broeks, Annegien | Cornelissen, Sten | Hogervorst, Frans B.L. | Li, Jingmei | Brand, Judith S. | Humphreys, Keith | Guénel, Pascal | Truong, Thérèse | Menegaux, Florence | Sanchez, Marie | Burwinkel, Barbara | Marmé, Frederik | Yang, Rongxi | Bugert, Peter | González-Neira, Anna | Benitez, Javier | Pilar Zamora, M. | Arias Perez, Jose I. | Cox, Angela | Cross, Simon S. | Reed, Malcolm W.R. | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Tchatchou, Sandrine | Sawyer, Elinor J. | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Haiman, Christopher A. | Schumacher, Fredrick | Henderson, Brian E. | Le Marchand, Loic | Lindblom, Annika | Margolin, Sara | Hooning, Maartje J. | Hollestelle, Antoinette | Kriege, Mieke | Koppert, Linetta B. | Hopper, John L. | Southey, Melissa C. | Tsimiklis, Helen | Apicella, Carmel | Slettedahl, Seth | Toland, Amanda E. | Vachon, Celine | Yannoukakos, Drakoulis | Giles, Graham G. | Milne, Roger L. | McLean, Catriona | Fasching, Peter A. | Ruebner, Matthias | Ekici, Arif B. | Beckmann, Matthias W. | Brenner, Hermann | Dieffenbach, Aida K. | Arndt, Volker | Stegmaier, Christa | Ashworth, Alan | Orr, Nicholas | Schoemaker, Minouk J. | Swerdlow, Anthony | García-Closas, Montserrat | Figueroa, Jonine | Chanock, Stephen J. | Lissowska, Jolanta | Goldberg, Mark S. | Labrèche, France | Dumont, Martine | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Radice, Paolo | Peterlongo, Paolo | Scuvera, Giulietta | Fortuzzi, Stefano | Bogdanova, Natalia | Dörk, Thilo | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Devilee, Peter | Tollenaar, Robert A.E.M. | Seynaeve, Caroline | Van Asperen, Christi J. | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Zheng, Wei | Shrubsole, Martha J. | Cai, Qiuyin | Torres, Diana | Anton-Culver, Hoda | Kristensen, Vessela | Bacot, François | Tessier, Daniel C. | Vincent, Daniel | Luccarini, Craig | Baynes, Caroline | Ahmed, Shahana | Maranian, Mel | Simard, Jacques | Chenevix-Trench, Georgia | Hall, Per | Pharoah, Paul D.P. | Dunning, Alison M. | Easton, Douglas F. | Hamann, Ute
Carcinogenesis  2015;36(2):256-271.
Summary
This is the first study investigating the contribution of inherited variants in core genes of the chromosomal passenger complex to breast cancer susceptibility. It was found that several INCENP variants are associated with the risk of ER-negative breast cancer in the European population.
The chromosomal passenger complex (CPC) plays a pivotal role in the regulation of cell division. Therefore, inherited CPC variability could influence tumor development. The present candidate gene approach investigates the relationship between single nucleotide polymorphisms (SNPs) in genes encoding key CPC components and breast cancer risk. Fifteen SNPs in four CPC genes (INCENP, AURKB, BIRC5 and CDCA8) were genotyped in 88 911 European women from 39 case-control studies of the Breast Cancer Association Consortium. Possible associations were investigated in fixed-effects meta-analyses. The synonymous SNP rs1675126 in exon 7 of INCENP was associated with overall breast cancer risk [per A allele odds ratio (OR) 0.95, 95% confidence interval (CI) 0.92–0.98, P = 0.007] and particularly with estrogen receptor (ER)-negative breast tumors (per A allele OR 0.89, 95% CI 0.83–0.95, P = 0.0005). SNPs not directly genotyped were imputed based on 1000 Genomes. The SNPs rs1047739 in the 3ʹ untranslated region and rs144045115 downstream of INCENP showed the strongest association signals for overall (per T allele OR 1.03, 95% CI 1.00–1.06, P = 0.0009) and ER-negative breast cancer risk (per A allele OR 1.06, 95% CI 1.02–1.10, P = 0.0002). Two genotyped SNPs in BIRC5 were associated with familial breast cancer risk (top SNP rs2071214: per G allele OR 1.12, 95% CI 1.04–1.21, P = 0.002). The data suggest that INCENP in the CPC pathway contributes to ER-negative breast cancer susceptibility in the European population. In spite of a modest contribution of CPC-inherited variants to the total burden of sporadic and familial breast cancer, their potential as novel targets for breast cancer treatment should be further investigated.
doi:10.1093/carcin/bgu326
PMCID: PMC4335262  PMID: 25586992
4.  CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer 
Thompson, Deborah J | O'Mara, Tracy A | Glubb, Dylan M | Painter, Jodie N | Cheng, Timothy | Folkerd, Elizabeth | Doody, Deborah | Dennis, Joe | Webb, Penelope M | Gorman, Maggie | Martin, Lynn | Hodgson, Shirley | Michailidou, Kyriaki | Tyrer, Jonathan P | Maranian, Mel J | Hall, Per | Czene, Kamila | Darabi, Hatef | Li, Jingmei | Fasching, Peter A | Hein, Alexander | Beckmann, Matthias W | Ekici, Arif B | Dörk, Thilo | Hillemanns, Peter | Dürst, Matthias | Runnebaum, Ingo | Zhao, Hui | Depreeuw, Jeroen | Schrauwen, Stefanie | Amant, Frederic | Goode, Ellen L | Fridley, Brooke L | Dowdy, Sean C | Winham, Stacey J | Salvesen, Helga B | Trovik, Jone | Njolstad, Tormund S | Werner, Henrica M J | Ashton, Katie | Proietto, Tony | Otton, Geoffrey | Carvajal-Carmona, Luis | Tham, Emma | Liu, Tao | Mints, Miriam | Scott, Rodney J | McEvoy, Mark | Attia, John | Holliday, Elizabeth G | Montgomery, Grant W | Martin, Nicholas G | Nyholt, Dale R | Henders, Anjali K | Hopper, John L | Traficante, Nadia | Ruebner, Matthias | Swerdlow, Anthony J | Burwinkel, Barbara | Brenner, Hermann | Meindl, Alfons | Brauch, Hiltrud | Lindblom, Annika | Lambrechts, Diether | Chang-Claude, Jenny | Couch, Fergus J | Giles, Graham G | Kristensen, Vessela N | Cox, Angela | Bolla, Manjeet K | Wang, Qin | Bojesen, Stig E | Shah, Mitul | Luben, Robert | Khaw, Kay-Tee | Pharoah, Paul D P | Dunning, Alison M | Tomlinson, Ian | Dowsett, Mitch | Easton, Douglas F | Spurdle, Amanda B
Endocrine-Related Cancer  2016;23(2):77-91.
Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol (E2) concentrations. We analyzed 2937 single nucleotide polymorphisms (SNPs) in 6608 endometrial cancer cases and 37 925 controls and report the first genome wide-significant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P=4.8×10−11). SNP rs727479 was also among those most strongly associated with circulating E2 concentrations in 2767 post-menopausal controls (P=7.4×10−8). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11–1.21) is compatible with that predicted by the observed effect on E2 concentrations (1.09, CI=1.03–1.21), consistent with the hypothesis that endometrial cancer risk is driven by E2. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associations with rs727479 were stronger among women with a higher BMI (Pinteraction=0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction.
doi:10.1530/ERC-15-0386
PMCID: PMC4697192  PMID: 26574572
endometrial cancer; CYP19A1; estradiol
5.  Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk 
Lin, Wei-Yu | Camp, Nicola J. | Ghoussaini, Maya | Beesley, Jonathan | Michailidou, Kyriaki | Hopper, John L. | Apicella, Carmel | Southey, Melissa C. | Stone, Jennifer | Schmidt, Marjanka K. | Broeks, Annegien | Van't Veer, Laura J. | Th Rutgers, Emiel J. | Muir, Kenneth | Lophatananon, Artitaya | Stewart-Brown, Sarah | Siriwanarangsan, Pornthep | Fasching, Peter A. | Haeberle, Lothar | Ekici, Arif B. | Beckmann, Matthias W. | Peto, Julian | Dos-Santos-Silva, Isabel | Fletcher, Olivia | Johnson, Nichola | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Sawyer, Elinor J. | Cheng, Timothy | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Marmé, Frederik | Surowy, Harald M. | Burwinkel, Barbara | Guénel, Pascal | Truong, Thérèse | Menegaux, Florence | Mulot, Claire | Bojesen, Stig E. | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Benitez, Javier | Zamora, M. Pilar | Arias Perez, Jose Ignacio | Menéndez, Primitiva | González-Neira, Anna | Pita, Guillermo | Alonso, M. Rosario | Álvarez, Nuria | Herrero, Daniel | Anton-Culver, Hoda | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Meindl, Alfons | Lichtner, Peter | Schmutzler, Rita K. | Müller-Myhsok, Bertram | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Tessier, Daniel C. | Vincent, Daniel | Bacot, Francois | Nevanlinna, Heli | Aittomäki, Kristiina | Blomqvist, Carl | Khan, Sofia | Matsuo, Keitaro | Ito, Hidemi | Iwata, Hiroji | Horio, Akiyo | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Dörk, Thilo | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Wu, Anna H. | Tseng, Chiu-Chen | Van Den Berg, David | Stram, Daniel O. | Neven, Patrick | Wauters, Els | Wildiers, Hans | Lambrechts, Diether | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Bonanni, Bernardo | Couch, Fergus J. | Wang, Xianshu | Vachon, Celine | Purrington, Kristen | Giles, Graham G. | Milne, Roger L. | Mclean, Catriona | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Simard, Jacques | Goldberg, Mark S. | Labrèche, France | Dumont, Martine | Teo, Soo Hwang | Yip, Cheng Har | Hassan, Norhashimah | Vithana, Eranga Nishanthie | Kristensen, Vessela | Zheng, Wei | Deming-Halverson, Sandra | Shrubsole, Martha J. | Long, Jirong | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Kauppila, Saila | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Tchatchou, Sandrine | Devilee, Peter | Tollenaar, Robert A.E.M. | Seynaeve, Caroline | Van Asperen, Christi J. | García-Closas, Montserrat | Figueroa, Jonine | Lissowska, Jolanta | Brinton, Louise | Czene, Kamila | Darabi, Hatef | Eriksson, Mikael | Brand, Judith S. | Hooning, Maartje J. | Hollestelle, Antoinette | Van Den Ouweland, Ans M.W. | Jager, Agnes | Li, Jingmei | Liu, Jianjun | Humphreys, Keith | Shu, Xiao-Ou | Lu, Wei | Gao, Yu-Tang | Cai, Hui | Cross, Simon S. | Reed, Malcolm W. R. | Blot, William | Signorello, Lisa B. | Cai, Qiuyin | Pharoah, Paul D.P. | Perkins, Barbara | Shah, Mitul | Blows, Fiona M. | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Hartman, Mikael | Miao, Hui | Chia, Kee Seng | Putti, Thomas Choudary | Hamann, Ute | Luccarini, Craig | Baynes, Caroline | Ahmed, Shahana | Maranian, Mel | Healey, Catherine S. | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Sangrajrang, Suleeporn | Gaborieau, Valerie | Brennan, Paul | Mckay, James | Slager, Susan | Toland, Amanda E. | Yannoukakos, Drakoulis | Shen, Chen-Yang | Hsiung, Chia-Ni | Wu, Pei-Ei | Ding, Shian-ling | Ashworth, Alan | Jones, Michael | Orr, Nick | Swerdlow, Anthony J | Tsimiklis, Helen | Makalic, Enes | Schmidt, Daniel F. | Bui, Quang M. | Chanock, Stephen J. | Hunter, David J. | Hein, Rebecca | Dahmen, Norbert | Beckmann, Lars | Aaltonen, Kirsimari | Muranen, Taru A. | Heikkinen, Tuomas | Irwanto, Astrid | Rahman, Nazneen | Turnbull, Clare A. | Waisfisz, Quinten | Meijers-Heijboer, Hanne E. J. | Adank, Muriel A. | Van Der Luijt, Rob B. | Hall, Per | Chenevix-Trench, Georgia | Dunning, Alison | Easton, Douglas F. | Cox, Angela
Human Molecular Genetics  2014;24(1):285-298.
Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03–1.07), P = 1 × 10−5. Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 × 10−6), yielding a combined OR (95% CI) of 1.06 (1.04–1.08), P = 1 × 10−9. Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.
doi:10.1093/hmg/ddu431
PMCID: PMC4334820  PMID: 25168388
6.  Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1 
Cheng, Timothy HT | Thompson, Deborah | Painter, Jodie | O’Mara, Tracy | Gorman, Maggie | Martin, Lynn | Palles, Claire | Jones, Angela | Buchanan, Daniel D. | Ko Win, Aung | Hopper, John | Jenkins, Mark | Lindor, Noralane M. | Newcomb, Polly A. | Gallinger, Steve | Conti, David | Schumacher, Fred | Casey, Graham | Giles, Graham G | Pharoah, Paul | Peto, Julian | Cox, Angela | Swerdlow, Anthony | Couch, Fergus | Cunningham, Julie M | Goode, Ellen L | Winham, Stacey J | Lambrechts, Diether | Fasching, Peter | Burwinkel, Barbara | Brenner, Hermann | Brauch, Hiltrud | Chang-Claude, Jenny | Salvesen, Helga B. | Kristensen, Vessela | Darabi, Hatef | Li, Jingmei | Liu, Tao | Lindblom, Annika | Hall, Per | de Polanco, Magdalena Echeverry | Sans, Monica | Carracedo, Angel | Castellvi-Bel, Sergi | Rojas-Martinez, Augusto | Aguiar Jnr, Samuel | Teixeira, Manuel R. | Dunning, Alison M | Dennis, Joe | Otton, Geoffrey | Proietto, Tony | Holliday, Elizabeth | Attia, John | Ashton, Katie | Scott, Rodney J | McEvoy, Mark | Dowdy, Sean C | Fridley, Brooke L | Werner, Henrica MJ | Trovik, Jone | Njolstad, Tormund S | Tham, Emma | Mints, Miriam | Runnebaum, Ingo | Hillemanns, Peter | Dörk, Thilo | Amant, Frederic | Schrauwen, Stefanie | Hein, Alexander | Beckmann, Matthias W | Ekici, Arif | Czene, Kamila | Meindl, Alfons | Bolla, Manjeet K | Michailidou, Kyriaki | Tyrer, Jonathan P | Wang, Qin | Ahmed, Shahana | Healey, Catherine S | Shah, Mitul | Annibali, Daniela | Depreeuw, Jeroen | Al-Tassan, Nada A. | Harris, Rebecca | Meyer, Brian F. | Whiffin, Nicola | Hosking, Fay J | Kinnersley, Ben | Farrington, Susan M. | Timofeeva, Maria | Tenesa, Albert | Campbell, Harry | Haile, Robert W. | Hodgson, Shirley | Carvajal-Carmona, Luis | Cheadle, Jeremy P. | Easton, Douglas | Dunlop, Malcolm | Houlston, Richard | Spurdle, Amanda | Tomlinson, Ian
Scientific Reports  2015;5:17369.
High-risk mutations in several genes predispose to both colorectal cancer (CRC) and endometrial cancer (EC). We therefore hypothesised that some lower-risk genetic variants might also predispose to both CRC and EC. Using CRC and EC genome-wide association series, totalling 13,265 cancer cases and 40,245 controls, we found that the protective allele [G] at one previously-identified CRC polymorphism, rs2736100 near TERT, was associated with EC risk (odds ratio (OR) = 1.08, P = 0.000167); this polymorphism influences the risk of several other cancers. A further CRC polymorphism near TERC also showed evidence of association with EC (OR = 0.92; P = 0.03). Overall, however, there was no good evidence that the set of CRC polymorphisms was associated with EC risk, and neither of two previously-reported EC polymorphisms was associated with CRC risk. A combined analysis revealed one genome-wide significant polymorphism, rs3184504, on chromosome 12q24 (OR = 1.10, P = 7.23 × 10−9) with shared effects on CRC and EC risk. This polymorphism, a missense variant in the gene SH2B3, is also associated with haematological and autoimmune disorders, suggesting that it influences cancer risk through the immune response. Another polymorphism, rs12970291 near gene TSHZ1, was associated with both CRC and EC (OR = 1.26, P = 4.82 × 10−8), with the alleles showing opposite effects on the risks of the two cancers.
doi:10.1038/srep17369
PMCID: PMC4664893  PMID: 26621817
7.  Genetic variation in the immunosuppression pathway genes and breast cancer susceptibility: a pooled analysis of 42,510 cases and 40,577 controls from the Breast Cancer Association Consortium 
Lei, Jieping | Rudolph, Anja | Moysich, Kirsten B. | Behrens, Sabine | Goode, Ellen L. | Bolla, Manjeet K. | Dennis, Joe | Dunning, Alison M. | Easton, Douglas F. | Wang, Qin | Benitez, Javier | Hopper, John L. | Southey, Melissa C. | Schmidt, Marjanka K. | Broeks, Annegien | Fasching, Peter A. | Haeberle, Lothar | Peto, Julian | dos-Santos-Silva, Isabel | Sawyer, Elinor J. | Tomlinson, Ian | Burwinkel, Barbara | Marmé, Frederik | Guénel, Pascal | Truong, Thérèse | Bojesen, Stig E. | Flyger, Henrik | Nielsen, Sune F. | Nordestgaard, Børge G. | González-Neira, Anna | Menéndez, Primitiva | Anton-Culver, Hoda | Neuhausen, Susan L. | Brenner, Hermann | Arndt, Volker | Meindl, Alfons | Schmutzler, Rita K. | Brauch, Hiltrud | Hamann, Ute | Nevanlinna, Heli | Fagerholm, Rainer | Dörk, Thilo | Bogdanova, Natalia V. | Mannermaa, Arto | Hartikainen, Jaana M. | Van Dijck, Laurien | Smeets, Ann | Flesch-Janys, Dieter | Eilber, Ursula | Radice, Paolo | Peterlongo, Paolo | Couch, Fergus J. | Hallberg, Emily | Giles, Graham G. | Milne, Roger L. | Haiman, Christopher A. | Schumacher, Fredrick | Simard, Jacques | Goldberg, Mark S. | Kristensen, Vessela | Borresen-Dale, Anne-Lise | Zheng, Wei | Beeghly-Fadiel, Alicia | Winqvist, Robert | Grip, Mervi | Andrulis, Irene L. | Glendon, Gord | García-Closas, Montserrat | Figueroa, Jonine | Czene, Kamila | Brand, Judith S. | Darabi, Hatef | Eriksson, Mikael | Hall, Per | Li, Jingmei | Cox, Angela | Cross, Simon S. | Pharoah, Paul D. P. | Shah, Mitul | Kabisch, Maria | Torres, Diana | Jakubowska, Anna | Lubinski, Jan | Ademuyiwa, Foluso | Ambrosone, Christine B. | Swerdlow, Anthony | Jones, Michael | Chang-Claude, Jenny
Human Genetics  2015;135:137-154.
Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according to estrogen receptor (ER) status, were assessed using multiple logistic regression models. Gene-level associations were assessed based on principal component analysis. Gene expression analyses were conducted using RNA sequencing level 3 data from The Cancer Genome Atlas for 989 breast tumor samples and 113 matched normal tissue samples. SNP rs1905339 (A>G) in the STAT3 region was associated with an increased breast cancer risk (per allele odds ratio 1.05, 95 % confidence interval 1.03–1.08; p value = 1.4 × 10−6). The association did not differ significantly by ER status. On the gene level, in addition to TGFBR2 and CCND1, IL5 and GM-CSF showed the strongest associations with overall breast cancer risk (p value = 1.0 × 10−3 and 7.0 × 10−3, respectively). Furthermore, STAT3 and IL5 but not GM-CSF were differentially expressed between breast tumor tissue and normal tissue (p value = 2.5 × 10−3, 4.5 × 10−4 and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3,IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-015-1616-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s00439-015-1616-8
PMCID: PMC4698282  PMID: 26621531
8.  Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade 
Purrington, Kristen S. | Slettedahl, Seth | Bolla, Manjeet K. | Michailidou, Kyriaki | Czene, Kamila | Nevanlinna, Heli | Bojesen, Stig E. | Andrulis, Irene L. | Cox, Angela | Hall, Per | Carpenter, Jane | Yannoukakos, Drakoulis | Haiman, Christopher A. | Fasching, Peter A. | Mannermaa, Arto | Winqvist, Robert | Brenner, Hermann | Lindblom, Annika | Chenevix-Trench, Georgia | Benitez, Javier | Swerdlow, Anthony | Kristensen, Vessela | Guénel, Pascal | Meindl, Alfons | Darabi, Hatef | Eriksson, Mikael | Fagerholm, Rainer | Aittomäki, Kristiina | Blomqvist, Carl | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Wang, Xianshu | Olswold, Curtis | Olson, Janet E. | Mulligan, Anna Marie | Knight, Julia A. | Tchatchou, Sandrine | Reed, Malcolm W.R. | Cross, Simon S. | Liu, Jianjun | Li, Jingmei | Humphreys, Keith | Clarke, Christine | Scott, Rodney | Fostira, Florentia | Fountzilas, George | Konstantopoulou, Irene | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Ekici, Arif B. | Hartmann, Arndt | Beckmann, Matthias W. | Hartikainen, Jaana M. | Kosma, Veli-Matti | Kataja, Vesa | Jukkola-Vuorinen, Arja | Pylkäs, Katri | Kauppila, Saila | Dieffenbach, Aida Karina | Stegmaier, Christa | Arndt, Volker | Margolin, Sara | Balleine, Rosemary | Arias Perez, Jose Ignacio | Pilar Zamora, M. | Menéndez, Primitiva | Ashworth, Alan | Jones, Michael | Orr, Nick | Arveux, Patrick | Kerbrat, Pierre | Truong, Thérèse | Bugert, Peter | Toland, Amanda E. | Ambrosone, Christine B. | Labrèche, France | Goldberg, Mark S. | Dumont, Martine | Ziogas, Argyrios | Lee, Eunjung | Dite, Gillian S. | Apicella, Carmel | Southey, Melissa C. | Long, Jirong | Shrubsole, Martha | Deming-Halverson, Sandra | Ficarazzi, Filomena | Barile, Monica | Peterlongo, Paolo | Durda, Katarzyna | Jaworska-Bieniek, Katarzyna | Tollenaar, Robert A.E.M. | Seynaeve, Caroline | Brüning, Thomas | Ko, Yon-Dschun | Van Deurzen, Carolien H.M. | Martens, John W.M. | Kriege, Mieke | Figueroa, Jonine D. | Chanock, Stephen J. | Lissowska, Jolanta | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Schneeweiss, Andreas | Tapper, William J. | Gerty, Susan M. | Durcan, Lorraine | Mclean, Catriona | Milne, Roger L. | Baglietto, Laura | dos Santos Silva, Isabel | Fletcher, Olivia | Johnson, Nichola | Van'T Veer, Laura J. | Cornelissen, Sten | Försti, Asta | Torres, Diana | Rüdiger, Thomas | Rudolph, Anja | Flesch-Janys, Dieter | Nickels, Stefan | Weltens, Caroline | Floris, Giuseppe | Moisse, Matthieu | Dennis, Joe | Wang, Qin | Dunning, Alison M. | Shah, Mitul | Brown, Judith | Simard, Jacques | Anton-Culver, Hoda | Neuhausen, Susan L. | Hopper, John L. | Bogdanova, Natalia | Dörk, Thilo | Zheng, Wei | Radice, Paolo | Jakubowska, Anna | Lubinski, Jan | Devillee, Peter | Brauch, Hiltrud | Hooning, Maartje | García-Closas, Montserrat | Sawyer, Elinor | Burwinkel, Barbara | Marmee, Frederick | Eccles, Diana M. | Giles, Graham G. | Peto, Julian | Schmidt, Marjanka | Broeks, Annegien | Hamann, Ute | Chang-Claude, Jenny | Lambrechts, Diether | Pharoah, Paul D.P. | Easton, Douglas | Pankratz, V. Shane | Slager, Susan | Vachon, Celine M. | Couch, Fergus J.
