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2.  Personalized screening for cancers: should we consider polygenic profiling? 
Personalized medicine  2013;10(6):10.2217/pme.13.46.
Summary
Polygenic profiling and risk stratification for population-based screening for cancer improve the efficiency of the screening programs. Translation of genomics into personalized screening programs requires evidence from empirical research on the balance of benefits and harms of personalized screening, and engagement with the public, professionals and policy makers.
doi:10.2217/pme.13.46
PMCID: PMC3837202  PMID: 24273588
Polygenic profiling; personalized screening; cancer
3.  ABO blood group and risk of epithelial ovarian cancer within the Ovarian Cancer Association Consortium 
Cancer causes & control : CCC  2012;23(11):1805-1810.
Purpose
Previous studies have examined the association between ABO blood group and ovarian cancer risk, with inconclusive results.
Methods
In 8 studies participating in the Ovarian Cancer Association Consortium (OCAC), we determined ABO blood groups and diplotypes by genotyping 3 SNPs in the ABO locus. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated in each study using logistic regression; individual study results were combined using random effects meta-analysis.
Results
Compared to blood group O, the A blood group was associated with a modestly increased ovarian cancer risk: (OR: 1.09; 95% CI: 1.01–1.18; p=0.03). In diplotype analysis, the AO, but not the AA diplotype was associated with increased risk (AO: OR: 1.11; 95% CI: 1.01–1.22; p=0.03; AA: OR: 1.03; 95% CI: 0.87–1.21; p=0.76). Neither AB nor the B blood groups were associated with risk. Results were similar across ovarian cancer histologic subtypes.
Conclusion
Consistent with most previous reports, the A blood type was associated modestly with increased ovarian cancer risk in this large analysis of multiple studies of ovarian cancer. Future studies investigating potential biologic mechanisms are warranted.
doi:10.1007/s10552-012-0059-y
PMCID: PMC3474344  PMID: 22961099
ovarian cancer; ABO blood group; Ovarian Cancer Association Consortium (OCAC); genetic epidemiology
4.  Analysis of Over 10,000 Cases Finds No Association between Previously-Reported Candidate Polymorphisms and Ovarian Cancer Outcome 
White, Kristin L. | Vierkant, Robert A. | Fogarty, Zachary C. | Charbonneau, Bridget | Block, Matthew S. | Pharoah, Paul D.P. | Chenevix-Trench, Georgia | Rossing, Mary Anne | Cramer, Daniel W. | Pearce, C. Leigh | Schildkraut, Joellen M. | Menon, Usha | Kjaer, Susanne Kruger | Levine, Douglas A. | Gronwald, Jacek | Culver, Hoda Anton | Whittemore, Alice S. | Karlan, Beth Y. | Lambrechts, Diether | Wentzensen, Nicolas | Kupryjanczyk, Jolanta | Chang-Claude, Jenny | Bandera, Elisa V. | Hogdall, Estrid | Heitz, Florian | Kaye, Stanley B. | Fasching, Peter A. | Campbell, Ian | Goodman, Marc T. | Pejovic, Tanja | Bean, Yukie | Lurie, Galina | Eccles, Diana | Hein, Alexander | Beckmann, Matthias W. | Ekici, Arif B. | Paul, James | Brown, Robert | Flanagan, James | Harter, Philipp | du Bois, Andreas | Schwaab, Ira | Hogdall, Claus K. | Lundvall, Lene | Olson, Sara H. | Orlow, Irene | Paddock, Lisa E. | Rudolph, Anja | Eilber, Ursula | Dansonka-Mieszkowska, Agnieszka | Rzepecka, Iwona K. | Ziolkowska-Seta, Izabela | Brinton, Louise | Yang, Hannah | Garcia-Closas, Montserrat | Despierre, Evelyn | Lambrechts, Sandrina | Vergote, Ignace | Walsh, Christine | Lester, Jenny | Sieh, Weiva | McGuire, Valerie | Rothstein, Joseph H. | Ziogas, Argyrios | Lubiński, Jan | Cybulski, Cezary | Menkiszak, Janusz | Jensen, Allan | Gayther, Simon A. | Ramus, Susan J. | Gentry-Maharaj, Aleksandra | Berchuck, Andrew | Wu, Anna H. | Pike, Malcolm C. | Van Den Berg, David | Terry, Kathryn L. | Vitonis, Allison F. | Doherty, Jennifer A. | Johnatty, Sharon | deFazio, Anna | Song, Honglin | Tyrer, Jonathan | Sellers, Thomas A. | Phelan, Catherine M. | Kalli, Kimberly R. | Cunningham, Julie M. | Fridley, Brooke L. | Goode, Ellen L.
