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1.  Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer 
Purpose
To analyse the effect of germline mutations in BRCA1 and BRCA2 on mortality in ovarian cancer patients up to ten years after diagnosis.
Experimental Design
We used unpublished survival time data for 2,242 patients from two case-control studies and extended survival-time data for 4,314 patients from previously reported studies. All participants had been screened for deleterious germline mutations in BRCA1 and BRCA2. Survival time was analysed for the combined data using Cox proportional hazard models with BRCA1 and BRCA2 as time-varying covariates. Competing risks were analysed using Fine and Gray model.
Results
The combined 10-year overall survival was 30% (95% CI, 28%-31%) for non-carriers, 25% (95% CI, 22%-28%) for BRCA1 carriers, and 35% (95% CI, 30%-41%) for BRCA2 carriers. The hazard ratio for BRCA1 was 0.53 at time zero and increased over time becoming greater than one at ·4.8 years. For BRCA2, the hazard ratio was 0.42 at time zero and increased over time (predicted to become greater than one at 10.5 years). The results were similar when restricted to 3,202 patients with high-grade serous tumors, and to ovarian cancer specific mortality.
Conclusions
BRCA1/2 mutations are associated with better short-term survival, but this advantage decreases over time and, in BRCA1 carriers is eventually reversed. This may have important implications for therapy of both primary and relapsed disease and for analysis of long-term survival in clinical trials of new agents, particularly those that are effective in BRCA1/2 mutation carriers.
doi:10.1158/1078-0432.CCR-14-2497
PMCID: PMC4338615  PMID: 25398451
Ovarian cancer; Epithelial ovarian cancer; BRCA1 gene; BRCA2 gene; Survival
2.  Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma 
Law, Matthew H. | Bishop, D. Timothy | Lee, Jeffrey E. | Brossard, Myriam | Martin, Nicholas G. | Moses, Eric K. | Song, Fengju | Barrett, Jennifer H. | Kumar, Rajiv | Easton, Douglas F. | Pharoah, Paul D. P. | Swerdlow, Anthony J. | Kypreou, Katerina P. | Taylor, John C. | Harland, Mark | Randerson-Moor, Juliette | Akslen, Lars A. | Andresen, Per A. | Avril, Marie-Françoise | Azizi, Esther | Scarrà, Giovanna Bianchi | Brown, Kevin M. | Dȩbniak, Tadeusz | Duffy, David L. | Elder, David E. | Fang, Shenying | Friedman, Eitan | Galan, Pilar | Ghiorzo, Paola | Gillanders, Elizabeth M. | Goldstein, Alisa M. | Gruis, Nelleke A. | Hansson, Johan | Helsing, Per | Hočevar, Marko | Höiom, Veronica | Ingvar, Christian | Kanetsky, Peter A. | Chen, Wei V. | Landi, Maria Teresa | Lang, Julie | Lathrop, G. Mark | Lubiński, Jan | Mackie, Rona M. | Mann, Graham J. | Molven, Anders | Montgomery, Grant W. | Novaković, Srdjan | Olsson, Håkan | Puig, Susana | Puig-Butille, Joan Anton | Qureshi, Abrar A. | Radford-Smith, Graham L. | van der Stoep, Nienke | van Doorn, Remco | Whiteman, David C. | Craig, Jamie E. | Schadendorf, Dirk | Simms, Lisa A. | Burdon, Kathryn P. | Nyholt, Dale R. | Pooley, Karen A. | Orr, Nicholas | Stratigos, Alexander J. | Cust, Anne E. | Ward, Sarah V. | Hayward, Nicholas K. | Han, Jiali | Schulze, Hans-Joachim | Dunning, Alison M. | Bishop, Julia A. Newton | Demenais, Florence | Amos, Christopher I. | MacGregor, Stuart | Iles, Mark M.
Nature genetics  2015;47(9):987-995.
Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international two-stage meta-analysis of 11 genome-wide association studies (GWAS, five unpublished) of CMM and Stage two datasets, totaling 15,990 cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5×10−8) as did two previously-reported but un-replicated loci and all thirteen established loci. Novel SNPs fall within putative melanocyte regulatory elements, and bioinformatic and eQTL data highlight candidate genes including one involved in telomere biology.
doi:10.1038/ng.3373
PMCID: PMC4557485  PMID: 26237428
3.  Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma 
Law, Matthew H. | Bishop, D. Timothy | Lee, Jeffrey E. | Brossard, Myriam | Martin, Nicholas G. | Moses, Eric K. | Song, Fengju | Barrett, Jennifer H. | Kumar, Rajiv | Easton, Douglas F. | Pharoah, Paul D. P. | Swerdlow, Anthony J. | Kypreou, Katerina P. | Taylor, John C. | Harland, Mark | Randerson-Moor, Juliette | Akslen, Lars A. | Andresen, Per A. | Avril, Marie-Françoise | Azizi, Esther | Scarrà, Giovanna Bianchi | Brown, Kevin M. | Dębniak, Tadeusz | Duffy, David L. | Elder, David E. | Fang, Shenying | Friedman, Eitan | Galan, Pilar | Ghiorzo, Paola | Gillanders, Elizabeth M. | Goldstein, Alisa M. | Gruis, Nelleke A. | Hansson, Johan | Helsing, Per | Hočevar, Marko | Höiom, Veronica | Ingvar, Christian | Kanetsky, Peter A. | Chen, Wei V. | Landi, Maria Teresa | Lang, Julie | Lathrop, G. Mark | Lubiński, Jan | Mackie, Rona M. | Mann, Graham J. | Molven, Anders | Montgomery, Grant W. | Novaković, Srdjan | Olsson, Håkan | Puig, Susana | Puig-Butille, Joan Anton | Qureshi, Abrar A. | Radford-Smith, Graham L. | van der Stoep, Nienke | van Doorn, Remco | Whiteman, David C. | Craig, Jamie E. | Schadendorf, Dirk | Simms, Lisa A. | Burdon, Kathryn P. | Nyholt, Dale R. | Pooley, Karen A. | Orr, Nick | Stratigos, Alexander J. | Cust, Anne E. | Ward, Sarah V. | Hayward, Nicholas K. | Han, Jiali | Schulze, Hans-Joachim | Dunning, Alison M. | Bishop, Julia A. Newton | Demenais, Florence | Amos, Christopher I. | MacGregor, Stuart | Iles, Mark M.
Nature genetics  2015;47(9):987-995.
Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5×10–8), as did two previously-reported but un-replicated loci and all thirteen established loci. Novel SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes including one involved in telomere biology.
doi:10.1038/ng.3373
PMCID: PMC4557485  PMID: 26237428
4.  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
5.  Computational pathology of pre-treatment biopsies identifies lymphocyte density as a predictor of response to neoadjuvant chemotherapy in breast cancer 
Background
There is a need to improve prediction of response to chemotherapy in breast cancer in order to improve clinical management and this may be achieved by harnessing computational metrics of tissue pathology. We investigated the association between quantitative image metrics derived from computational analysis of digital pathology slides and response to chemotherapy in women with breast cancer who received neoadjuvant chemotherapy.