Human Molecular Genetics  2014;23(22):6034-6046.
Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39 067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16–1.33, P = 4.2 × 10−10) and EIF3H (rs799890: OR = 1.07, 95% CI 1.04–1.11, P = 8.7 × 10−6) were significantly associated with risk of low-grade breast cancer. The TACC2 signal was retained (rs17550038: OR = 1.15, 95% CI 1.07–1.23, P = 7.9 × 10−5) after adjustment for breast cancer risk SNPs in the nearby FGFR2 gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk (P = 2.1 × 10−3). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer.
doi:10.1093/hmg/ddu300
PMCID: PMC4204763  PMID: 24927736
9.  SNP-SNP interaction analysis of NF-κB signaling pathway on breast cancer survival 
Oncotarget  2015;6(35):37979-37994.
In breast cancer, constitutive activation of NF-κB has been reported, however, the impact of genetic variation of the pathway on patient prognosis has been little studied. Furthermore, a combination of genetic variants, rather than single polymorphisms, may affect disease prognosis. Here, in an extensive dataset (n = 30,431) from the Breast Cancer Association Consortium, we investigated the association of 917 SNPs in 75 genes in the NF-κB pathway with breast cancer prognosis. We explored SNP-SNP interactions on survival using the likelihood-ratio test comparing multivariate Cox’ regression models of SNP pairs without and with an interaction term. We found two interacting pairs associating with prognosis: patients simultaneously homozygous for the rare alleles of rs5996080 and rs7973914 had worse survival (HRinteraction 6.98, 95% CI=3.3-14.4, P = 1.42E-07), and patients carrying at least one rare allele for rs17243893 and rs57890595 had better survival (HRinteraction 0.51, 95% CI=0.3-0.6, P = 2.19E-05). Based on in silico functional analyses and literature, we speculate that the rs5996080 and rs7973914 loci may affect the BAFFR and TNFR1/TNFR3 receptors and breast cancer survival, possibly by disturbing both the canonical and non-canonical NF-κB pathways or their dynamics, whereas, rs17243893-rs57890595 interaction on survival may be mediated through TRAF2-TRAIL-R4 interplay. These results warrant further validation and functional analyses.
PMCID: PMC4741978  PMID: 26317411
breast cancer; survival analysis; SNP-SNP interaction; NF-κB pathway
10.  Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer 
Michailidou, Kyriaki | Beesley, Jonathan | Lindstrom, Sara | Canisius, Sander | Dennis, Joe | Lush, Michael | Maranian, Mel J | Bolla, Manjeet K | Wang, Qin | Shah, Mitul | Perkins, Barbara J | Czene, Kamila | Eriksson, Mikael | Darabi, Hatef | Brand, Judith S | Bojesen, Stig E | Nordestgaard, Børge G | Flyger, Henrik | Nielsen, Sune F | Rahman, Nazneen | Turnbull, Clare | Fletcher, Olivia | Peto, Julian | Gibson, Lorna | dos-Santos-Silva, Isabel | Chang-Claude, Jenny | Flesch-Janys, Dieter | Rudolph, Anja | Eilber, Ursula | Behrens, Sabine | Nevanlinna, Heli | Muranen, Taru A | Aittomäki, Kristiina | Blomqvist, Carl | Khan, Sofia | Aaltonen, Kirsimari | Ahsan, Habibul | Kibriya, Muhammad G | Whittemore, Alice S | John, Esther M | Malone, Kathleen E | Gammon, Marilie D | Santella, Regina M | Ursin, Giske | Makalic, Enes | Schmidt, Daniel F | Casey, Graham | Hunter, David J | Gapstur, Susan M | Gaudet, Mia M | Diver, W Ryan | Haiman, Christopher A | Schumacher, Fredrick | Henderson, Brian E | Le Marchand, Loic | Berg, Christine D | Chanock, Stephen | Figueroa, Jonine | Hoover, Robert N | Lambrechts, Diether | Neven, Patrick | Wildiers, Hans | van Limbergen, Erik | Schmidt, Marjanka K | Broeks, Annegien | Verhoef, Senno | Cornelissen, Sten | Couch, Fergus J | Olson, Janet E | Hallberg, Emily | Vachon, Celine | Waisfisz, Quinten | Meijers-Heijboer, Hanne | Adank, Muriel A | van der Luijt, Rob B | Li, Jingmei | Liu, Jianjun | Humphreys, Keith | Kang, Daehee | Choi, Ji-Yeob | Park, Sue K | Yoo, Keun-Young | Matsuo, Keitaro | Ito, Hidemi | Iwata, Hiroji | Tajima, Kazuo | Guénel, Pascal | Truong, Thérèse | Mulot, Claire | Sanchez, Marie | Burwinkel, Barbara | Marme, Frederik | Surowy, Harald | Sohn, Christof | Wu, Anna H | Tseng, Chiu-chen | Van Den Berg, David | Stram, Daniel O | González-Neira, Anna | Benitez, Javier | Zamora, M Pilar | Perez, Jose Ignacio Arias | Shu, Xiao-Ou | Lu, Wei | Gao, Yu-Tang | Cai, Hui | Cox, Angela | Cross, Simon S | Reed, Malcolm WR | Andrulis, Irene L | Knight, Julia A | Glendon, Gord | Mulligan, Anna Marie | Sawyer, Elinor J | Tomlinson, Ian | Kerin, Michael J | Miller, Nicola | Lindblom, Annika | Margolin, Sara | Teo, Soo Hwang | Yip, Cheng Har | Taib, Nur Aishah Mohd | TAN, Gie-Hooi | Hooning, Maartje J | Hollestelle, Antoinette | Martens, John WM | Collée, J Margriet | Blot, William | Signorello, Lisa B | Cai, Qiuyin | Hopper, John L | Southey, Melissa C | Tsimiklis, Helen | Apicella, Carmel | Shen, Chen-Yang | Hsiung, Chia-Ni | Wu, Pei-Ei | Hou, Ming-Feng | Kristensen, Vessela N | Nord, Silje | Alnaes, Grethe I Grenaker | Giles, Graham G | Milne, Roger L | McLean, Catriona | Canzian, Federico | Trichopoulos, Dmitrios | Peeters, Petra | Lund, Eiliv | Sund, Malin | Khaw, Kay-Tee | Gunter, Marc J | Palli, Domenico | Mortensen, Lotte Maxild | Dossus, Laure | Huerta, Jose-Maria | Meindl, Alfons | Schmutzler, Rita K | Sutter, Christian | Yang, Rongxi | Muir, Kenneth | Lophatananon, Artitaya | Stewart-Brown, Sarah | Siriwanarangsan, Pornthep | Hartman, Mikael | Miao, Hui | Chia, Kee Seng | Chan, Ching Wan | Fasching, Peter A | Hein, Alexander | Beckmann, Matthias W | Haeberle, Lothar | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Ashworth, Alan | Orr, Nick | Schoemaker, Minouk J | Swerdlow, Anthony J | Brinton, Louise | Garcia-Closas, Montserrat | Zheng, Wei | Halverson, Sandra L | Shrubsole, Martha | Long, Jirong | Goldberg, Mark S | Labrèche, France | Dumont, Martine | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Brauch, Hiltrud | Hamann, Ute | Brüning, Thomas | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Bernard, Loris | Bogdanova, Natalia V | Dörk, Thilo | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M | Devilee, Peter | Tollenaar, Robert AEM | Seynaeve, Caroline | Van Asperen, Christi J | Jakubowska, Anna | Lubinski, Jan | Jaworska, Katarzyna | Huzarski, Tomasz | Sangrajrang, Suleeporn | Gaborieau, Valerie | Brennan, Paul | McKay, James | Slager, Susan | Toland, Amanda E | Ambrosone, Christine B | Yannoukakos, Drakoulis | Kabisch, Maria | Torres, Diana | Neuhausen, Susan L | Anton-Culver, Hoda | Luccarini, Craig | Baynes, Caroline | Ahmed, Shahana | Healey, Catherine S | Tessier, Daniel C | Vincent, Daniel | Bacot, Francois | Pita, Guillermo | Alonso, M Rosario | Álvarez, Nuria | Herrero, Daniel | Simard, Jacques | Pharoah, Paul PDP | Kraft, Peter | Dunning, Alison M | Chenevix-Trench, Georgia | Hall, Per | Easton, Douglas F
Nature genetics  2015;47(4):373-380.
Genome wide association studies (GWAS) and large scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ~14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS comprising of 15,748 breast cancer cases and 18,084 controls, and 46,785 cases and 42,892 controls from 41 studies genotyped on a 200K custom array (iCOGS). Analyses were restricted to women of European ancestry. Genotypes for more than 11M SNPs were generated by imputation using the 1000 Genomes Project reference panel. We identified 15 novel loci associated with breast cancer at P<5×10−8. Combining association analysis with ChIP-Seq data in mammary cell lines and ChIA-PET chromatin interaction data in ENCODE, we identified likely target genes in two regions: SETBP1 on 18q12.3 and RNF115 and PDZK1 on 1q21.1. One association appears to be driven by an amino-acid substitution in EXO1.
doi:10.1038/ng.3242
PMCID: PMC4549775  PMID: 25751625
11.  F2RL3 methylation in blood DNA is a strong predictor of mortality 
Background: Smoking is a major cause of morbidity and mortality. Smoking-related epigenetic biomarkers may open new avenues to better quantify the adverse health effects of smoking, and to better understanding of the underlying mechanisms. We aimed to evaluate the clinical implications of F2RL3 methylation, a novel epigenetic biomarker of smoking exposure disclosed by recent genome-wide methylation studies.
Methods: Blood DNA methylation at F2RL3 (also known as PAR-4) was quantified in baseline samples of 3588 participants aged 50–75 years in a large population-based prospective cohort study by MALDI-TOF mass spectrometry. Deaths were recorded during a median follow-up of 10.1 years. The associations of methylation intensity and of smoking with all-cause, cardiovascular, cancer and other mortality were assessed by Cox’s proportional hazards regression, controlling for potential confounding factors.
Results: Lower methylation intensity at F2RL3 was strongly associated with mortality. After adjustment for multiple covariates including smoking, hazard ratios [95% confidence interval (CI)] for death from any cause, cardiovascular disease, cancer or other causes were 2.60 (95% CI, 1.81-3.74), 2.45 (95% CI, 1.28-4.68), 2.94 (95% CI, 1.68-5.14) and 2.39 (95% CI, 1.11-5.16), respectively, in subjects in the lowest quartile of methylation intensity compared with subjects in the highest quartile. The associations with mortality outcomes were much stronger among men than among women. In addition, strong positive associations of smoking with each of the outcomes were substantially weakened, and almost disappeared when controlling for F2RL3 methylation intensity.
Conclusions: F2RL3 methylation is a strong predictor of mortality, including all-cause, cardiovascular, cancer and other mortality. Systemic adverse effects of smoking may be mediated by pathways associated with F2RL3 methylation.
doi:10.1093/ije/dyu006
PMCID: PMC4258765  PMID: 24510982
F2RL3 methylation; PAR-4; smoking; mortality; prospective study
12.  Capture and Amplification by Tailing and Switching (CATS) 
RNA Biology  2014;11(7):817-828.