Background
Ovarian cancer is a leading cause of cancer-related death among women. In an effort to understand contributors to disease outcome, we evaluated single-nucleotide polymorphisms (SNPs) previously associated with ovarian cancer recurrence or survival, specifically in angiogenesis, inflammation, mitosis, and drug disposition genes.
Methods
Twenty-seven SNPs in VHL, HGF, IL18, PRKACB, ABCB1, CYP2C8, ERCC2, and ERCC1 previously associated with ovarian cancer outcome were genotyped in 10,084 invasive cases from 28 studies from the Ovarian Cancer Association Consortium with over 37,000 observed person-years and 4,478 deaths. Cox proportional hazards models were used to examine the association between candidate SNPs and ovarian cancer recurrence or survival with and without adjustment for key covariates.
Results
We observed no association between genotype and ovarian cancer recurrence or survival for any of the SNPs examined.
Conclusions
These results refute prior associations between these SNPs and ovarian cancer outcome and underscore the importance of maximally powered genetic association studies.
Impact
These variants should not be used in prognostic models. Alternate approaches to uncovering inherited prognostic factors, if they exist, are needed.
doi:10.1158/1055-9965.EPI-13-0028
PMCID: PMC3650102  PMID: 23513043
5.  GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer 
Pharoah, Paul D. P. | Tsai, Ya-Yu | Ramus, Susan J. | Phelan, Catherine M. | Goode, Ellen L. | Lawrenson, Kate | Price, Melissa | Fridley, Brooke L. | Tyrer, Jonathan P. | Shen, Howard | Weber, Rachel | Karevan, Rod | Larson, Melissa C. | Song, Honglin | Tessier, Daniel C. | Bacot, François | Vincent, Daniel | Cunningham, Julie M. | Dennis, Joe | Dicks, Ed | Aben, Katja K. | Anton-Culver, Hoda | Antonenkova, Natalia | Armasu, Sebastian M. | Baglietto, Laura | Bandera, Elisa V. | Beckmann, Matthias W. | Birrer, Michael J. | Bloom, Greg | Bogdanova, Natalia | Brenton, James D. | Brinton, Louise A. | Brooks-Wilson, Angela | Brown, Robert | Butzow, Ralf | Campbell, Ian | Carney, Michael E | Carvalho, Renato S. | Chang-Claude, Jenny | Chen, Y. Anne | Chen, Zhihua | Chow, Wong-Ho | Cicek, Mine S. | Coetzee, Gerhard | Cook, Linda S. | Cramer, Daniel W. | Cybulski, Cezary | Dansonka-Mieszkowska, Agnieszka | Despierre, Evelyn | Doherty, Jennifer A | Dörk, Thilo | du Bois, Andreas | Dürst, Matthias | Eccles, Diana | Edwards, Robert | Ekici, Arif B. | Fasching, Peter A. | Fenstermacher, David | Flanagan, James | Gao, Yu-Tang | Garcia-Closas, Montserrat | Gentry-Maharaj, Aleksandra | Giles, Graham | Gjyshi, Anxhela | Gore, Martin | Gronwald, Jacek | Guo, Qi | Halle, Mari K | Harter, Philipp | Hein, Alexander | Heitz, Florian | Hillemanns, Peter | Hoatlin, Maureen | Høgdall, Estrid | Høgdall, Claus K. | Hosono, Satoyo | Jakubowska, Anna | Jensen, Allan | Kalli, Kimberly R. | Karlan, Beth Y. | Kelemen, Linda E. | Kiemeney, Lambertus A. | Kjaer, Susanne Krüger | Konecny, Gottfried E. | Krakstad, Camilla | Kupryjanczyk, Jolanta | Lambrechts, Diether | Lambrechts, Sandrina | Le, Nhu D. | Lee, Nathan | Lee, Janet | Leminen, Arto | Lim, Boon Kiong | Lissowska, Jolanta | Lubiński, Jan | Lundvall, Lene | Lurie, Galina | Massuger, Leon F.A.G. | Matsuo, Keitaro | McGuire, Valerie | McLaughlin, John R | Menon, Usha | Modugno, Francesmary | Moysich, Kirsten B. | Nakanishi, Toru | Narod, Steven A. | Ness, Roberta B. | Nevanlinna, Heli | Nickels, Stefan | Noushmehr, Houtan | Odunsi, Kunle | Olson, Sara | Orlow, Irene | Paul, James | Pejovic, Tanja | Pelttari, Liisa M | Permuth-Wey, Jenny | Pike, Malcolm C | Poole, Elizabeth M | Qu, Xiaotao | Risch, Harvey A. | Rodriguez-Rodriguez, Lorna | Rossing, Mary Anne | Rudolph, Anja | Runnebaum, Ingo | Rzepecka, Iwona K | Salvesen, Helga B. | Schwaab, Ira | Severi, Gianluca | Shen, Hui | Shridhar, Vijayalakshmi | Shu, Xiao-Ou | Sieh, Weiva | Southey, Melissa C. | Spellman, Paul | Tajima, Kazuo | Teo, Soo-Hwang | Terry, Kathryn L. | Thompson, Pamela J | Timorek, Agnieszka | Tworoger, Shelley S. | van Altena, Anne M. | Berg, David Van Den | Vergote, Ignace | Vierkant, Robert A. | Vitonis, Allison F. | Wang-Gohrke, Shan | Wentzensen, Nicolas | Whittemore, Alice S. | Wik, Elisabeth | Winterhoff, Boris | Woo, Yin Ling | Wu, Anna H | Yang, Hannah P. | Zheng, Wei | Ziogas, Argyrios | Zulkifli, Famida | Goodman, Marc T. | Hall, Per | Easton, Douglas F | Pearce, Celeste L | Berchuck, Andrew | Chenevix-Trench, Georgia | Iversen, Edwin | Monteiro, Alvaro N.A. | Gayther, Simon A. | Schildkraut, Joellen M. | Sellers, Thomas A.