Methods
We digitised tissue sections of both diagnostic and surgical samples of breast tumours from 768 patients enrolled in the Neo-tAnGo randomized controlled trial. We subjected digital images to systematic analysis optimised for detection of single cells. Machine-learning methods were used to classify cells as cancer, stromal or lymphocyte and we computed estimates of absolute numbers, relative fractions and cell densities using these data. Pathological complete response (pCR), a histological indicator of chemotherapy response, was the primary endpoint. Fifteen image metrics were tested for their association with pCR using univariate and multivariate logistic regression.
Results
Median lymphocyte density proved most strongly associated with pCR on univariate analysis (OR 4.46, 95 % CI 2.34-8.50, p < 0.0001; observations = 614) and on multivariate analysis (OR 2.42, 95 % CI 1.08-5.40, p = 0.03; observations = 406) after adjustment for clinical factors. Further exploratory analyses revealed that in approximately one quarter of cases there was an increase in lymphocyte density in the tumour removed at surgery compared to diagnostic biopsies. A reduction in lymphocyte density at surgery was strongly associated with pCR (OR 0.28, 95 % CI 0.17-0.47, p < 0.0001; observations = 553).
Conclusions
A data-driven analysis of computational pathology reveals lymphocyte density as an independent predictor of pCR. Paradoxically an increase in lymphocyte density, following exposure to chemotherapy, is associated with a lack of pCR. Computational pathology can provide objective, quantitative and reproducible tissue metrics and represents a viable means of outcome prediction in breast cancer.
Trial registration
ClinicalTrials.gov NCT00070278; 03/10/2003
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-016-0682-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-016-0682-8
PMCID: PMC4755003  PMID: 26882907
Breast cancer; Computational pathology; Neoadjuvant; Lymphocytes; Treatment resistance; Immunology
6.  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
7.  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
8.  Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC) 
Jim, Heather S.L. | Lin, Hui-Yi | Tyrer, Jonathan P. | Lawrenson, Kate | Dennis, Joe | Chornokur, Ganna | Chen, Zhihua | Chen, Ann Y. | Permuth-Wey, Jennifer | Aben, Katja KH. | Anton-Culver, Hoda | Antonenkova, Natalia | Bruinsma, Fiona | Bandera, Elisa V. | Bean, Yukie T. | Beckmann, Matthias W. | Bisogna, Maria | Bjorge, Line | Bogdanova, Natalia | Brinton, Louise A. | Brooks-Wilson, Angela | Bunker, Clareann H. | Butzow, Ralf | Campbell, Ian G. | Carty, Karen | Chang-Claude, Jenny | Cook, Linda S. | Cramer, Daniel W. | Cunningham, Julie M. | Cybulski, Cezary | Dansonka-Mieszkowska, Agnieszka | du Bois, Andreas | Despierre, Evelyn | Sieh, Weiva | Doherty, Jennifer A. | Dörk, Thilo | Dürst, Matthias | Easton, Douglas F. | Eccles, Diana M. | Edwards, Robert P. | Ekici, Arif B. | Fasching, Peter A. | Fridley, Brooke L. | Gao, Yu-Tang | Gentry-Maharaj, Aleksandra | Giles, Graham G. | Glasspool, Rosalind | Goodman, Marc T. | Gronwald, Jacek | Harter, Philipp | Hasmad, Hanis N. | Hein, Alexander | Heitz, Florian | Hildebrandt, Michelle A.T. | Hillemanns, Peter | Hogdall, Claus K. | Hogdall, Estrid | Hosono, Satoyo | Iversen, Edwin S. | Jakubowska, Anna | Jensen, Allan | Ji, Bu-Tian | Karlan, Beth Y. | Kellar, Melissa | Kiemeney, Lambertus A. | Krakstad, Camilla | Kjaer, Susanne K. | Kupryjanczyk, Jolanta | Vierkant, Robert A. | Lambrechts, Diether | Lambrechts, Sandrina | Le, Nhu D. | Lee, Alice W. | Lele, Shashi | Leminen, Arto | Lester, Jenny | Levine, Douglas A. | Liang, Dong | Lim, Boon Kiong | Lissowska, Jolanta | Lu, Karen | Lubinski, Jan | Lundvall, Lene | Massuger, Leon F.A.G. | Matsuo, Keitaro | McGuire, Valerie | McLaughlin, John R. | McNeish, Ian | Menon, Usha | Milne, Roger L. | Modugno, Francesmary | Thomsen, Lotte | Moysich, Kirsten B. | Ness, Roberta B. | Nevanlinna, Heli | Eilber, Ursula | Odunsi, Kunle | Olson, Sara H. | Orlow, Irene | Orsulic, Sandra | Palmieri Weber, Rachel | Paul, James | Pearce, Celeste L. | Pejovic, Tanja | Pelttari, Liisa M. | Pike, Malcolm C. | Poole, Elizabeth M. | Schernhammer, Eva | Risch, Harvey A. | Rosen, Barry | Rossing, Mary Anne | Rothstein, Joseph H. | Rudolph, Anja | Runnebaum, Ingo B. | Rzepecka, Iwona K. | Salvesen, Helga B. | Schwaab, Ira | Shu, Xiao-Ou | Shvetsov, Yurii B. | Siddiqui, Nadeem | Song, Honglin | Southey, Melissa C. | Spiewankiewicz, Beata | Sucheston-Campbell, Lara | Teo, Soo-Hwang | Terry, Kathryn L. | Thompson, Pamela J. | Tangen, Ingvild L. | Tworoger, Shelley S. | van Altena, Anne M. | Vergote, Ignace | Walsh, Christine S. | Wang-Gohrke, Shan | Wentzensen, Nicolas | Whittemore, Alice S. | Wicklund, Kristine G. | Wilkens, Lynne R. | Wu, Anna H. | Wu, Xifeng | Woo, Yin-Ling | Yang, Hannah | Zheng, Wei | Ziogas, Argyrios | Amankwah, Ernest | Berchuck, Andrew | Schildkraut, Joellen M. | Kelemen, Linda E. | Ramus, Susan J. | Monteiro, Alvaro N.A. | Goode, Ellen L. | Narod, Steven A. | Gayther, Simon A. | Pharoah, Paul D. P. | Sellers, Thomas A. | Phelan, Catherine M.
Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68–0.90, p = 5.59 × 10−4]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1, may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways.