Massive parallel sequencing (MPS) technologies have paved the way into new areas of research including individualized medicine. However, sequencing of trace amounts of DNA or RNA still remains a major challenge, especially for degraded nucleic acids like circulating DNA. This together with high cost and time requirements impedes many important applications of MPS in medicine and fundamental science. We have established a fast, cheap and highly efficient protocol called ‘Capture and Amplification by Tailing and Switching’ (CATS) to directly generate ready-to-sequence libraries for MPS from nanogram and picogram quantities of both DNA and RNA. Furthermore, those DNA libraries are strand-specific, can be prepared within 2–3 h and do not require preliminary sample amplification steps. To exemplify the capacity of the technique, we have generated and sequenced DNA libraries from hundred-picogram amounts of circulating nucleic acids isolated from human blood plasma, one nanogram of mRNA-enriched total RNA from cultured cells and few nanograms of bisulfite-converted DNA. The approach for DNA library preparation from minimal and fragmented input described here will find broad application in diverse research areas such as translational medicine including therapy monitoring, prediction, prognosis and early detection of various human disorders and will permit high-throughput DNA sequencing from previously inaccessible material such as minute forensic and archeological samples.
doi:10.4161/rna.29304
PMCID: PMC4179956  PMID: 24922482
13.  Common germline polymorphisms associated with breast cancer-specific survival 
Pirie, Ailith | Guo, Qi | Kraft, Peter | Canisius, Sander | Eccles, Diana M | Rahman, Nazneen | Nevanlinna, Heli | Chen, Constance | Khan, Sofia | Tyrer, Jonathan | Bolla, Manjeet K | Wang, Qin | Dennis, Joe | Michailidou, Kyriaki | Lush, Michael | Dunning, Alison M | Shah, Mitul | Czene, Kamila | Darabi, Hatef | Eriksson, Mikael | Lambrechts, Dieter | Weltens, Caroline | Leunen, Karin | van Ongeval, Chantal | Nordestgaard, Børge G | Nielsen, Sune F | Flyger, Henrik | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Blomqvist, Carl | Aittomäki, Kristiina | Fagerholm, Rainer | Muranen, Taru A | Olsen, Janet E | Hallberg, Emily | Vachon, Celine | Knight, Julia A | Glendon, Gord | Mulligan, Anna Marie | Broeks, Annegien | Cornelissen, Sten | Haiman, Christopher A | Henderson, Brian E | Schumacher, Frederick | Le Marchand, Loic | Hopper, John L | Tsimiklis, Helen | Apicella, Carmel | Southey, Melissa C | Cross, Simon S | Reed, Malcolm WR | Giles, Graham G | Milne, Roger L | McLean, Catriona | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Hooning, Maartje J | Hollestelle, Antoinette | Martens, John WM | van den Ouweland, Ans MW | Marme, Federick | Schneeweiss, Andreas | Yang, Rongxi | Burwinkel, Barbara | Figueroa, Jonine | Chanock, Stephen J | Lissowska, Jolanta | Sawyer, Elinor J | Tomlinson, Ian | Kerin, Michael J | Miller, Nicola | Brenner, Hermann | Butterbach, Katja | Holleczek, Bernd | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M | Li, Jingmei | Brand, Judith S | Humphreys, Keith | Devilee, Peter | Tollenaar, Robert AEM | Seynaeve, Caroline | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Ficarazzi, Filomena | Beckmann, Matthias W | Hein, Alexander | Ekici, Arif B | Balleine, Rosemary | Phillips, Kelly-Anne | Benitez, Javier | Zamora, M Pilar | Perez, Jose Ignacio Arias | Menéndez, Primitiva | Jakubowska, Anna | Lubinski, Jan | Gronwald, Jacek | Durda, Katarzyna | Hamann, Ute | Kabisch, Maria | Ulmer, Hans Ulrich | Rüdiger, Thomas | Margolin, Sara | Kristensen, Vessela | Nord, Siljie | Evans, D Gareth | Abraham, Jean | Earl, Helena | Poole, Christopher J | Hiller, Louise | Dunn, Janet A | Bowden, Sarah | Yang, Rose | Campa, Daniele | Diver, W Ryan | Gapstur, Susan M | Gaudet, Mia M | Hankinson, Susan | Hoover, Robert N | Hüsing, Anika | Kaaks, Rudolf | Machiela, Mitchell J | Willett, Walter | Barrdahl, Myrto | Canzian, Federico | Chin, Suet-Feung | Caldas, Carlos | Hunter, David J | Lindstrom, Sara | Garcia-Closas, Montserrat | Couch, Fergus J | Chenevix-Trench, Georgia | Mannermaa, Arto | Andrulis, Irene L | Hall, Per | Chang-Claude, Jenny | Easton, Douglas F | Bojesen, Stig E | Cox, Angela | Fasching, Peter A | Pharoah, Paul DP | Schmidt, Marjanka K
Introduction
Previous studies have identified common germline variants nominally associated with breast cancer survival. These associations have not been widely replicated in further studies. The purpose of this study was to evaluate the association of previously reported SNPs with breast cancer-specific survival using data from a pooled analysis of eight breast cancer survival genome-wide association studies (GWAS) from the Breast Cancer Association Consortium.
Methods
A literature review was conducted of all previously published associations between common germline variants and three survival outcomes: breast cancer-specific survival, overall survival and disease-free survival. All associations that reached the nominal significance level of P value <0.05 were included. Single nucleotide polymorphisms that had been previously reported as nominally associated with at least one survival outcome were evaluated in the pooled analysis of over 37,000 breast cancer cases for association with breast cancer-specific survival. Previous associations were evaluated using a one-sided test based on the reported direction of effect.
Results
Fifty-six variants from 45 previous publications were evaluated in the meta-analysis. Fifty-four of these were evaluated in the full set of 37,954 breast cancer cases with 2,900 events and the two additional variants were evaluated in a reduced sample size of 30,000 samples in order to ensure independence from the previously published studies. Five variants reached nominal significance (P <0.05) in the pooled GWAS data compared to 2.8 expected under the null hypothesis. Seven additional variants were associated (P <0.05) with ER-positive disease.
Conclusions
Although no variants reached genome-wide significance (P <5 x 10−8), these results suggest that there is some evidence of association between candidate common germline variants and breast cancer prognosis. Larger studies from multinational collaborations are necessary to increase the power to detect associations, between common variants and prognosis, at more stringent significance levels.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-015-0570-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-015-0570-7
PMCID: PMC4484708  PMID: 25897948
14.  Identification of Novel Genetic Markers of Breast Cancer Survival 
Guo, Qi | Schmidt, Marjanka K. | Kraft, Peter | Canisius, Sander | Chen, Constance | Khan, Sofia | Tyrer, Jonathan | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Michailidou, Kyriaki | Lush, Michael | Kar, Siddhartha | Beesley, Jonathan | Dunning, Alison M. | Shah, Mitul | Czene, Kamila | Darabi, Hatef | Eriksson, Mikael | Lambrechts, Diether | Weltens, Caroline | Leunen, Karin | Bojesen, Stig E. | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Blomqvist, Carl | Aittomäki, Kristiina | Fagerholm, Rainer | Muranen, Taru A. | Couch, Fergus J. | Olson, Janet E. | Vachon, Celine | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Mulligan, Anna Marie | Broeks, Annegien | Hogervorst, Frans B. | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Hopper, John L. | Tsimiklis, Helen | Apicella, Carmel | Southey, Melissa C. | Cox, Angela | Cross, Simon S. | Reed, Malcolm W. R. | Giles, Graham G. | Milne, Roger L. | McLean, Catriona | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Hooning, Maartje J. | Hollestelle, Antoinette | Martens, John W. M. | van den Ouweland, Ans M. W. | Marme, Federik | Schneeweiss, Andreas | Yang, Rongxi | Burwinkel, Barbara | Figueroa, Jonine | Chanock, Stephen J. | Lissowska, Jolanta | Sawyer, Elinor J. | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Holleczek, Bernd | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Li, Jingmei | Brand, Judith S. | Humphreys, Keith | Devilee, Peter | Tollenaar, Rob A. E. M. | Seynaeve, Caroline | Radice, Paolo | Peterlongo, Paolo | Bonanni, Bernardo | Mariani, Paolo | Fasching, Peter A. | Beckmann, Matthias W. | Hein, Alexander | Ekici, Arif B. | Chenevix-Trench, Georgia | Balleine, Rosemary | Phillips, Kelly-Anne | Benitez, Javier | Zamora, M. Pilar | Arias Perez, Jose Ignacio | Menéndez, Primitiva | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Hamann, Ute | Kabisch, Maria | Ulmer, Hans Ulrich | Rüdiger, Thomas | Margolin, Sara | Kristensen, Vessela | Nord, Silje | Evans, D. Gareth | Abraham, Jean E. | Earl, Helena M. | Hiller, Louise | Dunn, Janet A. | Bowden, Sarah | Berg, Christine | Campa, Daniele | Diver, W. Ryan | Gapstur, Susan M. | Gaudet, Mia M. | Hankinson, Susan E. | Hoover, Robert N. | Hüsing, Anika | Kaaks, Rudolf | Machiela, Mitchell J. | Willett, Walter | Barrdahl, Myrto | Canzian, Federico | Chin, Suet-Feung | Caldas, Carlos | Hunter, David J. | Lindstrom, Sara | García-Closas, Montserrat | Hall, Per | Easton, Douglas F. | Eccles, Diana M. | Rahman, Nazneen | Nevanlinna, Heli | Pharoah, Paul D. P.
Background:
Survival after a diagnosis of breast cancer varies considerably between patients, and some of this variation may be because of germline genetic variation. We aimed to identify genetic markers associated with breast cancer–specific survival.
Methods:
We conducted a large meta-analysis of studies in populations of European ancestry, including 37954 patients with 2900 deaths from breast cancer. Each study had been genotyped for between 200000 and 900000 single nucleotide polymorphisms (SNPs) across the genome; genotypes for nine million common variants were imputed using a common reference panel from the 1000 Genomes Project. We also carried out subtype-specific analyses based on 6881 estrogen receptor (ER)–negative patients (920 events) and 23059 ER-positive patients (1333 events). All statistical tests were two-sided.
Results:
We identified one new locus (rs2059614 at 11q24.2) associated with survival in ER-negative breast cancer cases (hazard ratio [HR] = 1.95, 95% confidence interval [CI] = 1.55 to 2.47, P = 1.91 x 10–8). Genotyping a subset of 2113 case patients, of which 300 were ER negative, provided supporting evidence for the quality of the imputation. The association in this set of case patients was stronger for the observed genotypes than for the imputed genotypes. A second locus (rs148760487 at 2q24.2) was associated at genome-wide statistical significance in initial analyses; the association was similar in ER-positive and ER-negative case patients. Here the results of genotyping suggested that the finding was less robust.
Conclusions:
This is currently the largest study investigating genetic variation associated with breast cancer survival. Our results have potential clinical implications, as they confirm that germline genotype can provide prognostic information in addition to standard tumor prognostic factors.