Nature genetics  2013;45(4):362-370e2.
Genome wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC) with another two loci being close to genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the United Kingdom. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. Follow-up genotyping was carried out in 18,174 cases and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 previously near genome-wide significance and identified three novel loci associated with risk; two loci associated with all EOC subtypes, at 8q21 (rs11782652, P=5.5×10-9) and 10p12 (rs1243180; P=1.8×10-8), and another locus specific to the serous subtype at 17q12 (rs757210; P=8.1×10-10). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility that implicates CHMP4C in the pathogenesis of ovarian cancer.
doi:10.1038/ng.2564
PMCID: PMC3693183  PMID: 23535730
6.  The role of genetic breast cancer susceptibility variants as prognostic factors 
Fasching, Peter A. | Pharoah, Paul D.P. | Cox, Angela | Nevanlinna, Heli | Bojesen, Stig E. | Karn, Thomas | Broeks, Annegien | van Leeuwen, Flora E. | van 't Veer, Laura J. | Udo, Renate | Dunning, Alison M. | Greco, Dario | Aittomäki, Kristiina | Blomqvist, Carl | Shah, Mitul | Nordestgaard, Børge G. | Flyger, Henrik | Hopper, John L. | Southey, Melissa C. | Apicella, Carmel | Garcia-Closas, Montserrat | Sherman, Mark | Lissowska, Jolanta | Seynaeve, Caroline | Huijts, Petra E.A. | Tollenaar, Rob A.E.M. | Ziogas, Argyrios | Ekici, Arif B. | Rauh, Claudia | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Andrulis, Irene L. | Ozcelik, Hilmi | Mulligan, Anna-Marie | Glendon, Gord | Hall, Per | Czene, Kamila | Liu, Jianjun | Chang-Claude, Jenny | Wang-Gohrke, Shan | Eilber, Ursula | Nickels, Stefan | Dörk, Thilo | Schiekel, Maria | Bremer, Michael | Park-Simon, Tjoung-Won | Giles, Graham G. | Severi, Gianluca | Baglietto, Laura | Hooning, Maartje J. | Martens, John W.M. | Jager, Agnes | Kriege, Mieke | Lindblom, Annika | Margolin, Sara | Couch, Fergus J. | Stevens, Kristen N. | Olson, Janet E. | Kosel, Matthew | Cross, Simon S. | Balasubramanian, Sabapathy P. | Reed, Malcolm W.R. | Miron, Alexander | John, Esther M. | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Kauppila, Saila | Burwinkel, Barbara | Marme, Frederik | Schneeweiss, Andreas | Sohn, Christof | Chenevix-Trench, Georgia | Lambrechts, Diether | Dieudonne, Anne-Sophie | Hatse, Sigrid | van Limbergen, Erik | Benitez, Javier | Milne, Roger L. | Zamora, M. Pilar | Pérez, José Ignacio Arias | Bonanni, Bernardo | Peissel, Bernard | Loris, Bernard | Peterlongo, Paolo | Rajaraman, Preetha | Schonfeld, Sara J. | Anton-Culver, Hoda | Devilee, Peter | Beckmann, Matthias W. | Slamon, Dennis J. | Phillips, Kelly-Anne | Figueroa, Jonine D. | Humphreys, Manjeet K. | Easton, Douglas F. | Schmidt, Marjanka K.
Human Molecular Genetics  2012;21(17):3926-3939.