PMCID: PMC4722961  PMID: 26807442
9.  Epithelial-Mesenchymal Transition (EMT) gene variants and Epithelial Ovarian Cancer (EOC) risk 
Amankwah, Ernest K. | Lin, Hui-Yi | Tyrer, Jonathan P. | Lawrenson, Kate | Dennis, Joe | Chornokur, Ganna | Aben, Katja KH. | Anton-Culver, Hoda | Antonenkova, Natalia | Bruinsma, Fiona | Bandera, Elisa V. | Bean, Yukie T. | Beckmann, Matthias W. | Bisogna, Maria | Bjorge, Line | Bogdanova, Natalia | Brinton, Louise A. | Brooks-Wilson, Angela | Bunker, Clareann H. | Butzow, Ralf | Campbell, Ian G. | Carty, Karen | Chen, Zhihua | Chen, Y. Ann | Chang-Claude, Jenny | Cook, Linda S. | Cramer, Daniel W. | Cunningham, Julie M. | Cybulski, Cezary | Dansonka-Mieszkowska, Agnieszka | du Bois, Andreas | Despierre, Evelyn | Dicks, Ed | Doherty, Jennifer A. | Dörk, Thilo | Dürst, Matthias | Easton, Douglas F. | Eccles, Diana M. | Edwards, Robert P. | Ekici, Arif B. | Fasching, Peter A. | Fridley, Brooke L. | Gao, Yu-Tang | Gentry-Maharaj, Aleksandra | Giles, Graham G. | Glasspool, Rosalind | Goodman, Marc T. | Gronwald, Jacek | Harrington, Patricia | Harter, Philipp | Hasmad, Hanis N. | Hein, Alexander | Heitz, Florian | Hildebrandt, Michelle A.T. | Hillemanns, Peter | Hogdall, Claus K. | Hogdall, Estrid | Hosono, Satoyo | Iversen, Edwin S. | Jakubowska, Anna | Jensen, Allan | Ji, Bu-Tian | Karlan, Beth Y. | Jim, Heather | Kellar, Melissa | Kiemeney, Lambertus A. | Krakstad, Camilla | Kjaer, Susanne K. | Kupryjanczyk, Jolanta | Lambrechts, Diether | Lambrechts, Sandrina | Le, Nhu D. | Lee, Alice W. | Lele, Shashi | Leminen, Arto | Lester, Jenny | Levine, Douglas A. | Liang, Dong | Lim, Boon Kiong | Lissowska, Jolanta | Lu, Karen | Lubinski, Jan | Lundvall, Lene | Massuger, Leon F.A.G. | Matsuo, Keitaro | McGuire, Valerie | McLaughlin, John R. | McNeish, Ian | Menon, Usha | Milne, Roger L. | Modugno, Francesmary | Moysich, Kirsten B. | Ness, Roberta B. | Nevanlinna, Heli | Eilber, Ursula | Odunsi, Kunle | Olson, Sara H. | Orlow, Irene | Orsulic, Sandra | Weber, Rachel Palmieri | Paul, James | Pearce, Celeste L. | Pejovic, Tanja | Pelttari, Liisa M. | Permuth-Wey, Jennifer | Pike, Malcolm C. | Poole, Elizabeth M. | Risch, Harvey A. | Rosen, Barry | Rossing, Mary Anne | Rothstein, Joseph H. | Rudolph, Anja | Runnebaum, Ingo B. | Rzepecka, Iwona K. | Salvesen, Helga B. | Schernhammer, Eva | Schwaab, Ira | Shu, Xiao-Ou | Shvetsov, Yurii B. | Siddiqui, Nadeem | Sieh, Weiva | Song, Honglin | Southey, Melissa C. | Spiewankiewicz, Beata | Sucheston-Campbell, Lara | Teo, Soo-Hwang | Terry, Kathryn L. | Thompson, Pamela J. | Thomsen, Lotte | Tangen, Ingvild L. | Tworoger, Shelley S. | van Altena, Anne M. | Vierkant, Robert A. | Vergote, Ignace | Walsh, Christine S. | Wang-Gohrke, Shan | Wentzensen, Nicolas | Whittemore, Alice S. | Wicklund, Kristine G. | Wilkens, Lynne R. | Wu, Anna H. | Wu, Xifeng | Woo, Yin-Ling | Yang, Hannah | Zheng, Wei | Ziogas, Argyrios | Kelemen, Linda E. | Berchuck, Andrew | Schildkraut, Joellen M. | Ramus, Susan J. | Goode, Ellen L. | Monteiro, Alvaro N.A. | Gayther, Simon A. | Narod, Steven A. | Pharoah, Paul D. P. | Sellers, Thomas A. | Phelan, Catherine M.
Genetic epidemiology  2015;39(8):689-697.
Introduction
Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to EOC risk have been based on small sample sizes and none have sought replication in an independent population.
Methods
We screened 1254 SNPs in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (p<0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A p-value <0.05 and a false discovery rate (FDR) <0.2 was considered statistically significant.
Results
In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (OR=1.16, 95%CI=1.07–1.25, p=0.0003, FDR=0.19), while F8 rs7053448 (OR=1.69, 95%CI=1.27–2.24, p=0.0003, FDR=0.12), F8 rs7058826 (OR=1.69, 95%CI=1.27–2.24, p=0.0003, FDR=0.12), and CAPN13 rs1983383 (OR=0.79, 95%CI=0.69–0.90, p=0.0005, FDR=0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements.
Conclusion
These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC.
doi:10.1002/gepi.21921
PMCID: PMC4721602  PMID: 26399219
ovarian cancer; epithelial-mesenchymal transition; single nucleotide polymorphisms
10.  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
11.  A nested cohort study of 6,248 early breast cancer patients treated in neoadjuvant and adjuvant chemotherapy trials investigating the prognostic value of chemotherapy-related toxicities 
BMC Medicine  2015;13:306.
Background
The relationship between chemotherapy-related toxicities and prognosis is unclear. Previous studies have examined the association of myelosuppression parameters or neuropathy with survival and reported conflicting results. This study aims to investigate 13 common chemotherapy toxicities and their association with relapse-free survival and breast cancer-specific survival.
Methods
Chemotherapy-related toxicities were collected prospectively for 6,248 women with early-stage breast cancer from four randomised controlled trials (NEAT; BR9601; tAnGo; Neo-tAnGo). Cox proportional-hazards modelling was used to analyse the association between chemotherapy-related toxicities and both breast cancer-specific survival and relapse-free survival. Models included important prognostic factors and stratified by variables violating the proportional hazards assumption.
Results
Multivariable analysis identified severe neutropenia (grades ≥3) as an independent predictor of relapse-free survival (hazard ratio (HR) = 0.86; 95 % confidence interval (CI), 0.76–0.97; P = 0.02). A similar trend was seen for breast cancer-specific survival (HR = 0.87; 95 % CI, 0.75–1.01; P = 0.06). Normal/low BMI patients experienced more severe neutropenia (P = 0.008) than patients with higher BMI. Patients with fatigue (grades ≥3) showed a trend towards reduced survival (breast cancer-specific survival: HR = 1.17; 95 % CI, 0.99–1.37; P = 0.06). In the NEAT/BR9601 sub-group analysis by treatment component, this effect was statistically significant (HR = 1.61; 95 % CI, 1.13–2.30; P = 0.009).