doi:10.1093/jnci/djv081
PMCID: PMC4555642  PMID: 25890600
15.  Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants 
Mavaddat, Nasim | Pharoah, Paul D. P. | Michailidou, Kyriaki | Tyrer, Jonathan | Brook, Mark N. | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Dunning, Alison M. | Shah, Mitul | Luben, Robert | Brown, Judith | Bojesen, Stig E. | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Czene, Kamila | Darabi, Hatef | Eriksson, Mikael | Peto, Julian | dos-Santos-Silva, Isabel | Dudbridge, Frank | Johnson, Nichola | Schmidt, Marjanka K. | Broeks, Annegien | Verhoef, Senno | Rutgers, Emiel J. | Swerdlow, Anthony | Ashworth, Alan | Orr, Nick | Schoemaker, Minouk J. | Figueroa, Jonine | Chanock, Stephen J. | Brinton, Louise | Lissowska, Jolanta | Couch, Fergus J. | Olson, Janet E. | Vachon, Celine | Pankratz, Vernon S. | Lambrechts, Diether | Wildiers, Hans | Van Ongeval, Chantal | van Limbergen, Erik | Kristensen, Vessela | Grenaker Alnæs, Grethe | Nord, Silje | Borresen-Dale, Anne-Lise | Nevanlinna, Heli | Muranen, Taru A. | Aittomäki, Kristiina | Blomqvist, Carl | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Fasching, Peter A. | Haeberle, Lothar | Ekici, Arif B. | Beckmann, Matthias W. | Burwinkel, Barbara | Marme, Frederik | Schneeweiss, Andreas | Sohn, Christof | Trentham-Dietz, Amy | Newcomb, Polly | Titus, Linda | Egan, Kathleen M. | Hunter, David J. | Lindstrom, Sara | Tamimi, Rulla M. | Kraft, Peter | Rahman, Nazneen | Turnbull, Clare | Renwick, Anthony | Seal, Sheila | Li, Jingmei | Liu, Jianjun | Humphreys, Keith | Benitez, Javier | Pilar Zamora, M. | Arias Perez, Jose Ignacio | Menéndez, Primitiva | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Dörk, Thilo | Anton-Culver, Hoda | Neuhausen, Susan L. | Ziogas, Argyrios | Bernstein, Leslie | Devilee, Peter | Tollenaar, Robert A. E. M. | Seynaeve, Caroline | van Asperen, Christi J. | Cox, Angela | Cross, Simon S. | Reed, Malcolm W. R. | Khusnutdinova, Elza | Bermisheva, Marina | Prokofyeva, Darya | Takhirova, Zalina | Meindl, Alfons | Schmutzler, Rita K. | Sutter, Christian | Yang, Rongxi | Schürmann, Peter | Bremer, Michael | Christiansen, Hans | Park-Simon, Tjoung-Won | Hillemanns, Peter | Guénel, Pascal | Truong, Thérèse | Menegaux, Florence | Sanchez, Marie | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Pensotti, Valeria | Hopper, John L. | Tsimiklis, Helen | Apicella, Carmel | Southey, Melissa C. | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Sigurdson, Alice J. | Doody, Michele M. | Hamann, Ute | Torres, Diana | Ulmer, Hans-Ulrich | Försti, Asta | Sawyer, Elinor J. | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Marie Mulligan, Anna | Chenevix-Trench, Georgia | Balleine, Rosemary | Giles, Graham G. | Milne, Roger L. | McLean, Catriona | Lindblom, Annika | Margolin, Sara | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Eilber, Ursula | Wang-Gohrke, Shan | Hooning, Maartje J. | Hollestelle, Antoinette | van den Ouweland, Ans M. W. | Koppert, Linetta B. | Carpenter, Jane | Clarke, Christine | Scott, Rodney | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Brenner, Hermann | Arndt, Volker | Stegmaier, Christa | Karina Dieffenbach, Aida | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Offit, Kenneth | Vijai, Joseph | Robson, Mark | Rau-Murthy, Rohini | Dwek, Miriam | Swann, Ruth | Annie Perkins, Katherine | Goldberg, Mark S. | Labrèche, France | Dumont, Martine | Eccles, Diana M. | Tapper, William J. | Rafiq, Sajjad | John, Esther M. | Whittemore, Alice S. | Slager, Susan | Yannoukakos, Drakoulis | Toland, Amanda E. | Yao, Song | Zheng, Wei | Halverson, Sandra L. | González-Neira, Anna | Pita, Guillermo | Rosario Alonso, M. | Álvarez, Nuria | Herrero, Daniel | Tessier, Daniel C. | Vincent, Daniel | Bacot, Francois | Luccarini, Craig | Baynes, Caroline | Ahmed, Shahana | Maranian, Mel | Healey, Catherine S. | Simard, Jacques | Hall, Per | Easton, Douglas F. | Garcia-Closas, Montserrat
Background:
Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking.
Methods:
We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates.
Results:
There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer.
Conclusions:
The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.
doi:10.1093/jnci/djv036
PMCID: PMC4754625  PMID: 25855707
16.  A large-scale assessment of two-way SNP interactions in breast cancer susceptibility using 46 450 cases and 42 461 controls from the breast cancer association consortium 
Milne, Roger L. | Herranz, Jesús | Michailidou, Kyriaki | Dennis, Joe | Tyrer, Jonathan P. | Zamora, M. Pilar | Arias-Perez, José Ignacio | González-Neira, Anna | Pita, Guillermo | Alonso, M. Rosario | Wang, Qin | Bolla, Manjeet K. | Czene, Kamila | Eriksson, Mikael | Humphreys, Keith | Darabi, Hatef | Li, Jingmei | Anton-Culver, Hoda | Neuhausen, Susan L. | Ziogas, Argyrios | Clarke, Christina A. | Hopper, John L. | Dite, Gillian S. | Apicella, Carmel | Southey, Melissa C. | Chenevix-Trench, Georgia | Swerdlow, Anthony | Ashworth, Alan | Orr, Nicholas | Schoemaker, Minouk | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Mulligan, Anna Marie | Bojesen, Stig E. | Nordestgaard, Børge G. | Flyger, Henrik | Nevanlinna, Heli | Muranen, Taru A. | Aittomäki, Kristiina | Blomqvist, Carl | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Wang, Xianshu | Olson, Janet E. | Vachon, Celine | Purrington, Kristen | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Dunning, Alison M. | Shah, Mitul | Guénel, Pascal | Truong, Thérèse | Sanchez, Marie | Mulot, Claire | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Lindblom, Annika | Margolin, Sara | Hooning, Maartje J. | Hollestelle, Antoinette | Collée, J. Margriet | Jager, Agnes | Cox, Angela | Brock, Ian W. | Reed, Malcolm W.R. | Devilee, Peter | Tollenaar, Robert A.E.M. | Seynaeve, Caroline | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Simard, Jacques | Dumont, Martine | Soucy, Penny | Dörk, Thilo | Bogdanova, Natalia V. | Hamann, Ute | Försti, Asta | Rüdiger, Thomas | Ulmer, Hans-Ulrich | Fasching, Peter A. | Häberle, Lothar | Ekici, Arif B. | Beckmann, Matthias W. | Fletcher, Olivia | Johnson, Nichola | dos Santos Silva, Isabel | Peto, Julian | Radice, Paolo | Peterlongo, Paolo | Peissel, Bernard | Mariani, Paolo | Giles, Graham G. | Severi, Gianluca | Baglietto, Laura | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael | Miller, Nicola | Marme, Federik | Burwinkel, Barbara | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Lambrechts, Diether | Yesilyurt, Betul T. | Floris, Giuseppe | Leunen, Karin | Alnæs, Grethe Grenaker | Kristensen, Vessela | Børresen-Dale, Anne-Lise | García-Closas, Montserrat | Chanock, Stephen J. | Lissowska, Jolanta | Figueroa, Jonine D. | Schmidt, Marjanka K. | Broeks, Annegien | Verhoef, Senno | Rutgers, Emiel J. | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Couch, Fergus J. | Toland, Amanda E. | Yannoukakos, Drakoulis | Pharoah, Paul D.P. | Hall, Per | Benítez, Javier | Malats, Núria | Easton, Douglas F.
Human Molecular Genetics  2013;23(7):1934-1946.
Part of the substantial unexplained familial aggregation of breast cancer may be due to interactions between common variants, but few studies have had adequate statistical power to detect interactions of realistic magnitude. We aimed to assess all two-way interactions in breast cancer susceptibility between 70 917 single nucleotide polymorphisms (SNPs) selected primarily based on prior evidence of a marginal effect. Thirty-eight international studies contributed data for 46 450 breast cancer cases and 42 461 controls of European origin as part of a multi-consortium project (COGS). First, SNPs were preselected based on evidence (P < 0.01) of a per-allele main effect, and all two-way combinations of those were evaluated by a per-allele (1 d.f.) test for interaction using logistic regression. Second, all 2.5 billion possible two-SNP combinations were evaluated using Boolean operation-based screening and testing, and SNP pairs with the strongest evidence of interaction (P < 10−4) were selected for more careful assessment by logistic regression. Under the first approach, 3277 SNPs were preselected, but an evaluation of all possible two-SNP combinations (1 d.f.) identified no interactions at P < 10−8. Results from the second analytic approach were consistent with those from the first (P > 10−10). In summary, we observed little evidence of two-way SNP interactions in breast cancer susceptibility, despite the large number of SNPs with potential marginal effects considered and the very large sample size. This finding may have important implications for risk prediction, simplifying the modelling required. Further comprehensive, large-scale genome-wide interaction studies may identify novel interacting loci if the inherent logistic and computational challenges can be overcome.
doi:10.1093/hmg/ddt581
PMCID: PMC3943524  PMID: 24242184
17.  Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2 
Orr, Nick | Dudbridge, Frank | Dryden, Nicola | Maguire, Sarah | Novo, Daniela | Perrakis, Eleni | Johnson, Nichola | Ghoussaini, Maya | Hopper, John L. | Southey, Melissa C. | Apicella, Carmel | Stone, Jennifer | Schmidt, Marjanka K. | Broeks, Annegien | Van't Veer, Laura J. | Hogervorst, Frans B. | Fasching, Peter A. | Haeberle, Lothar | Ekici, Arif B. | Beckmann, Matthias W. | Gibson, Lorna | Aitken, Zoe | Warren, Helen | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Burwinkel, Barbara | Marme, Frederik | Schneeweiss, Andreas | Sohn, Chistof | Guénel, Pascal | Truong, Thérèse | Cordina-Duverger, Emilie | Sanchez, Marie | Bojesen, Stig E. | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Benitez, Javier | Zamora, Maria Pilar | Arias Perez, Jose Ignacio | Menéndez, Primitiva | Anton-Culver, Hoda | Neuhausen, Susan L. | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Hamann, Ute | Brauch, Hiltrud | Justenhoven, Christina | Brüning, Thomas | Ko, Yon-Dschun | Nevanlinna, Heli | Aittomäki, Kristiina | Blomqvist, Carl | Khan, Sofia | Bogdanova, Natalia | Dörk, Thilo | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Chenevix-Trench, Georgia | Beesley, Jonathan | Lambrechts, Diether | Moisse, Matthieu | Floris, Guiseppe | Beuselinck, Benoit | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Radice, Paolo | Peterlongo, Paolo | Peissel, Bernard | Pensotti, Valeria | Couch, Fergus J. | Olson, Janet E. | Slettedahl, Seth | Vachon, Celine | Giles, Graham G. | Milne, Roger L. | McLean, Catriona | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Simard, Jacques | Goldberg, Mark S. | Labrèche, France | Dumont, Martine | Kristensen, Vessela | Alnæs, Grethe Grenaker | Nord, Silje | Borresen-Dale, Anne-Lise | Zheng, Wei | Deming-Halverson, Sandra | Shrubsole, Martha | Long, Jirong | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Tchatchou, Sandrine | Devilee, Peter | Tollenaar, Robertus A. E. M. | Seynaeve, Caroline M. | Van Asperen, Christi J. | Garcia-Closas, Montserrat | Figueroa, Jonine | Chanock, Stephen J. | Lissowska, Jolanta | Czene, Kamila | Darabi, Hatef | Eriksson, Mikael | Klevebring, Daniel | Hooning, Maartje J. | Hollestelle, Antoinette | van Deurzen, Carolien H. M. | Kriege, Mieke | Hall, Per | Li, Jingmei | Liu, Jianjun | Humphreys, Keith | Cox, Angela | Cross, Simon S. | Reed, Malcolm W. R. | Pharoah, Paul D. P. | Dunning, Alison M. | Shah, Mitul | Perkins, Barbara J. | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Ashworth, Alan | Swerdlow, Anthony | Jones, Michael | Schoemaker, Minouk J. | Meindl, Alfons | Schmutzler, Rita K. | Olswold, Curtis | Slager, Susan | Toland, Amanda E. | Yannoukakos, Drakoulis | Muir, Kenneth | Lophatananon, Artitaya | Stewart-Brown, Sarah | Siriwanarangsan, Pornthep | Matsuo, Keitaro | Ito, Hidema | Iwata, Hiroji | Ishiguro, Junko | Wu, Anna H. | Tseng, Chiu-chen | Van Den Berg, David | Stram, Daniel O. | Teo, Soo Hwang | Yip, Cheng Har | Kang, Peter | Ikram, Mohammad Kamran | Shu, Xiao-Ou | Lu, Wei | Gao, Yu-Tang | Cai, Hui | Kang, Daehee | Choi, Ji-Yeob | Park, Sue K. | Noh, Dong-Young | Hartman, Mikael | Miao, Hui | Lim, Wei Yen | Lee, Soo Chin | Sangrajrang, Suleeporn | Gaborieau, Valerie | Brennan, Paul | Mckay, James | Wu, Pei-Ei | Hou, Ming-Feng | Yu, Jyh-Cherng | Shen, Chen-Yang | Blot, William | Cai, Qiuyin | Signorello, Lisa B. | Luccarini, Craig | Bayes, Caroline | Ahmed, Shahana | Maranian, Mel | Healey, Catherine S. | González-Neira, Anna | Pita, Guillermo | Alonso, M. Rosario | Álvarez, Nuria | Herrero, Daniel | Tessier, Daniel C. | Vincent, Daniel | Bacot, Francois | Hunter, David J. | Lindstrom, Sara | Dennis, Joe | Michailidou, Kyriaki | Bolla, Manjeet K. | Easton, Douglas F. | dos Santos Silva, Isabel | Fletcher, Olivia | Peto, Julian
Human Molecular Genetics  2015;24(10):2966-2984.