Recent genome-wide association studies identified 11 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic relevance. Confirmed BC risk SNPs rs17468277 (CASP8), rs1982073 (TGFB1), rs2981582 (FGFR2), rs13281615 (8q24), rs3817198 (LSP1), rs889312 (MAP3K1), rs3803662 (TOX3), rs13387042 (2q35), rs4973768 (SLC4A7), rs6504950 (COX11) and rs10941679 (5p12) were genotyped for 25 853 BC patients with the available follow-up; 62 other SNPs, which have been suggested as BC risk SNPs by a GWAS or as candidate SNPs from individual studies, were genotyped for replication purposes in subsets of these patients. Cox proportional hazard models were used to test the association of these SNPs with overall survival (OS) and BC-specific survival (BCS). For the confirmed loci, we performed an accessory analysis of publicly available gene expression data and the prognosis in a different patient group. One of the 11 SNPs, rs3803662 (TOX3) and none of the 62 candidate/GWAS SNPs were associated with OS and/or BCS at P<0.01. The genotypic-specific survival for rs3803662 suggested a recessive mode of action [hazard ratio (HR) of rare homozygous carriers=1.21; 95% CI: 1.09–1.35, P=0.0002 and HR=1.29; 95% CI: 1.12–1.47, P=0.0003 for OS and BCS, respectively]. This association was seen similarly in all analyzed tumor subgroups defined by nodal status, tumor size, grade and estrogen receptor. Breast tumor expression of these genes was not associated with prognosis. With the exception of rs3803662 (TOX3), there was no evidence that any of the SNPs associated with BC susceptibility were associated with the BC survival. Survival may be influenced by a distinct set of germline variants from those influencing susceptibility.
doi:10.1093/hmg/dds159
PMCID: PMC3412377  PMID: 22532573
7.  Ovarian Cancer Risk Associated with Inherited Inflammation-Related Variants 
Cancer Research  2012;72(5):1064-1069.
The importance of inflammation pathways to the development of many human cancers prompted us to examine the associations between single-nucleotide polymorphisms (SNPs) in inflammation-related genes and risk of ovarian cancer. In a multi-site case-control study, we genotyped SNPs in a large panel of inflammatory genes in 930 epithelial ovarian cancer cases and 1,037 controls using a custom array and analyzed by logistic regression. SNPs with p<0.10 were evaluated among 3,143 cases and 2,102 controls from the Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI) collaboration. Combined analysis revealed association with SNPs rs17561 and rs4848300 in the interleukin gene IL1A which varied by histologic subtype (heterogeneity p=0.03). For example, IL1A rs17561, which correlates with numerous inflammatory phenotypes, was associated with decreased risk of clear cell, mucinous, and endometrioid subtype, but not with the most common serous subtype. Genotype at rs1864414 in the arachidonate 5-lipoxygenase ALOX5 was also associated with decreased risk. Thus, inherited variation in IL1A and ALOX5 appears to affect ovarian cancer risk which, for IL1A, is limited to rarer subtypes. Given the importance of inflammation in tumorigenesis and growing evidence of subtype-specific features in ovarian cancer, functional investigations will be important to help clarify the importance of inherited variation related to inflammation in ovarian carcinogenesis.
doi:10.1158/0008-5472.CAN-11-3512
PMCID: PMC3293997  PMID: 22282663
epidemiology; cytokine
8.  Ovarian Cancer Risk Associated with Inherited Inflammation-Related Variants 
Cancer research  2012;72(5):1064-1069.
The importance of inflammation pathways to the development of many human cancers prompted us to examine the associations between single-nucleotide polymorphisms (SNPs) in inflammation-related genes and risk of ovarian cancer. In a multi-site case-control study, we genotyped SNPs in a large panel of inflammatory genes in 930 epithelial ovarian cancer cases and 1,037 controls using a custom array and analyzed by logistic regression. SNPs with p<0.10 were evaluated among 3,143 cases and 2,102 controls from the Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI) collaboration. Combined analysis revealed association with SNPs rs17561 and rs4848300 in the interleukin gene IL1A which varied by histologic subtype (heterogeneity p=0.03). For example, IL1A rs17561, which correlates with numerous inflammatory phenotypes, was associated with decreased risk of clear cell, mucinous, and endometrioid subtype, but not with the most common serous subtype. Genotype at rs1864414 in the arachidonate 5-lipoxygenase ALOX5 was also associated with decreased risk. Thus, inherited variation in IL1A and ALOX5 appears to affect ovarian cancer risk which, for IL1A, is limited to rarer subtypes. Given the importance of inflammation in tumorigenesis and growing evidence of subtype-specific features in ovarian cancer, functional investigations will be important to help clarify the importance of inherited variation related to inflammation in ovarian carcinogenesis.
doi:10.1158/0008-5472.CAN-11-3512
PMCID: PMC3293997  PMID: 22282663
epidemiology; cytokine
9.  Genetic variation in insulin-like growth factor 2 may play a role in ovarian cancer risk 
Human Molecular Genetics  2011;20(11):2263-2272.