Conclusions
This large study shows a significant association between chemotherapy-induced neutropenia and increased survival. It also identifies a strong relationship between low/normal BMI and increased incidence of severe neutropenia. It provides evidence to support the development of neutropenia-adapted clinical trials to investigate optimal dose calculation and its impact on clinical outcome. This is important in populations where obesity may lead to sub-optimal chemotherapy doses.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-015-0547-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12916-015-0547-5
PMCID: PMC4693418  PMID: 26715442
Adverse events; Breast cancer; Chemotherapy; Prognosis; Survival; Toxicity
13.  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
14.  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
15.  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
16.  Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk 
Kelemen, Linda E. | Terry, Kathryn L. | Goodman, Marc T. | Webb, Penelope M. | Bandera, Elisa V. | McGuire, Valerie | Rossing, Mary Anne | Wang, Qinggang | Dicks, Ed | Tyrer, Jonathan P. | Song, Honglin | Kupryjanczyk, Jolanta | Dansonka-Mieszkowska, Agnieszka | Plisiecka-Halasa, Joanna | Timorek, Agnieszka | Menon, Usha | Gentry-Maharaj, Aleksandra | Gayther, Simon A. | Ramus, Susan J. | Narod, Steven A. | Risch, Harvey A. | McLaughlin, John R. | Siddiqui, Nadeem | Glasspool, Rosalind | Paul, James | Carty, Karen | Gronwald, Jacek | Lubiński, Jan | Jakubowska, Anna | Cybulski, Cezary | Kiemeney, Lambertus A. | Massuger, Leon F. A. G. | van Altena, Anne M. | Aben, Katja K. H. | Olson, Sara H. | Orlow, Irene | Cramer, Daniel W. | Levine, Douglas A. | Bisogna, Maria | Giles, Graham G. | Southey, Melissa C. | Bruinsma, Fiona | Kjær, Susanne Krüger | Høgdall, Estrid | Jensen, Allan | Høgdall, Claus K. | Lundvall, Lene | Engelholm, Svend-Aage | Heitz, Florian | du Bois, Andreas | Harter, Philipp | Schwaab, Ira | Butzow, Ralf | Nevanlinna, Heli | Pelttari, Liisa M. | Leminen, Arto | Thompson, Pamela J. | Lurie, Galina | Wilkens, Lynne R. | Lambrechts, Diether | Van Nieuwenhuysen, Els | Lambrechts, Sandrina | Vergote, Ignace | Beesley, Jonathan | Fasching, Peter A. | Beckmann, Matthias W. | Hein, Alexander | Ekici, Arif B. | Doherty, Jennifer A. | Wu, Anna H. | Pearce, Celeste L. | Pike, Malcolm C. | Stram, Daniel | Chang-Claude, Jenny | Rudolph, Anja | Dörk, Thilo | Dürst, Matthias | Hillemanns, Peter | Runnebaum, Ingo B. | Bogdanova, Natalia | Antonenkova, Natalia | Odunsi, Kunle | Edwards, Robert P. | Kelley, Joseph L. | Modugno, Francesmary | Ness, Roberta B. | Karlan, Beth Y. | Walsh, Christine | Lester, Jenny | Orsulic, Sandra | Fridley, Brooke L. | Vierkant, Robert A. | Cunningham, Julie M. | Wu, Xifeng | Lu, Karen | Liang, Dong | Hildebrandt, Michelle A.T. | Weber, Rachel Palmieri | Iversen, Edwin S. | Tworoger, Shelley S. | Poole, Elizabeth M. | Salvesen, Helga B. | Krakstad, Camilla | Bjorge, Line | Tangen, Ingvild L. | Pejovic, Tanja | Bean, Yukie | Kellar, Melissa | Wentzensen, Nicolas | Brinton, Louise A. | Lissowska, Jolanta | Garcia-Closas, Montserrat | Campbell, Ian G. | Eccles, Diana | Whittemore, Alice S. | Sieh, Weiva | Rothstein, Joseph H. | Anton-Culver, Hoda | Ziogas, Argyrios | Phelan, Catherine M. | Moysich, Kirsten B. | Goode, Ellen L. | Schildkraut, Joellen M. | Berchuck, Andrew | Pharoah, Paul D.P. | Sellers, Thomas A. | Brooks-Wilson, Angela | Cook, Linda S. | Le, Nhu D.
Molecular nutrition & food research  2014;58(10):2023-2035.
Scope
We re-evaluated previously reported associations between variants in pathways of one-carbon (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake.
Methods and Results
Odds ratios (OR) for 446 genetic variants were estimated among 13,410 OC cases and 22,635 controls and among 2,281 cases and 3,444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for DPYD variants rs11587873 (OR=0.92, P=6x10−5) and rs828054 (OR=1.06, P=1x10−4). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT and TYMS, also interacted significantly with folate in a multi-variant analysis (corrected P=9.9x10−6) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in one-carbon transfer, previously reported with OC, suggested lower risk at higher folate (Pinteraction=0.03-0.006).
Conclusions
Variation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP-byfolate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.
doi:10.1002/mnfr.201400068
PMCID: PMC4197821  PMID: 25066213
case-control; DPYD; folate; polymorphism; SHMT1
17.  The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population 
Human Molecular Genetics  2014;23(17):4703-4709.
The aim of this study was to estimate the contribution of deleterious mutations in BRCA1, BRCA2, MLH1, MSH2, MSH6 and PMS2 to invasive epithelial ovarian cancer (EOC) in the population. The coding sequence and splice site boundaries of all six genes were amplified in germline DNA from 2240 invasive EOC cases and 1535 controls. Barcoded fragment libraries were sequenced using the Illumina GAII or HiSeq and sequence data for each subject de-multiplexed prior to interpretation. GATK and Annovar were used for variant detection and annotation. After quality control 2222 cases (99.2%) and 1528 controls (99.5%) were included in the final analysis. We identified 193 EOC cases (8.7%) carrying a deleterious mutation in at least one gene compared with 10 controls (0.65%). Mutations were most frequent in BRCA1 and BRCA2, with 84 EOC cases (3.8%) carrying a BRCA1 mutation and 94 EOC cases (4.2%) carrying a BRCA2 mutation. The combined BRCA1 and BRCA2 mutation prevalence was 11% in high-grade serous disease. Seventeen EOC cases carried a mutation in a mismatch repair gene, including 10 MSH6 mutation carriers (0.45%) and 4 MSH2 mutation carriers (0.18%). At least 1 in 10 women with high-grade serous EOC has a BRCA1 or BRCA2 mutation. The development of next generation sequencing technologies enables rapid mutation screening for multiple susceptibility genes at once, suggesting that routine clinical testing of all incidence cases should be considered.
doi:10.1093/hmg/ddu172
PMCID: PMC4119409  PMID: 24728189
18.  A comprehensive evaluation of interaction between genetic variants and use of menopausal hormone therapy on mammographic density 
Introduction
Mammographic density is an established breast cancer risk factor with a strong genetic component and can be increased in women using menopausal hormone therapy (MHT). Here, we aimed to identify genetic variants that may modify the association between MHT use and mammographic density.