We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88–0.92]; P-value = 1.58 × 10−25). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ∼14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08–1.17]; P-value = 7.89 × 10−09) and rs13294895 (OR = 1.09 [1.06–1.12]; P-value = 2.97 × 10−11). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06–1.18]; P-value = 2.77 × 10−05). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis.
doi:10.1093/hmg/ddv035
PMCID: PMC4406292  PMID: 25652398
18.  Check and mate to exosomal extracellular miRNA: new lesson from a new approach 
MicroRNAs (miRNAs) are 19–24 nt single-stranded RNAs which regulate gene expression by sequence-specific targeting of corresponding mRNAs. Extracellular miRNAs have been consistently detected in all human body fluids, and were shown to be prominent non-invasive biomarkers for various diseases including cancer. Albeit biological function of cell-free miRNA remains questionable, some studies demonstrated that exosomes encapsulated extracellular miRNAs could mediate inter-cellular signaling. While others suggested that these miRNAs are mostly by-products of cellular activity and do not carry any significant biological function. This article aims to discuss the current theories of origin of extracellular miRNA, and to highlight recent application of a novel technique of micro-vesicles counting, that may challenge the existence of exosomal miRNA.
doi:10.3389/fmolb.2015.00011
PMCID: PMC4428470  PMID: 25988178
miRNA; exosomes; microvesicles; cell-cell communication; argonaute proteins; nanoparticle tracking analysis
19.  Refined histopathological predictors of BRCA1 and BRCA2 mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia 
Spurdle, Amanda B | Couch, Fergus J | Parsons, Michael T | McGuffog, Lesley | Barrowdale, Daniel | Bolla, Manjeet K | Wang, Qin | Healey, Sue | Schmutzler, Rita Katharina | Wappenschmidt, Barbara | Rhiem, Kerstin | Hahnen, Eric | Engel, Christoph | Meindl, Alfons | Ditsch, Nina | Arnold, Norbert | Plendl, Hansjoerg | Niederacher, Dieter | Sutter, Christian | Wang-Gohrke, Shan | Steinemann, Doris | Preisler-Adams, Sabine | Kast, Karin | Varon-Mateeva, Raymonda | Ellis, Steve | Frost, Debra | Platte, Radka | Perkins, Jo | Evans, D Gareth | Izatt, Louise | Eeles, Ros | Adlard, Julian | Davidson, Rosemarie | Cole, Trevor | Scuvera, Giulietta | Manoukian, Siranoush | Bonanni, Bernardo | Mariette, Frederique | Fortuzzi, Stefano | Viel, Alessandra | Pasini, Barbara | Papi, Laura | Varesco, Liliana | Balleine, Rosemary | Nathanson, Katherine L | Domchek, Susan M | Offitt, Kenneth | Jakubowska, Anna | Lindor, Noralane | Thomassen, Mads | Jensen, Uffe Birk | Rantala, Johanna | Borg, Åke | Andrulis, Irene L | Miron, Alexander | Hansen, Thomas VO | Caldes, Trinidad | Neuhausen, Susan L | Toland, Amanda E | Nevanlinna, Heli | Montagna, Marco | Garber, Judy | Godwin, Andrew K | Osorio, Ana | Factor, Rachel E | Terry, Mary B | Rebbeck, Timothy R | Karlan, Beth Y | Southey, Melissa | Rashid, Muhammad Usman | Tung, Nadine | Pharoah, Paul DP | Blows, Fiona M | Dunning, Alison M | Provenzano, Elena | Hall, Per | Czene, Kamila | Schmidt, Marjanka K | Broeks, Annegien | Cornelissen, Sten | Verhoef, Senno | Fasching, Peter A | Beckmann, Matthias W | Ekici, Arif B | Slamon, Dennis J | Bojesen, Stig E | Nordestgaard, Børge G | Nielsen, Sune F | Flyger, Henrik | Chang-Claude, Jenny | Flesch-Janys, Dieter | Rudolph, Anja | Seibold, Petra | Aittomäki, Kristiina | Muranen, Taru A | Heikkilä, Päivi | Blomqvist, Carl | Figueroa, Jonine | Chanock, Stephen J | Brinton, Louise | Lissowska, Jolanta | Olson, Janet E | Pankratz, Vernon S | John, Esther M | Whittemore, Alice S | West, Dee W | Hamann, Ute | Torres, Diana | Ulmer, Hans Ulrich | Rüdiger, Thomas | Devilee, Peter | Tollenaar, Robert AEM | Seynaeve, Caroline | Van Asperen, Christi J | Eccles, Diana M | Tapper, William J | Durcan, Lorraine | Jones, Louise | Peto, Julian | dos-Santos-Silva, Isabel | Fletcher, Olivia | Johnson, Nichola | Dwek, Miriam | Swann, Ruth | Bane, Anita L | Glendon, Gord | Mulligan, Anna M | Giles, Graham G | Milne, Roger L | Baglietto, Laura | McLean, Catriona | Carpenter, Jane | Clarke, Christine | Scott, Rodney | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Cox, Angela | Cross, Simon S | Reed, Malcolm WR | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Gronwald, Jacek | Dörk, Thilo | Bogdanova, Natalia | Park-Simon, Tjoung-Won | Hillemanns, Peter | Haiman, Christopher A | Henderson, Brian E | Schumacher, Fredrick | Le Marchand, Loic | Burwinkel, Barbara | Marme, Frederik | Surovy, Harald | Yang, Rongxi | Anton-Culver, Hoda | Ziogas, Argyrios | Hooning, Maartje J | Collée, J Margriet | Martens, John WM | Tilanus-Linthorst, Madeleine MA | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volke | Stegmaier, Christa | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Lindblom, Annika | Margolin, Sara | Joseph, Vijai | Robson, Mark | Rau-Murthy, Rohini | González-Neira, Anna | Arias, José Ignacio | Zamora, Pilar | Benítez, Javier | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M | Peterlongo, Paolo | Zaffaroni, Daniela | Barile, Monica | Capra, Fabio | Radice, Paolo | Teo, Soo H | Easton, Douglas F | Antoniou, Antonis C | Chenevix-Trench, Georgia | Goldgar, David E
Breast Cancer Research : BCR  2014;16(6):3419.
Introduction
The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling.
Methods
Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach.
Results
ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)).
Conclusions
These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-014-0474-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-014-0474-y
PMCID: PMC4352262  PMID: 25857409
20.  MicroRNA Related Polymorphisms and Breast Cancer Risk 
Khan, Sofia | Greco, Dario | Michailidou, Kyriaki | Milne, Roger L. | Muranen, Taru A. | Heikkinen, Tuomas | Aaltonen, Kirsimari | Dennis, Joe | Bolla, Manjeet K. | Liu, Jianjun | Hall, Per | Irwanto, Astrid | Humphreys, Keith | Li, Jingmei | Czene, Kamila | Chang-Claude, Jenny | Hein, Rebecca | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Fletcher, Olivia | Peto, Julian | dos Santos Silva, Isabel | Johnson, Nichola | Gibson, Lorna | Aitken, Zoe | Hopper, John L. | Tsimiklis, Helen | Bui, Minh | Makalic, Enes | Schmidt, Daniel F. | Southey, Melissa C. | Apicella, Carmel | Stone, Jennifer | Waisfisz, Quinten | Meijers-Heijboer, Hanne | Adank, Muriel A. | van der Luijt, Rob B. | Meindl, Alfons | Schmutzler, Rita K. | Müller-Myhsok, Bertram | Lichtner, Peter | Turnbull, Clare | Rahman, Nazneen | Chanock, Stephen J. | Hunter, David J. | Cox, Angela | Cross, Simon S. | Reed, Malcolm W. R. | Schmidt, Marjanka K. | Broeks, Annegien | Veer, Laura J. V. a. n't. | Hogervorst, Frans B. | Fasching, Peter A. | Schrauder, Michael G. | Ekici, Arif B. | Beckmann, Matthias W. | Bojesen, Stig E. | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Benitez, Javier | Zamora, Pilar M. | Perez, Jose I. A. | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Pharoah, Paul D. P. | Dunning, Alison M. | Shah, Mitul | Luben, Robert | Brown, Judith | Couch, Fergus J. | Wang, Xianshu | Vachon, Celine | Olson, Janet E. | Lambrechts, Diether | Moisse, Matthieu | Paridaens, Robert | Christiaens, Marie-Rose | Guénel, Pascal | Truong, Thérèse | Laurent-Puig, Pierre | Mulot, Claire | Marme, Frederick | Burwinkel, Barbara | Schneeweiss, Andreas | Sohn, Christof | Sawyer, Elinor J. | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Andrulis, Irene L. | Knight, Julia A. | Tchatchou, Sandrine | Mulligan, Anna Marie | Dörk, Thilo | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Anton-Culver, Hoda | Darabi, Hatef | Eriksson, Mikael | Garcia-Closas, Montserrat | Figueroa, Jonine | Lissowska, Jolanta | Brinton, Louise | Devilee, Peter | Tollenaar, Robert A. E. M. | Seynaeve, Caroline | van Asperen, Christi J. | Kristensen, Vessela N. | Slager, Susan | Toland, Amanda E. | Ambrosone, Christine B. | Yannoukakos, Drakoulis | Lindblom, Annika | Margolin, Sara | Radice, Paolo | Peterlongo, Paolo | Barile, Monica | Mariani, Paolo | Hooning, Maartje J. | Martens, John W. M. | Collée, J. Margriet | Jager, Agnes | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Giles, Graham G. | McLean, Catriona | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Swerdlow, Anthony | Ashworth, Alan | Orr, Nick | Jones, Michael | Simard, Jacques | Goldberg, Mark S. | Labrèche, France | Dumont, Martine | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Mannermaa, Arto | Hamann, Ute | Chenevix-Trench, Georgia | Blomqvist, Carl | Aittomäki, Kristiina | Easton, Douglas F. | Nevanlinna, Heli
PLoS ONE  2014;9(11):e109973.
Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval (CI): 0.88–0.96), rs1052532 (OR 0.97; 95% CI: 0.95–0.99), rs10719 (OR 0.97; 95% CI: 0.94–0.99), rs4687554 (OR 0.97; 95% CI: 0.95–0.99, and rs3134615 (OR 1.03; 95% CI: 1.01–1.05) located in the 3′ UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects.
doi:10.1371/journal.pone.0109973
PMCID: PMC4229095  PMID: 25390939
21.  Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk 
Painter, Jodie N. | O'Mara, Tracy A. | Batra, Jyotsna | Cheng, Timothy | Lose, Felicity A. | Dennis, Joe | Michailidou, Kyriaki | Tyrer, Jonathan P. | Ahmed, Shahana | Ferguson, Kaltin | Healey, Catherine S. | Kaufmann, Susanne | Hillman, Kristine M. | Walpole, Carina | Moya, Leire | Pollock, Pamela | Jones, Angela | Howarth, Kimberley | Martin, Lynn | Gorman, Maggie | Hodgson, Shirley | De Polanco, Ma. Magdalena Echeverry | Sans, Monica | Carracedo, Angel | Castellvi-Bel, Sergi | Rojas-Martinez, Augusto | Santos, Erika | Teixeira, Manuel R. | Carvajal-Carmona, Luis | Shu, Xiao-Ou | Long, Jirong | Zheng, Wei | Xiang, Yong-Bing | Montgomery, Grant W. | Webb, Penelope M. | Scott, Rodney J. | McEvoy, Mark | Attia, John | Holliday, Elizabeth | Martin, Nicholas G. | Nyholt, Dale R. | Henders, Anjali K. | Fasching, Peter A. | Hein, Alexander | Beckmann, Matthias W. | Renner, Stefan P. | Dörk, Thilo | Hillemanns, Peter | Dürst, Matthias | Runnebaum, Ingo | Lambrechts, Diether | Coenegrachts, Lieve | Schrauwen, Stefanie | Amant, Frederic | Winterhoff, Boris | Dowdy, Sean C. | Goode, Ellen L. | Teoman, Attila | Salvesen, Helga B. | Trovik, Jone | Njolstad, Tormund S. | Werner, Henrica M.J. | Ashton, Katie | Proietto, Tony | Otton, Geoffrey | Tzortzatos, Gerasimos | Mints, Miriam | Tham, Emma | Hall, Per | Czene, Kamila | Liu, Jianjun | Li, Jingmei | Hopper, John L. | Southey, Melissa C. | Ekici, Arif B. | Ruebner, Matthias | Johnson, Nicola | Peto, Julian | Burwinkel, Barbara | Marme, Frederik | Brenner, Hermann | Dieffenbach, Aida K. | Meindl, Alfons | Brauch, Hiltrud | Lindblom, Annika | Depreeuw, Jeroen | Moisse, Matthieu | Chang-Claude, Jenny | Rudolph, Anja | Couch, Fergus J. | Olson, Janet E. | Giles, Graham G. | Bruinsma, Fiona | Cunningham, Julie M. | Fridley, Brooke L. | Børresen-Dale, Anne-Lise | Kristensen, Vessela N. | Cox, Angela | Swerdlow, Anthony J. | Orr, Nicholas | Bolla, Manjeet K. | Wang, Qin | Weber, Rachel Palmieri | Chen, Zhihua | Shah, Mitul | French, Juliet D. | Pharoah, Paul D.P. | Dunning, Alison M. | Tomlinson, Ian | Easton, Douglas F. | Edwards, Stacey L. | Thompson, Deborah J. | Spurdle, Amanda B.