The insulin-like growth factor (IGF) signaling axis plays an important role in cancer biology. We hypothesized that genetic variation in this pathway may influence risk of ovarian cancer. A three-center study of non-Hispanic whites including 1880 control women, 1135 women with invasive epithelial ovarian cancer and 321 women with borderline epithelial ovarian tumors was carried out to test the association between tag single-nucleotide polymorphisms (tSNPs) (n=58) in this pathway and risk of ovarian cancer. We found no association between variation in IGF1, IGFBP1 or IGFBP3 and risk of invasive disease, whereas five tSNPs in IGF2 were associated with risk of invasive epithelial ovarian cancer at P<0.05 and followed-up one of the associated SNPs. We conducted genotyping in 3216 additional non-Hispanic white cases and 5382 additional controls and were able to independently replicate our initial findings. In the combined set of studies, rs4320932 was associated with a 13% decreased risk of ovarian cancer per copy of the minor allele carried (95% confidence interval 0.81–0.93, P-trend=7.4 × 10−5). No heterogeneity of effect across study centers was observed (phet=0.25). IGF2 is emerging as an important gene for ovarian cancer; additional genotyping is warranted to further confirm these associations with IGF2 and to narrow down the region harboring the causal SNP.
doi:10.1093/hmg/ddr087
PMCID: PMC3090188  PMID: 21422097
10.  Vitamin D receptor rs2228570 polymorphism and invasive ovarian carcinoma risk: pooled analysis in five studies within the Ovarian Cancer Association Consortium 
The association of invasive ovarian carcinoma risk with the functional polymorphism rs2228570 (aka rs10735810; FokI polymorphism) in the vitamin D receptor (VDR) gene was examined in 1820 white non-Hispanic cases and 3479 controls in a pooled analysis of five population-based case-control studies within the Ovarian Cancer Association Consortium. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. Carriers of the rare T allele were at increased risk of ovarian carcinoma compared to women with the CC genotype in all studies combined; each copy of the T allele was associated with a modest 9% increased risk (OR=1.09; 95% CI:1.01–1.19; p=0.04). No significant heterogeneity among studies was observed (p=0.37) and, after excluding the dataset from the Hawaii study, the risk association for rs2228570 among replication studies was unchanged (OR=1.09; 95% CI: 1.00–1.19; p=0.06). A stronger association of rs2228570 with risk was observed among younger women (aged < 50 years versus 50 years or older) (p=0.04). In all studies combined, the increased risk per copy of the T allele among younger women was 24% (OR=1.24; 95% CI: 1.04–1.47; p=0.02). This association remained statistically significant after excluding the Hawaii data (OR= 1.20; 95% CI: 1.01–1.43; p=0.04). No heterogeneity of the association was observed by stage (p= 0.46), tumor histology (p=0.98), or time between diagnosis and interview (p=0.94). This pooled analysis provides further evidence that the VDR rs2228570 polymorphism might influence ovarian cancer susceptibility.
doi:10.1002/ijc.25403
PMCID: PMC2972411  PMID: 20473893
invasive ovarian carcinoma; vitamin D receptor gene (VDR); single nucleotide polymorphism; pooled analysis; case-control study
11.  Genetic Variation at 9p22.2 and Ovarian Cancer Risk for BRCA1 and BRCA2 Mutation Carriers 