Methods
The study comprised 6,298 postmenopausal women from the Mayo Mammography Health Study and nine studies included in the Breast Cancer Association Consortium. We selected for evaluation 1327 single nucleotide polymorphisms (SNPs) showing the lowest P-values for interaction (Pint) in a meta-analysis of genome-wide gene-environment interaction studies with MHT use on risk of breast cancer, 2541 SNPs in candidate genes (AKR1C4, CYP1A1-CYP1A2, CYP1B1, ESR2, PPARG, PRL, SULT1A1-SULT1A2 and TNF) and ten SNPs (AREG-rs10034692, PRDM6-rs186749, ESR1-rs12665607, ZNF365-rs10995190, 8p11.23-rs7816345, LSP1-rs3817198, IGF1-rs703556, 12q24-rs1265507, TMEM184B-rs7289126, and SGSM3-rs17001868) associated with mammographic density in genome-wide studies. We used multiple linear regression models adjusted for potential confounders to evaluate interactions between SNPs and current use of MHT on mammographic density.
Results
No significant interactions were identified after adjustment for multiple testing. The strongest SNP-MHT interaction (unadjusted Pint <0.0004) was observed with rs9358531 6.5kb 5′ of PRL. Furthermore, three SNPs in PLCG2 that had previously been shown to modify the association of MHT use with breast cancer risk were found to modify also the association of MHT use with mammographic density (unadjusted Pint <0.002), but solely among cases (unadjusted Pint SNP×MHT×case-status <0.02).
Conclusions
The study identified potential interactions on mammographic density between current use of MHT and SNPs near PRL and in PLCG2, which require confirmation. Given the moderate size of the interactions observed, larger studies are needed to identify genetic modifiers of the association of MHT use with mammographic density.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-015-0625-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-015-0625-9
PMCID: PMC4537547  PMID: 26275715
19.  Annexin A1 expression in a pooled breast cancer series: association with tumor subtypes and prognosis 
BMC Medicine  2015;13:156.
Background
Annexin A1 (ANXA1) is a protein related with the carcinogenesis process and metastasis formation in many tumors. However, little is known about the prognostic value of ANXA1 in breast cancer. The purpose of this study is to evaluate the association between ANXA1 expression, BRCA1/2 germline carriership, specific tumor subtypes and survival in breast cancer patients.
Methods
Clinical-pathological information and follow-up data were collected from nine breast cancer studies from the Breast Cancer Association Consortium (BCAC) (n = 5,752) and from one study of familial breast cancer patients with BRCA1/2 mutations (n = 107). ANXA1 expression was scored based on the percentage of immunohistochemical staining in tumor cells. Survival analyses were performed using a multivariable Cox model.
Results
The frequency of ANXA1 positive tumors was higher in familial breast cancer patients with BRCA1/2 mutations than in BCAC patients, with 48.6 % versus 12.4 %, respectively; P <0.0001. ANXA1 was also highly expressed in BCAC tumors that were poorly differentiated, triple negative, EGFR-CK5/6 positive or had developed in patients at a young age. In the first 5 years of follow-up, patients with ANXA1 positive tumors had a worse breast cancer-specific survival (BCSS) than ANXA1 negative (HRadj = 1.35; 95 % CI = 1.05–1.73), but the association weakened after 10 years (HRadj = 1.13; 95 % CI = 0.91–1.40). ANXA1 was a significant independent predictor of survival in HER2+ patients (10-years BCSS: HRadj = 1.70; 95 % CI = 1.17–2.45).
Conclusions
ANXA1 is overexpressed in familial breast cancer patients with BRCA1/2 mutations and correlated with poor prognosis features: triple negative and poorly differentiated tumors. ANXA1 might be a biomarker candidate for breast cancer survival prediction in high risk groups such as HER2+ cases.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-015-0392-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s12916-015-0392-6
PMCID: PMC4489114  PMID: 26137966
Breast cancer; Annexin A1; BRCA1 and BRCA2 mutations
20.  Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers 
Peterlongo, Paolo | Chang-Claude, Jenny | Moysich, Kirsten B. | Rudolph, Anja | Schmutzler, Rita K. | Simard, Jacques | Soucy, Penny | Eeles, Rosalind A. | Easton, Douglas F. | Hamann, Ute | Wilkening, Stefan | Chen, Bowang | Rookus, Matti A. | Schmidt, Marjanka K | van der Baan, Frederieke H. | Spurdle, Amanda B. | Walker, Logan C. | Lose, Felicity | Maia, Ana-Teresa | Montagna, Marco | Matricardi, Laura | Lubinski, Jan | Jakubowska, Anna | Gómez Garcia, Encarna B. | Olopade, Olufunmilayo I. | Nussbaum, Robert L. | Nathanson, Katherine L. | Domchek, Susan M. | Rebbeck, Timothy R. | Arun, Banu K. | Karlan, Beth Y. | Orsulic, Sandra | Lester, Jenny | Chung, Wendy K. | Miron, Alex | Southey, Melissa C. | Goldgar, David E. | Buys, Saundra S. | Janavicius, Ramunas | Dorfling, Cecilia M. | van Rensburg, Elizabeth J. | Ding, Yuan Chun | Neuhausen, Susan L. | Hansen, Thomas V. O. | Gerdes, Anne-Marie | Ejlertsen, Bent | Jønson, Lars | Osorio, Ana | Martínez-Bouzas, Cristina | Benitez, Javier | Conway, Edye E. | Blazer, Kathleen R. | Weitzel, Jeffrey N. | Manoukian, Siranoush | Peissel, Bernard | Zaffaroni, Daniela | Scuvera, Giulietta | Barile, Monica | Ficarazzi, Filomena | Mariette, Frederique | Fortuzzi, Stefano | Viel, Alessandra | Giannini, Giuseppe | Papi, Laura | Martayan, Aline | Tibiletti, Maria Grazia | Radice, Paolo | Vratimos, Athanassios | Fostira, Florentia | Garber, Judy E. | Donaldson, Alan | Brewer, Carole | Foo, Claire | Evans, D. Gareth R. | Frost, Debra | Eccles, Diana | Brady, Angela | Cook, Jackie | Tischkowitz, Marc | Adlard, Julian | Barwell, Julian | Walker, Lisa | Izatt, Louise | Side, Lucy E. | Kennedy, M. John | Rogers, Mark T. | Porteous, Mary E. | Morrison, Patrick J. | Platte, Radka | Davidson, Rosemarie | Hodgson, Shirley V. | Ellis, Steve | Cole, Trevor | Godwin, Andrew K. | Claes, Kathleen | Van Maerken, Tom | Meindl, Alfons | Gehrig, Andrea | Sutter, Christian | Engel, Christoph | Niederacher, Dieter | Steinemann, Doris | Plendl, Hansjoerg | Kast, Karin | Rhiem, Kerstin | Ditsch, Nina | Arnold, Norbert | Varon-Mateeva, Raymonda | Wappenschmidt, Barbara | Wang-Gohrke, Shan | Paillerets, Brigitte Bressac-de | Buecher, Bruno | Delnatte, Capucine | Houdayer, Claude | Stoppa-Lyonnet, Dominique | Damiola, Francesca | Coupier, Isabelle | Barjhoux, Laure | Venat-Bouvet, Laurence | Golmard, Lisa | Boutry-Kryza, Nadia | Sinilnikova, Olga M. | Caron, Olivier | Pujol, Pascal | Mazoyer, Sylvie | Belotti, Muriel | Piedmonte, Marion | Friedlander, Michael L. | Rodriguez, Gustavo C. | Copeland, Larry J | de la Hoya, Miguel | Segura, Pedro Perez | Nevanlinna, Heli | Aittomäki, Kristiina | van Os, Theo A.M. | Meijers-Heijboer, Hanne E.J. | van der Hout, Annemarie H. | Vreeswijk, Maaike P.G. | Hoogerbrugge, Nicoline | Ausems, Margreet G.E.M. | van Doorn, Helena C. | Collée, J. Margriet | Olah, Edith | Diez, Orland | Blanco, Ignacio | Lazaro, Conxi | Brunet, Joan | Feliubadalo, Lidia | Cybulski, Cezary | Gronwald, Jacek | Durda, Katarzyna | Jaworska-Bieniek, Katarzyna | Sukiennicki, Grzegorz | Arason, Adalgeir | Chiquette, Jocelyne | Teixeira, Manuel R. | Olswold, Curtis | Couch, Fergus J. | Lindor, Noralane M. | Wang, Xianshu | Szabo, Csilla I. | Offit, Kenneth | Corines, Marina | Jacobs, Lauren | Robson, Mark E. | Zhang, Liying | Joseph, Vijai | Berger, Andreas | Singer, Christian F. | Rappaport, Christine | Kaulich, Daphne Geschwantler | Pfeiler, Georg | Tea, Muy-Kheng M. | Phelan, Catherine M. | Greene, Mark H. | Mai, Phuong L. | Rennert, Gad | Mulligan, Anna Marie | Glendon, Gord | Tchatchou, Sandrine | Andrulis, Irene L. | Toland, Amanda Ewart | Bojesen, Anders | Pedersen, Inge Sokilde | Thomassen, Mads | Jensen, Uffe Birk | Laitman, Yael | Rantala, Johanna | von Wachenfeldt, Anna | Ehrencrona, Hans | Askmalm, Marie Stenmark | Borg, Åke | Kuchenbaecker, Karoline B. | McGuffog, Lesley | Barrowdale, Daniel | Healey, Sue | Lee, Andrew | Pharoah, Paul D.P. | Chenevix-Trench, Georgia | Antoniou, Antonis C. | Friedman, Eitan
Background
BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and non-genetic modifying factors. In this study we evaluated the putative role of variants in many candidate modifier genes.
Methods
Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n=3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach.
Results
The observed p-values of association ranged between 0.005–1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments.
Conclusion
There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers.
Impact
Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.
doi:10.1158/1055-9965.EPI-14-0532
PMCID: PMC4294951  PMID: 25336561
BRCA1 BRCA2 mutations; BRCA-mutation carriers; Breast cancer risk; Ovarian cancer risk; Candidate genetic risk modifiers
21.  Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers 
Peterlongo, Paolo | Chang-Claude, Jenny | Moysich, Kirsten B. | Rudolph, Anja | Schmutzler, Rita K. | Simard, Jacques | Soucy, Penny | Eeles, Rosalind A. | Easton, Douglas F. | Hamann, Ute | Wilkening, Stefan | Chen, Bowang | Rookus, Matti A. | Schmidt, Marjanka K | van der Baan, Frederieke H. | Spurdle, Amanda B. | Walker, Logan C. | Lose, Felicity | Maia, Ana-Teresa | Montagna, Marco | Matricardi, Laura | Lubinski, Jan | Jakubowska, Anna | Gómez Garcia, Encarna B. | Olopade, Olufunmilayo I. | Nussbaum, Robert L. | Nathanson, Katherine L. | Domchek, Susan M. | Rebbeck, Timothy R. | Arun, Banu K. | Karlan, Beth Y. | Orsulic, Sandra | Lester, Jenny | Chung, Wendy K. | Miron, Alex | Southey, Melissa C. | Goldgar, David E. | Buys, Saundra S. | Janavicius, Ramunas | Dorfling, Cecilia M. | van Rensburg, Elizabeth J. | Ding, Yuan Chun | Neuhausen, Susan L. | Hansen, Thomas V. O. | Gerdes, Anne-Marie | Ejlertsen, Bent | Jønson, Lars | Osorio, Ana | Martínez-Bouzas, Cristina | Benitez, Javier | Conway, Edye E. | Blazer, Kathleen R. | Weitzel, Jeffrey N. | Manoukian, Siranoush | Peissel, Bernard | Zaffaroni, Daniela | Scuvera, Giulietta | Barile, Monica | Ficarazzi, Filomena | Mariette, Frederique | Fortuzzi, Stefano | Viel, Alessandra | Giannini, Giuseppe | Papi, Laura | Martayan, Aline | Tibiletti, Maria Grazia | Radice, Paolo | Vratimos, Athanassios | Fostira, Florentia | Garber, Judy E. | Donaldson, Alan | Brewer, Carole | Foo, Claire | Evans, D. Gareth R. | Frost, Debra | Eccles, Diana | Brady, Angela | Cook, Jackie | Tischkowitz, Marc | Adlard, Julian | Barwell, Julian | Walker, Lisa | Izatt, Louise | Side, Lucy E. | Kennedy, M. John | Rogers, Mark T. | Porteous, Mary E. | Morrison, Patrick J. | Platte, Radka | Davidson, Rosemarie | Hodgson, Shirley V. | Ellis, Steve | Cole, Trevor | Godwin, Andrew K. | Claes, Kathleen | Van Maerken, Tom | Meindl, Alfons | Gehrig, Andrea | Sutter, Christian | Engel, Christoph | Niederacher, Dieter | Steinemann, Doris | Plendl, Hansjoerg | Kast, Karin | Rhiem, Kerstin | Ditsch, Nina | Arnold, Norbert | Varon-Mateeva, Raymonda | Wappenschmidt, Barbara | Wang-Gohrke, Shan | Bressac-de Paillerets, Brigitte | Buecher, Bruno | Delnatte, Capucine | Houdayer, Claude | Stoppa-Lyonnet, Dominique | Damiola, Francesca | Coupier, Isabelle | Barjhoux, Laure | Venat-Bouvet, Laurence | Golmard, Lisa | Boutry-Kryza, Nadia | Sinilnikova, Olga M. | Caron, Olivier | Pujol, Pascal | Mazoyer, Sylvie | Belotti, Muriel | Piedmonte, Marion | Friedlander, Michael L. | Rodriguez, Gustavo C. | Copeland, Larry J | de la Hoya, Miguel | Segura, Pedro Perez | Nevanlinna, Heli | Aittomäki, Kristiina | van Os, Theo A.M. | Meijers-Heijboer, Hanne E.J. | van der Hout, Annemarie H. | Vreeswijk, Maaike P.G. | Hoogerbrugge, Nicoline | Ausems, Margreet G.E.M. | van Doorn, Helena C. | Collée, J. Margriet | Olah, Edith | Diez, Orland | Blanco, Ignacio | Lazaro, Conxi | Brunet, Joan | Feliubadalo, Lidia | Cybulski, Cezary | Gronwald, Jacek | Durda, Katarzyna | Jaworska-Bieniek, Katarzyna | Sukiennicki, Grzegorz | Arason, Adalgeir | Chiquette, Jocelyne | Teixeira, Manuel R. | Olswold, Curtis | Couch, Fergus J. | Lindor, Noralane M. | Wang, Xianshu | Szabo, Csilla I. | Offit, Kenneth | Corines, Marina | Jacobs, Lauren | Robson, Mark E. | Zhang, Liying | Joseph, Vijai | Berger, Andreas | Singer, Christian F. | Rappaport, Christine | Kaulich, Daphne Geschwantler | Pfeiler, Georg | Tea, Muy-Kheng M. | Phelan, Catherine M. | Greene, Mark H. | Mai, Phuong L. | Rennert, Gad | Mulligan, Anna Marie | Glendon, Gord | Tchatchou, Sandrine | Andrulis, Irene L. | Toland, Amanda Ewart | Bojesen, Anders | Pedersen, Inge Sokilde | Thomassen, Mads | Jensen, Uffe Birk | Laitman, Yael | Rantala, Johanna | von Wachenfeldt, Anna | Ehrencrona, Hans | Askmalm, Marie Stenmark | Borg, Åke | Kuchenbaecker, Karoline B. | McGuffog, Lesley | Barrowdale, Daniel | Healey, Sue | Lee, Andrew | Pharoah, Paul D.P. | Chenevix-Trench, Georgia | Antoniou, Antonis C. | Friedman, Eitan
Background
BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and non-genetic modifying factors. In this study we evaluated the putative role of variants in many candidate modifier genes.