Human Molecular Genetics  2014;24(5):1478-1492.
Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10−14, odds ratio = 0.86, 95% confidence interval = 0.82–0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression.
doi:10.1093/hmg/ddu552
PMCID: PMC4321445  PMID: 25378557
22.  Confirmation of 5p12 as a susceptibility locus for progesterone-receptor-positive, lower grade breast cancer 
Milne, Roger L. | Goode, Ellen L. | García-Closas, Montserrat | Couch, Fergus J. | Severi, Gianluca | Hein, Rebecca | Fredericksen, Zachary | Malats, Núria | Zamora, M. Pilar | Pérez, Jose Ignacio Arias | Benítez, Javier | Dörk, Thilo | Schürmann, Peter | Karstens, Johann H. | Hillemanns, Peter | Cox, Angela | Brock, Ian W. | Elliot, Graeme | Cross, Simon S. | Seal, Sheila | Turnbull, Clare | Renwick, Anthony | Rahman, Nazneen | Shen, Chen-Yang | Yu, Jyh-Cherng | Huang, Chiun-Sheng | Hou, Ming-Feng | Nordestgaard, Børge G. | Bojesen, Stig E. | Lanng, Charlotte | Alnæs, Grethe Grenaker | Kristensen, Vessela | Børrensen-Dale, Anne-Lise | Hopper, John L. | Dite, Gillian S. | Apicella, Carmel | Southey, Melissa C. | Lambrechts, Diether | Yesilyurt, Betül T. | Floris, Giuseppe | Leunen, Karin | Sangrajrang, Suleeporn | Gaborieau, Valerie | Brennan, Paul | McKay, James | Chang-Claude, Jenny | Wang-Gohrke, Shan | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Barile, Monica | Giles, Graham G. | Baglietto, Laura | John, Esther M. | Miron, Alexander | Chanock, Stephen J. | Lissowska, Jolanta | Sherman, Mark E. | Figueroa, Jonine D. | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Zalutsky, Iosif V. | Rogov, Yuri I. | Fasching, Peter A. | Bayer, Christian M. | Ekici, Arif B. | Beckmann, Matthias W. | Brenner, Hermann | Müller, Heiko | Arndt, Volker | Stegmaier, Christa | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Mulligan, Anna Marie | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Meindl, Alfons | Heil, Joerg | Bartram, Claus R. | Schmutzler, Rita K. | Thomas, Gilles D. | Hoover, Robert N. | Fletcher, Olivia | Gibson, Lorna J. | Silva, Isabel dos Santos | Peto, Julian | Nickels, Stefan | Flesch-Janys, Dieter | Anton-Culver, Hoda | Ziogas, Argyrios | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael | Miller, Nicola | Schmidt, Marjanka K. | Broeks, Annegien | Van ‘t Veer, Laura J. | Tollenaar, Rob A.E.M. | Pharoah, Paul D.P. | Dunning, Alison M. | Pooley, Karen A. | Marme, Frederik | Schneeweiss, Andreas | Sohn, Christof | Burwinkel, Barbara | Jakubowska, Anna | Lubinski, Jan | Jaworska, Katarzyna | Durda, Katarzyna | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Ahn, Sei-Hyun | Hunter, David J. | Hankinson, Susan E. | Kraft, Peter | Lindstrom, Sara | Chen, Xiaoqing | Beesley, Jonathan | Hamann, Ute | Harth, Volker | Justenhoven, Christina | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Hooning, Maartje | Hollestelle, Antoinette | Oldenburg, Rogier A. | Tilanus-Linthorst, Madeleine | Khusnutdinova, Elza | Bermisheva, Marina | Prokofieva, Darya | Farahtdinova, Albina | Olson, Janet E. | Wang, Xianshu | Humphreys, Manjeet K. | Wang, Qin | Chenevix-Trench, Georgia | Easton, Douglas F.
Background
The single nucleotide polymorphism 5p12-rs10941679has been found to be associated with risk of breast cancer, particularly estrogen receptor (ER)-positive disease. We aimed to further explore this association overall, and by tumor histopathology, in the Breast Cancer Association Consortium.
Methods
Data were combined from 37 studies, including 40,972 invasive cases, 1,398 cases of ductal carcinoma in situ (DCIS) and 46,334 controls, all of white European ancestry, as well as 3,007 invasive cases and 2,337 controls of Asian ancestry. Associations overall and by tumor invasiveness and histopathology were assessed using logistic regression.
Results
For white Europeans, the per-allele odds ratio (OR) associated with 5p12-rs10941679 was 1.11 (95% confidence interval [CI] =1.08–1.14, P=7×10−18) for invasive breast cancer and 1.10 (95%CI=1.01–1.21, P=0.03) for DCIS. For Asian women, the estimated OR for invasive disease was similar (OR=1.07, 95%CI=0.99–1.15, P=0.09). Further analyses suggested that the association in white Europeans was largely limited to progesterone receptor (PR)-positive disease (per-allele OR=1.16, 95%CI=1.12–1.20, P=1×10−18 versus OR=1.03, 95%CI=0.99–1.07, P=0.2 for PR-negative disease; P-heterogeneity=2×10−7); heterogeneity by estrogen receptor status was not observed (P=0.2) once PR status was accounted for. The association was also stronger for lower-grade tumors (per-allele OR [95%CI]=1.20 [1.14–1.25], 1.13 [1.09–1.16] and 1.04 [0.99–1.08] for grade 1, 2 and 3/4, respectively; P–trend=5×10−7).
Conclusion
5p12 is a breast cancer susceptibility locus for PR-positive, lower gradebreast cancer.
Impact
Multi-centre fine-mapping studies of this region are needed as a first step to identifying the causal variant or variants.
doi:10.1158/1055-9965.EPI-11-0569
PMCID: PMC4164116  PMID: 21795498
Breast cancer; SNP; susceptibility; disease subtypes
23.  Serial enumeration of circulating tumor cells predicts treatment response and prognosis in metastatic breast cancer: a prospective study in 393 patients 
BMC Cancer  2014;14:512.
Background
To prospectively assess circulating tumor cell (CTC) status at baseline (CTCBL) and after one cycle of a new line of systemic therapy (CTC1C), and changes from CTCBL to CTC1C (CTC kinetics, CTCKIN) for their utility in predicting response, progression-free (PFS) and overall survival (OS) in metastatic breast cancer (MBC).
Methods
CTCBL and CTC1C status was determined as negative (-) or positive (+) for < 5 or ≥ 5 CTCs/7.5 ml blood using CellSearch™ (Veridex). CTCKIN was categorized as favorable (CTC1C-) or unfavorable (CTC1C+). Tumor response was to be assessed every 2–3 months using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Statistical analysis focused on the relation between CTC status and CTCKIN, and response, PFS, and OS.
Results
133/393 (34%) patients enrolled were CTCBL+. CTC1C status after one cycle and radiological tumor response were assessed after median (range) periods of 1.2 (0.5–3.2) and 2.9 (0.5–4.8) months, respectively. 57/201 (28%) were CTC1C+. Median [95% confidence interval] PFS and OS (months) were significantly reduced in CTCBL+ vs. CTCBL- patients (PFS 4.7 [3.7–6.1] vs. 7.8 [6.4–9.2]; OS 10.4 [7.9–15.0] vs. 27.2 [22.3–29.9]), and for CTC1C+ vs. CTC1C- patients (PFS 4.3 [3.6–6.0] vs. 8.5 [6.6–10.4]; OS 7.7 [6.4–13.9] vs. 30.6 [22.6–not available]). Unfavorable CTCKIN was significantly associated with progressive disease. Multivariate Cox regression analysis revealed prognostic factors for shorter PFS (CTCBL+, persistent CTCs after one cycle, ≥ 3rd-line therapy, and triple-negative receptor status) and shorter OS (CTCBL+, persistent CTCs after one cycle, bone-and-visceral/local metastases, ≥ 3rd-line therapy, and triple-negative receptor status).
Conclusions
CTCBL, CTC1C, and CTCKIN are predictive of outcome in MBC. Serial CTC enumeration is useful in tailoring systemic treatment of MBC.
Trial registration
Not applicable.