Ramus, Susan J. | Kartsonaki, Christiana | Gayther, Simon A. | Pharoah, Paul D. P. | Sinilnikova, Olga M. | Beesley, Jonathan | Chen, Xiaoqing | McGuffog, Lesley | Healey, Sue | Couch, Fergus J. | Wang, Xianshu | Fredericksen, Zachary | Peterlongo, Paolo | Manoukian, Siranoush | Peissel, Bernard | Zaffaroni, Daniela | Roversi, Gaia | Barile, Monica | Viel, Alessandra | Allavena, Anna | Ottini, Laura | Papi, Laura | Gismondi, Viviana | Capra, Fabio | Radice, Paolo | Greene, Mark H. | Mai, Phuong L. | Andrulis, Irene L. | Glendon, Gord | Ozcelik, Hilmi | Thomassen, Mads | Gerdes, Anne-Marie | Kruse, Torben A. | Cruger, Dorthe | Jensen, Uffe Birk | Caligo, Maria Adelaide | Olsson, Håkan | Kristoffersson, Ulf | Lindblom, Annika | Arver, Brita | Karlsson, Per | Stenmark Askmalm, Marie | Borg, Ake | Neuhausen, Susan L. | Ding, Yuan Chun | Nathanson, Katherine L. | Domchek, Susan M. | Jakubowska, Anna | Lubiński, Jan | Huzarski, Tomasz | Byrski, Tomasz | Gronwald, Jacek | Górski, Bohdan | Cybulski, Cezary | Dębniak, Tadeusz | Osorio, Ana | Durán, Mercedes | Tejada, Maria-Isabel | Benítez, Javier | Hamann, Ute | Rookus, Matti A. | Verhoef, Senno | Tilanus-Linthorst, Madeleine A. | Vreeswijk, Maaike P. | Bodmer, Danielle | Ausems, Margreet G. E. M. | van Os, Theo A. | Asperen, Christi J. | Blok, Marinus J. | Meijers-Heijboer, Hanne E. J. | Peock, Susan | Cook, Margaret | Oliver, Clare | Frost, Debra | Dunning, Alison M. | Evans, D. Gareth | Eeles, Ros | Pichert, Gabriella | Cole, Trevor | Hodgson, Shirley | Brewer, Carole | Morrison, Patrick J. | Porteous, Mary | Kennedy, M. John | Rogers, Mark T. | Side, Lucy E. | Donaldson, Alan | Gregory, Helen | Godwin, Andrew | Stoppa-Lyonnet, Dominique | Moncoutier, Virginie | Castera, Laurent | Mazoyer, Sylvie | Barjhoux, Laure | Bonadona, Valérie | Leroux, Dominique | Faivre, Laurence | Lidereau, Rosette | Nogues, Catherine | Bignon, Yves-Jean | Prieur, Fabienne | Collonge-Rame, Marie-Agnès | Venat-Bouvet, Laurence | Fert-Ferrer, Sandra | Miron, Alex | Buys, Saundra S. | Hopper, John L. | Daly, Mary B. | John, Esther M. | Terry, Mary Beth | Goldgar, David | Hansen, Thomas v. O. | Jønson, Lars | Ejlertsen, Bent | Agnarsson, Bjarni A. | Offit, Kenneth | Kirchhoff, Tomas | Vijai, Joseph | Dutra-Clarke, Ana V. C. | Przybylo, Jennifer A. | Montagna, Marco | Casella, Cinzia | Imyanitov, Evgeny N. | Janavicius, Ramunas | Blanco, Ignacio | Lázaro, Conxi | Moysich, Kirsten B. | Karlan, Beth Y. | Gross, Jenny | Beattie, Mary S. | Schmutzler, Rita | Wappenschmidt, Barbara | Meindl, Alfons | Ruehl, Ina | Fiebig, Britta | Sutter, Christian | Arnold, Norbert | Deissler, Helmut | Varon-Mateeva, Raymonda | Kast, Karin | Niederacher, Dieter | Gadzicki, Dorothea | Caldes, Trinidad | de la Hoya, Miguel | Nevanlinna, Heli | Aittomäki, Kristiina | Simard, Jacques | Soucy, Penny | Spurdle, Amanda B. | Holland, Helene | Chenevix-Trench, Georgia | Easton, Douglas F. | Antoniou, Antonis C.
Background
Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-wide association study recently identified an association between the rare allele of the single-nucleotide polymorphism (SNP) rs3814113 (ie, the C allele) at 9p22.2 and decreased risk of ovarian cancer for women in the general population. We evaluated the association of this SNP with ovarian cancer risk among BRCA1 or BRCA2 mutation carriers by use of data from the Consortium of Investigators of Modifiers of BRCA1/2.
Methods
We genotyped rs3814113 in 10 029 BRCA1 mutation carriers and 5837 BRCA2 mutation carriers. Associations with ovarian and breast cancer were assessed with a retrospective likelihood approach. All statistical tests were two-sided.
Results
The minor allele of rs3814113 was associated with a reduced risk of ovarian cancer among BRCA1 mutation carriers (per-allele hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.72 to 0.85; P = 4.8 × 10-9) and BRCA2 mutation carriers (hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.67 to 0.90; P = 5.5 × 10-4). This SNP was not associated with breast cancer risk among either BRCA1 or BRCA2 mutation carriers. BRCA1 mutation carriers with the TT genotype at SNP rs3814113 were predicted to have an ovarian cancer risk to age 80 years of 48%, and those with the CC genotype were predicted to have a risk of 33%.