Methods
Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n=3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach.
Results
The observed p-values of association ranged between 0.005-1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments.
Conclusion
There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers.
Impact
Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.
doi:10.1158/1055-9965.EPI-14-0532
PMCID: PMC4294951  PMID: 25336561
BRCA1 BRCA2 mutations; BRCA-mutation carriers, Breast cancer risk; Ovarian cancer risk; Candidate genetic risk modifiers
22.  Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk 
Chornokur, Ganna | Lin, Hui-Yi | Tyrer, Jonathan P. | Lawrenson, Kate | Dennis, Joe | Amankwah, Ernest K. | Qu, Xiaotao | Tsai, Ya-Yu | Jim, Heather S. L. | Chen, Zhihua | Chen, Ann Y. | Permuth-Wey, Jennifer | Aben, Katja KH. | Anton-Culver, Hoda | Antonenkova, Natalia | Bruinsma, Fiona | Bandera, Elisa V. | Bean, Yukie T. | Beckmann, Matthias W. | Bisogna, Maria | Bjorge, Line | Bogdanova, Natalia | Brinton, Louise A. | Brooks-Wilson, Angela | Bunker, Clareann H. | Butzow, Ralf | Campbell, Ian G. | Carty, Karen | Chang-Claude, Jenny | Cook, Linda S. | Cramer, Daniel W. | Cunningham, Julie M. | Cybulski, Cezary | Dansonka-Mieszkowska, Agnieszka | du Bois, Andreas | Despierre, Evelyn | Dicks, Ed | Doherty, Jennifer A. | Dörk, Thilo | Dürst, Matthias | Easton, Douglas F. | Eccles, Diana M. | Edwards, Robert P. | Ekici, Arif B. | Fasching, Peter A. | Fridley, Brooke L. | Gao, Yu-Tang | Gentry-Maharaj, Aleksandra | Giles, Graham G. | Glasspool, Rosalind | Goodman, Marc T. | Gronwald, Jacek | Harrington, Patricia | Harter, Philipp | Hein, Alexander | Heitz, Florian | Hildebrandt, Michelle A. T. | Hillemanns, Peter | Hogdall, Claus K. | Hogdall, Estrid | Hosono, Satoyo | Jakubowska, Anna | Jensen, Allan | Ji, Bu-Tian | Karlan, Beth Y. | Kelemen, Linda E. | Kellar, Mellissa | Kiemeney, Lambertus A. | Krakstad, Camilla | Kjaer, Susanne K. | Kupryjanczyk, Jolanta | Lambrechts, Diether | Lambrechts, Sandrina | Le, Nhu D. | Lee, Alice W. | Lele, Shashi | Leminen, Arto | Lester, Jenny | Levine, Douglas A. | Liang, Dong | Lim, Boon Kiong | Lissowska, Jolanta | Lu, Karen | Lubinski, Jan | Lundvall, Lene | Massuger, Leon F. A. G. | Matsuo, Keitaro | McGuire, Valerie | McLaughlin, John R. | McNeish, Iain | Menon, Usha | Milne, Roger L. | Modugno, Francesmary | Moysich, Kirsten B. | Ness, Roberta B. | Nevanlinna, Heli | Eilber, Ursula | Odunsi, Kunle | Olson, Sara H. | Orlow, Irene | Orsulic, Sandra | Weber, Rachel Palmieri | Paul, James | Pearce, Celeste L. | Pejovic, Tanja | Pelttari, Liisa M. | Pike, Malcolm C. | Poole, Elizabeth M. | Risch, Harvey A. | Rosen, Barry | Rossing, Mary Anne | Rothstein, Joseph H. | Rudolph, Anja | Runnebaum, Ingo B. | Rzepecka, Iwona K. | Salvesen, Helga B. | Schernhammer, Eva | Schwaab, Ira | Shu, Xiao-Ou | Shvetsov, Yurii B. | Siddiqui, Nadeem | Sieh, Weiva | Song, Honglin | Southey, Melissa C. | Spiewankiewicz, Beata | Sucheston, Lara | Teo, Soo-Hwang | Terry, Kathryn L. | Thompson, Pamela J. | Thomsen, Lotte | Tangen, Ingvild L. | Tworoger, Shelley S. | van Altena, Anne M. | Vierkant, Robert A. | Vergote, Ignace | Walsh, Christine S. | Wang-Gohrke, Shan | Wentzensen, Nicolas | Whittemore, Alice S. | Wicklund, Kristine G. | Wilkens, Lynne R. | Wu, Anna H. | Wu, Xifeng | Woo, Yin-Ling | Yang, Hannah | Zheng, Wei | Ziogas, Argyrios | Hasmad, Hanis N. | Berchuck, Andrew | Iversen, Edwin S. | Schildkraut, Joellen M. | Ramus, Susan J. | Goode, Ellen L. | Monteiro, Alvaro N. A. | Gayther, Simon A. | Narod, Steven A. | Pharoah, Paul D. P. | Sellers, Thomas A. | Phelan, Catherine M.
PLoS ONE  2015;10(6):e0128106.
Background
Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk.
Methods
In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons.
Results
The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4).