doi:10.1186/1471-2407-14-512
PMCID: PMC4226959  PMID: 25015676
Metastatic breast cancer; Circulating tumor cells; Systemic therapy; Treatment response; Survival
24.  Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium 
Milne, Roger L. | Burwinkel, Barbara | Michailidou, Kyriaki | Arias-Perez, Jose-Ignacio | Zamora, M. Pilar | Menéndez-Rodríguez, Primitiva | Hardisson, David | Mendiola, Marta | González-Neira, Anna | Pita, Guillermo | Alonso, M. Rosario | Dennis, Joe | Wang, Qin | Bolla, Manjeet K. | Swerdlow, Anthony | Ashworth, Alan | Orr, Nick | Schoemaker, Minouk | Ko, Yon-Dschun | Brauch, Hiltrud | Hamann, Ute | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Tchatchou, Sandrine | Matsuo, Keitaro | Ito, Hidemi | Iwata, Hiroji | Tajima, Kazuo | Li, Jingmei | Brand, Judith S. | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Lambrechts, Diether | Peuteman, Gilian | Christiaens, Marie-Rose | Smeets, Ann | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katazyna | Hartman, Mikael | Hui, Miao | Yen Lim, Wei | Wan Chan, Ching | Marme, Federick | Yang, Rongxi | Bugert, Peter | Lindblom, Annika | Margolin, Sara | García-Closas, Montserrat | Chanock, Stephen J. | Lissowska, Jolanta | Figueroa, Jonine D. | Bojesen, Stig E. | Nordestgaard, Børge G. | Flyger, Henrik | Hooning, Maartje J. | Kriege, Mieke | van den Ouweland, Ans M.W. | Koppert, Linetta B. | Fletcher, Olivia | Johnson, Nichola | dos-Santos-Silva, Isabel | Peto, Julian | Zheng, Wei | Deming-Halverson, Sandra | Shrubsole, Martha J. | Long, Jirong | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Cox, Angela | Cross, Simon S. | Reed, Malcolm W.R. | Schmidt, Marjanka K. | Broeks, Annegien | Cornelissen, Sten | Braaf, Linde | Kang, Daehee | Choi, Ji-Yeob | Park, Sue K. | Noh, Dong-Young | Simard, Jacques | Dumont, Martine | Goldberg, Mark S. | Labrèche, France | Fasching, Peter A. | Hein, Alexander | Ekici, Arif B. | Beckmann, Matthias W. | Radice, Paolo | Peterlongo, Paolo | Azzollini, Jacopo | Barile, Monica | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael | Miller, Nicola | Hopper, John L. | Schmidt, Daniel F. | Makalic, Enes | Southey, Melissa C. | Hwang Teo, Soo | Har Yip, Cheng | Sivanandan, Kavitta | Tay, Wan-Ting | Shen, Chen-Yang | Hsiung, Chia-Ni | Yu, Jyh-Cherng | Hou, Ming-Feng | Guénel, Pascal | Truong, Therese | Sanchez, Marie | Mulot, Claire | Blot, William | Cai, Qiuyin | Nevanlinna, Heli | Muranen, Taru A. | Aittomäki, Kristiina | Blomqvist, Carl | Wu, Anna H. | Tseng, Chiu-Chen | Van Den Berg, David | Stram, Daniel O. | Bogdanova, Natalia | Dörk, Thilo | Muir, Kenneth | Lophatananon, Artitaya | Stewart-Brown, Sarah | Siriwanarangsan, Pornthep | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Shu, Xiao-Ou | Lu, Wei | Gao, Yu-Tang | Zhang, Ben | Couch, Fergus J. | Toland, Amanda E. | Yannoukakos, Drakoulis | Sangrajrang, Suleeporn | McKay, James | Wang, Xianshu | Olson, Janet E. | Vachon, Celine | Purrington, Kristen | Severi, Gianluca | Baglietto, Laura | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Devilee, Peter | Tollenaar, Robert A.E.M. | Seynaeve, Caroline | Czene, Kamila | Eriksson, Mikael | Humphreys, Keith | Darabi, Hatef | Ahmed, Shahana | Shah, Mitul | Pharoah, Paul D.P. | Hall, Per | Giles, Graham G. | Benítez, Javier | Dunning, Alison M. | Chenevix-Trench, Georgia | Easton, Douglas F. | Berchuck, Andrew | Eeles, Rosalind A. | Olama, Ali Amin Al | Kote-Jarai, Zsofia | Benlloch, Sara | Antoniou, Antonis | McGuffog, Lesley | Offit, Ken | Lee, Andrew | Dicks, Ed | Luccarini, Craig | Tessier, Daniel C. | Bacot, Francois | Vincent, Daniel | LaBoissière, Sylvie | Robidoux, Frederic | Nielsen, Sune F. | Cunningham, Julie M. | Windebank, Sharon A. | Hilker, Christopher A. | Meyer, Jeffrey | Angelakos, Maggie | Maskiell, Judi | van der Schoot, Ellen | Rutgers, Emiel | Verhoef, Senno | Hogervorst, Frans | Boonyawongviroj, Prat | Siriwanarungsan, Pornthep | Schrauder, Michael | Rübner, Matthias | Oeser, Sonja | Landrith, Silke | Williams, Eileen | Ryder-Mills, Elaine | Sargus, Kara | McInerney, Niall | Colleran, Gabrielle | Rowan, Andrew | Jones, Angela | Sohn, Christof | Schneeweiß, Andeas | Bugert, Peter | Álvarez, Núria | Lacey, James | Wang, Sophia | Ma, Huiyan | Lu, Yani | Deapen, Dennis | Pinder, Rich | Lee, Eunjung | Schumacher, Fred | Horn-Ross, Pam | Reynolds, Peggy | Nelson, David | Ziegler, Hartwig | Wolf, Sonja | Hermann, Volker | Lo, Wing-Yee | Justenhoven, Christina | Baisch, Christian | Fischer, Hans-Peter | Brüning, Thomas | Pesch, Beate | Rabstein, Sylvia | Lotz, Anne | Harth, Volker | Heikkinen, Tuomas | Erkkilä, Irja | Aaltonen, Kirsimari | von Smitten, Karl | Antonenkova, Natalia | Hillemanns, Peter | Christiansen, Hans | Myöhänen, Eija | Kemiläinen, Helena | Thorne, Heather | Niedermayr, Eveline | Bowtell, D | Chenevix-Trench, G | deFazio, A | Gertig, D | Green, A | Webb, P | Green, A. | Parsons, P. | Hayward, N. | Webb, P. | Whiteman, D. | Fung, Annie | Yashiki, June | Peuteman, Gilian | Smeets, Dominiek | Brussel, Thomas Van | Corthouts, Kathleen | Obi, Nadia | Heinz, Judith | Behrens, Sabine | Eilber, Ursula | Celik, Muhabbet | Olchers, Til | Manoukian, Siranoush | Peissel, Bernard | Scuvera, Giulietta | Zaffaroni, Daniela | Bonanni, Bernardo | Feroce, Irene | Maniscalco, Angela | Rossi, Alessandra | Bernard, Loris | Tranchant, Martine | Valois, Marie-France | Turgeon, Annie | Heguy, Lea | Sze Yee, Phuah | Kang, Peter | Nee, Kang In | Mariapun, Shivaani | Sook-Yee, Yoon | Lee, Daphne | Ching, Teh Yew | Taib, Nur Aishah Mohd | Otsukka, Meeri | Mononen, Kari | Selander, Teresa | Weerasooriya, Nayana | staff, OFBCR | Krol-Warmerdam, E. | Molenaar, J. | Blom, J. | Brinton, Louise | Szeszenia-Dabrowska, Neonila | Peplonska, Beata | Zatonski, Witold | Chao, Pei | Stagner, Michael | Bos, Petra | Blom, Jannet | Crepin, Ellen | Nieuwlaat, Anja | Heemskerk, Annette | Higham, Sue | Cross, Simon | Cramp, Helen | Connley, Dan | Balasubramanian, Sabapathy | Brock, Ian | Luccarini, Craig | Conroy, Don | Baynes, Caroline | Chua, Kimberley
Human Molecular Genetics  2014;23(22):6096-6111.
Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04–1.10, P = 2.9 × 10−6], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03–1.07, P = 1.7 × 10−6) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07–1.12, P = 5.1 × 10−17). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05–1.10, P = 1.0 × 10−8); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04–1.07, P = 2.0 × 10−10). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.
doi:10.1093/hmg/ddu311
PMCID: PMC4204770  PMID: 24943594
25.  Genetic variation at CYP3A is associated with age at menarche and breast cancer risk: a case-control study 
Johnson, Nichola | Dudbridge, Frank | Orr, Nick | Gibson, Lorna | Jones, Michael E | Schoemaker, Minouk J | Folkerd, Elizabeth J | Haynes, Ben P | Hopper, John L | Southey, Melissa C | Dite, Gillian S | Apicella, Carmel | Schmidt, Marjanka K | Broeks, Annegien | Van’t Veer, Laura J | Atsma, Femke | Muir, Kenneth | Lophatananon, Artitaya | Fasching, Peter A | Beckmann, Matthias W | Ekici, Arif B | Renner, Stefan P | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael | Miller, Nicola | Burwinkel, Barbara | Marme, Frederik | Schneeweiss, Andreas | Sohn, Christof | Guénel, Pascal | Truong, Therese | Cordina, Emilie | Menegaux, Florence | Bojesen, Stig E | Nordestgaard, Børge G | Flyger, Henrik | Milne, Roger | Zamora, M Pilar | Arias Perez, Jose Ignacio | Benitez, Javier | Bernstein, Leslie | Anton-Culver, Hoda | Ziogas, Argyrios | Clarke Dur, Christina | Brenner, Hermann | Müller, Heiko | Arndt, Volker | Dieffenbach, Aida Karina | Meindl, Alfons | Heil, Joerg | Bartram, Claus R | Schmutzler, Rita K | Brauch, Hiltrud | Justenhoven, Christina | Ko, Yon-Dschun | Nevanlinna, Heli | Muranen, Taru A | Aittomäki, Kristiina | Blomqvist, Carl | Matsuo, Keitaro | Dörk, Thilo | Bogdanova, Natalia V | Antonenkova, Natalia N | Lindblom, Annika | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M | Chenevix-Trench, Georgia | Beesley, Jonathan | Wu, Anna H | Van den Berg, David | Tseng, Chiu-Chen | Lambrechts, Diether | Smeets, Dominiek | Neven, Patrick | Wildiers, Hans | Chang-Claude, Jenny | Rudolph, Anja | Nickels, Stefan | Flesch-Janys, Dieter | Radice, Paolo | Peterlongo, Paolo | Bonanni, Bernardo | Pensotti, Valeria | Couch, Fergus J | Olson, Janet E | Wang, Xianshu | Fredericksen, Zachary | Pankratz, Vernon S | Giles, Graham G | Severi, Gianluca | Baglietto, Laura | Haiman, Chris | Simard, Jacques | Goldberg, Mark S | Labrèche, France | Dumont, Martine | Soucy, Penny | Teo, Soo | Yip, Cheng Har | Phuah, Sze Yee | Cornes, Belinda K | Kristensen, Vessela N | Grenaker Alnæs, Grethe | Børresen-Dale, Anne-Lise | Zheng, Wei | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Andrulis, Irene L | Knight, Julia A | Glendon, Gord | Mulligan, Anna Marie | Devillee, Peter | Figueroa, Jonine | Chanock, Stephen J | Lissowska, Jolanta | Sherman, Mark E | Hall, Per | Schoof, Nils | Hooning, Maartje | Hollestelle, Antoinette | Oldenburg, Rogier A | Tilanus-Linthorst, Madeleine | Liu, Jianjun | Cox, Angie | Brock, Ian W | Reed, Malcolm WR | Cross, Simon S | Blot, William | Signorello, Lisa B | Pharoah, Paul DP | Dunning, Alison M | Shah, Mitul | Kang, Daehee | Noh, Dong-Young | Park, Sue K | Choi, Ji-Yeob | Hartman, Mikael | Miao, Hui | Lim, Wei Yen | Tang, Anthony | Hamann, Ute | Försti, Asta | Rüdiger, Thomas | Ulmer, Hans Ulrich | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Sangrajrang, Suleeporn | Gaborieau, Valerie | Brennan, Paul | McKay, James | Slager, Susan | Toland, Amanda E | Vachon, Celine | Yannoukakos, Drakoulis | Shen, Chen-Yang | Yu, Jyh-Cherng | Huang, Chiun-Sheng | Hou, Ming-Feng | González-Neira, Anna | Tessier, Daniel C | Vincent, Daniel | Bacot, Francois | Luccarini, Craig | Dennis, Joe | Michailidou, Kyriaki | Bolla, Manjeet K | Wang, Jean | Easton, Douglas F | García-Closas, Montserrat | Dowsett, Mitch | Ashworth, Alan | Swerdlow, Anthony J | Peto, Julian | dos Santos Silva, Isabel | Fletcher, Olivia
Introduction
We have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to the CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and a modest reduction in risk of breast cancer in women age ≤50 years.
Methods
We further investigated the association of rs10235235 with breast cancer risk in a large case control study of 47,346 cases and 47,570 controls from 52 studies participating in the Breast Cancer Association Consortium. Genotyping of rs10235235 was conducted using a custom Illumina Infinium array. Stratified analyses were conducted to determine whether this association was modified by age at diagnosis, ethnicity, age at menarche or tumor characteristics.
Results
We confirmed the association of rs10235235 with breast cancer risk for women of European ancestry but found no evidence that this association differed with age at diagnosis. Heterozygote and homozygote odds ratios (ORs) were OR = 0.98 (95% CI 0.94, 1.01; P = 0.2) and OR = 0.80 (95% CI 0.69, 0.93; P = 0.004), respectively (Ptrend = 0.02). There was no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche in controls (Ptrend = 0.005) but not cases (Ptrend = 0.97). Consequently the association between rs10235235 and breast cancer risk differed according to age at menarche (Phet = 0.02); the rare allele of rs10235235 was associated with a reduction in breast cancer risk for women who had their menarche age ≥15 years (ORhet = 0.84, 95% CI 0.75, 0.94; ORhom = 0.81, 95% CI 0.51, 1.30; Ptrend = 0.002) but not for those who had their menarche age ≤11 years (ORhet = 1.06, 95% CI 0.95, 1.19, ORhom = 1.07, 95% CI 0.67, 1.72; Ptrend = 0.29).
Conclusions
To our knowledge rs10235235 is the first single nucleotide polymorphism to be associated with both breast cancer risk and age at menarche consistent with the well-documented association between later age at menarche and a reduction in breast cancer risk. These associations are likely mediated via an effect on circulating hormone levels.
doi:10.1186/bcr3662
PMCID: PMC4522594  PMID: 24887515

Results 1-25 (64)