Conclusion
Common genetic variation at the 9p22.2 locus was associated with decreased risk of ovarian cancer for carriers of a BRCA1 or BRCA2 mutation.
doi:10.1093/jnci/djq494
PMCID: PMC3107565  PMID: 21169536
12.  The role of KRAS rs61764370 in invasive epithelial ovarian cancer: implications for clinical testing 
Pharoah, Paul D. P. | Palmieri, Rachel T. | Ramus, Susan J. | Gayther, Simon A. | Andrulis, Irene L. | Anton-Culver, Hoda | Antonenkova, Natalia | Antoniou, Antonis C. | Beattie, Mary S. | Beckmann, Matthias W. | Birrer, Michael J. | Bogdanova, Natalia | Bolton, Kelly L. | Brewster, Wendy | Brooks-Wilson, Angela | Brown, Robert | Butzow, Ralf | Caldes, Trinidad | Caligo, Maria Adelaide | Campbell, Ian | Chang-Claude, Jenny | Chen, Y. Ann | Chenevix-Trench, Georgia | Cook, Linda S. | Couch, Fergus J. | Cramer, Daniel W. | Cunningham, Julie M. | Despierre, Evelyn | Doherty, Jennifer A. | Dörk, Thilo | Dürst, Matthias | Eccles, Diana M. | Ekici, Arif B. | Fasching, Peter A. | de Fazio, Anna | Fenstermacher, David A. | Flanagan, James M. | Fridley, Brooke L. | Friedman, Eitan | Gao, Bo | Gentry-Maharaj, Aleksandra | Godwin, Andrew K. | Goode, Ellen L. | Goodman, Marc T. | Gross, Jenny | Hansen, Thomas V. O. | Harnett, Paul | Heikkinen, Tuomas | Hein, Rebecca | Høgdall, Claus | Høgdall, Estrid | Iversen, Edwin S. | Jakubowska, Anna | Johnatty, Sharon E. | Karlan, Beth Y. | Kauff, Noah D. | Kaye, Stanley B. | Kelemen, Linda E. | Kiemeney, Lambertus A. | Kjaer, Susanne Krüger | Lambrechts, Diether | LaPolla, James P. | Lázaro, Conxi | Le, Nhu D. | Leminen, Arto | Leunen, Karin | Levine, Douglas A. | Lu, Yi | Lundvall, Lene | Macgregor, Stuart | Marees, Tamara | Massuger, Leon F. | McLaughlin, John R. | Menon, Usha | Montagna, Marco | Moysich, Kirsten B. | Narod, Steven A. | Nathanson, Katherine L. | Nedergaard, Lotte | Ness, Roberta B. | Nevanlinna, Heli | Nickels, Stefan | Osorio, Ana | Paul, Jim | Pearce, Celeste Leigh | Phelan, Catherine M. | Pike, Malcolm C. | Radice, Paolo | Rossing, Mary Anne | Schildkraut, Joellen M. | Sellers, Thomas A. | Singer, Christian F. | Song, Honglin | Stram, Daniel O. | Sutphen, Rebecca | Terry, Kathryn L. | Tsai, Ya-Yu | van Altena, Anne M. | Vergote, Ignace | Vierkant, Robert A. | Vitonis, Allison F. | Walsh, Christine | Wang-Gohrke, Shan | Wappenschmidt, Barbara | Wu, Anna H. | Ziogas, Argyrios | Berchuck, Andrew | Risch, Harvey A.
Purpose
An assay for the single nucleotide polymorphism (SNP) rs61764370 has recently been commercially marketed as a clinical test to aid ovarian cancer risk evaluation in women with family histories of the disease. rs67164370 is in a 3′UTR miRNA binding site of the KRAS oncogene, and is a candidate for epithelial ovarian cancer (EOC) susceptibility. However, only one published paper, analyzing fewer than 1,000 subjects in total, has examined this association.
Experimental Design
Risk association was evaluated in 8,669 cases of invasive EOC and 10,012 controls from nineteen studies participating in the Ovarian Cancer Association Consortium, and in 683 cases and 2,044 controls carrying BRCA1 mutations from studies in the Consortium of Investigators of Modifiers of BRCA1/2. Prognosis association was also examined in a subset of five studies with progression-free survival data and eighteen studies with all-cause mortality data.
Results
No evidence of association was observed between genotype and risk of unselected EOC (odds ratio (OR)=1.02, 95% confidence interval (CI)=0.95–1.10), serous EOC (OR=1.08, 95%CI=0.98–1.18), familial EOC (OR=1.09, 95%CI=0.78–1.54), or among women carrying deleterious mutations in BRCA1 (OR=1.09, 95%CI=0.88–1.36). There was little evidence for association with survival time among unselected cases (hazard ratio (HR)=1.10, 95%CI=0.99–1.22), among serous cases (HR=1.12, 95%CI=0.99–1.28), or with progression-free survival in 540 cases treated with carboplatin and paclitaxel (HR=1.18, 95%CI=0.93–1.52).