Conclusion
These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.
doi:10.1371/journal.pone.0128106
PMCID: PMC4474865  PMID: 26091520
23.  Crowdsourcing the General Public for Large Scale Molecular Pathology Studies in Cancer 
EBioMedicine  2015;2(7):681-689.
Background
Citizen science, scientific research conducted by non-specialists, has the potential to facilitate biomedical research using available large-scale data, however validating the results is challenging. The Cell Slider is a citizen science project that intends to share images from tumors with the general public, enabling them to score tumor markers independently through an internet-based interface.
Methods
From October 2012 to June 2014, 98,293 Citizen Scientists accessed the Cell Slider web page and scored 180,172 sub-images derived from images of 12,326 tissue microarray cores labeled for estrogen receptor (ER). We evaluated the accuracy of Citizen Scientist's ER classification, and the association between ER status and prognosis by comparing their test performance against trained pathologists.
Findings
The area under ROC curve was 0.95 (95% CI 0.94 to 0.96) for cancer cell identification and 0.97 (95% CI 0.96 to 0.97) for ER status. ER positive tumors scored by Citizen Scientists were associated with survival in a similar way to that scored by trained pathologists. Survival probability at 15 years were 0.78 (95% CI 0.76 to 0.80) for ER-positive and 0.72 (95% CI 0.68 to 0.77) for ER-negative tumors based on Citizen Scientists classification. Based on pathologist classification, survival probability was 0.79 (95% CI 0.77 to 0.81) for ER-positive and 0.71 (95% CI 0.67 to 0.74) for ER-negative tumors. The hazard ratio for death was 0.26 (95% CI 0.18 to 0.37) at diagnosis and became greater than one after 6.5 years of follow-up for ER scored by Citizen Scientists, and 0.24 (95% CI 0.18 to 0.33) at diagnosis increasing thereafter to one after 6.7 (95% CI 4.1 to 10.9) years of follow-up for ER scored by pathologists.
Interpretation
Crowdsourcing of the general public to classify cancer pathology data for research is viable, engages the public and provides accurate ER data. Crowdsourced classification of research data may offer a valid solution to problems of throughput requiring human input.
Highlights
•Crowdsourcing of the general public to classify estrogen receptor in breast tumors was evaluated.•More than 95 thousand volunteers participated of the project over two years.•Citizen Scientists were able to classify estrogen receptors with high accuracy.•The estrogen receptor score assigned by Citizens Scientists was associated with breast cancer patient survival.
doi:10.1016/j.ebiom.2015.05.009
PMCID: PMC4534635  PMID: 26288840
Citizen science; Crowd science; Crowdsourcing; Breast cancer
24.  Genome-wide Association Study of Subtype-Specific Epithelial Ovarian Cancer Risk Alleles Using Pooled DNA 
Earp, Madalene A. | Kelemen, Linda E. | Magliocco, Anthony M. | Swenerton, Kenneth D. | Chenevix–Trench, Georgia | Lu, Yi | Hein, Alexander | Ekici, Arif B. | Beckmann, Matthias W. | Fasching, Peter A. | Lambrechts, Diether | Despierre, Evelyn | Vergote, Ignace | Lambrechts, Sandrina | Doherty, Jennifer A. | Rossing, Mary Anne | Chang-Claude, Jenny | Rudolph, Anja | Friel, Grace | Moysich, Kirsten B. | Odunsi, Kunle | Sucheston-Campbell, Lara | Lurie, Galina | Goodman, Marc T. | Carney, Michael E. | Thompson, Pamela J. | Runnebaum, Ingo B. | Dürst, Matthias | Hillemanns, Peter | Dörk, Thilo | Antonenkova, Natalia | Bogdanova, Natalia | Leminen, Arto | Nevanlinna, Heli | Pelttari, Liisa M. | Butzow, Ralf | Bunker, Clareann H. | Modugno, Francesmary | Edwards, Robert P. | Ness, Roberta B. | du Bois, Andreas | Heitz, Florian | Schwaab, Ira | Harter, Philipp | Karlan, Beth Y. | Walsh, Christine | Lester, Jenny | Jensen, Allan | Kjær, Susanne K. | Høgdall, Claus K. | Høgdall, Estrid | Lundvall, Lene | Sellers, Thomas A. | Fridley, Brooke L. | Goode, Ellen L. | Cunningham, Julie M. | Vierkant, Robert A. | Giles, Graham G. | Baglietto, Laura | Severi, Gianluca | Southey, Melissa C. | Liang, Dong | Wu, Xifeng | Lu, Karen | Hildebrandt, Michelle A.T. | Levine, Douglas A. | Bisogna, Maria | Schildkraut, Joellen M. | Iversen, Edwin S. | Weber, Rachel Palmieri | Berchuck, Andrew | Cramer, Daniel W. | Terry, Kathryn L. | Poole, Elizabeth M. | Tworoger, Shelley S. | Bandera, Elisa V. | Chandran, Urmila | Orlow, Irene | Olson, Sara H. | Wik, Elisabeth | Salvesen, Helga B. | Bjorge, Line | Halle, Mari K. | van Altena, Anne M. | Aben, Katja K.H. | Kiemeney, Lambertus A. | Massuger, Leon F.A.G. | Pejovic, Tanja | Bean, Yukie T. | Cybulski, Cezary | Gronwald, Jacek | Lubinski, Jan | Wentzensen, Nicolas | Brinton, Louise A. | Lissowska, Jolanta | Garcia–Closas, Montserrat | Dicks, Ed | Dennis, Joe | Easton, Douglas F. | Song, Honglin | Tyrer, Jonathan P. | Pharoah, Paul D. P. | Eccles, Diana | Campbell, Ian G. | Whittemore, Alice S. | McGuire, Valerie | Sieh, Weiva | Rothstein, Joseph H. | Flanagan, James M. | Paul, James | Brown, Robert | Phelan, Catherine M. | Risch, Harvey A. | McLaughlin, John R. | Narod, Steven A. | Ziogas, Argyrios | Anton-Culver, Hoda | Gentry-Maharaj, Aleksandra | Menon, Usha | Gayther, Simon A. | Ramus, Susan J. | Wu, Anna H. | Pearce, Celeste L. | Pike, Malcolm C. | Dansonka-Mieszkowska, Agnieszka | Rzepecka, Iwona K | Szafron, Lukasz M | Kupryjanczyk, Jolanta | Cook, Linda S. | Le, Nhu D. | Brooks–Wilson, Angela
Human genetics  2013;133(5):481-497.
Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS (56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low malignant potential (LMP) serous, and 24 for invasive serous EOC), selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95% confidence intervals are reported. Nine variants tagging 6 loci were associated with subtype-specific EOC risk at P<0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR=1.17, P=0.029, n=1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P=0.014, n=2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR=0.86, P=0.0043, n=892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR=0.84, P=0.0007) and LMP serous EOC risk remained statistically significant at P<0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes.
doi:10.1007/s00439-013-1383-3
PMCID: PMC4063682  PMID: 24190013
histological subtype; serous; endometrioid; clear cell; mucinous; BPIL2
25.  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

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