Conclusions
These data exclude the possibility of an association between rs61764370 and a clinically significant risk of ovarian cancer or of familial ovarian cancer. Use of this SNP for ovarian cancer clinical risk prediction therefore appears unwarranted.
doi:10.1158/1078-0432.CCR-10-3405
PMCID: PMC3107901  PMID: 21385923
13.  The role of KRAS rs61764370 in invasive epithelial ovarian cancer: implications for clinical testing 
Pharoah, Paul D. P. | Palmieri, Rachel T. | Ramus, Susan J. | Gayther, Simon A. | Andrulis, Irene L. | Anton-Culver, Hoda | Antonenkova, Natalia | Antoniou, Antonis C. | Beattie, Mary S. | Beckmann, Matthias W. | Birrer, Michael J. | Bogdanova, Natalia | Bolton, Kelly L. | Brewster, Wendy | Brooks-Wilson, Angela | Brown, Robert | Butzow, Ralf | Caldes, Trinidad | Caligo, Maria Adelaide | Campbell, Ian | Chang-Claude, Jenny | Chen, Y. Ann | Chenevix-Trench, Georgia | Cook, Linda S. | Couch, Fergus J. | Cramer, Daniel W. | Cunningham, Julie M. | Despierre, Evelyn | Doherty, Jennifer A. | Dörk, Thilo | Dürst, Matthias | Eccles, Diana M. | Ekici, Arif B. | Fasching, Peter A. | de Fazio, Anna | Fenstermacher, David A. | Flanagan, James M. | Fridley, Brooke L. | Friedman, Eitan | Gao, Bo | Gentry-Maharaj, Aleksandra | Godwin, Andrew K. | Goode, Ellen L. | Goodman, Marc T. | Gross, Jenny | Hansen, Thomas V. O. | Harnett, Paul | Heikkinen, Tuomas | Hein, Rebecca | Høgdall, Claus | Høgdall, Estrid | Iversen, Edwin S. | Jakubowska, Anna | Johnatty, Sharon E. | Karlan, Beth Y. | Kauff, Noah D. | Kaye, Stanley B. | Kelemen, Linda E. | Kiemeney, Lambertus A. | Kjaer, Susanne Krüger | Lambrechts, Diether | LaPolla, James P. | Lázaro, Conxi | Le, Nhu D. | Leminen, Arto | Leunen, Karin | Levine, Douglas A. | Lu, Yi | Lundvall, Lene | Macgregor, Stuart | Marees, Tamara | Massuger, Leon F. | McLaughlin, John R. | Menon, Usha | Montagna, Marco | Moysich, Kirsten B. | Narod, Steven A. | Nathanson, Katherine L. | Nedergaard, Lotte | Ness, Roberta B. | Nevanlinna, Heli | Nickels, Stefan | Osorio, Ana | Paul, Jim | Pearce, Celeste Leigh | Phelan, Catherine M. | Pike, Malcolm C. | Radice, Paolo | Rossing, Mary Anne | Schildkraut, Joellen M. | Sellers, Thomas A. | Singer, Christian F. | Song, Honglin | Stram, Daniel O. | Sutphen, Rebecca | Terry, Kathryn L. | Tsai, Ya-Yu | van Altena, Anne M. | Vergote, Ignace | Vierkant, Robert A. | Vitonis, Allison F. | Walsh, Christine | Wang-Gohrke, Shan | Wappenschmidt, Barbara | Wu, Anna H. | Ziogas, Argyrios | Berchuck, Andrew | Risch, Harvey A.
Purpose
An assay for the single nucleotide polymorphism (SNP) rs61764370 has recently been commercially marketed as a clinical test to aid ovarian cancer risk evaluation in women with family histories of the disease. rs67164370 is in a 3′UTR miRNA binding site of the KRAS oncogene, and is a candidate for epithelial ovarian cancer (EOC) susceptibility. However, only one published paper, analyzing fewer than 1,000 subjects in total, has examined this association.
Experimental Design
Risk association was evaluated in 8,669 cases of invasive EOC and 10,012 controls from nineteen studies participating in the Ovarian Cancer Association Consortium, and in 683 cases and 2,044 controls carrying BRCA1 mutations from studies in the Consortium of Investigators of Modifiers of BRCA1/2. Prognosis association was also examined in a subset of five studies with progression-free survival data and eighteen studies with all-cause mortality data.
Results
No evidence of association was observed between genotype and risk of unselected EOC (odds ratio (OR)=1.02, 95% confidence interval (CI)=0.95-1.10), serous EOC (OR=1.08, 95%CI=0.98-1.18), familial EOC (OR=1.09, 95%CI=0.78-1.54), or among women carrying deleterious mutations in BRCA1 (OR=1.09, 95%CI=0.88-1.36). There was little evidence for association with survival time among unselected cases (hazard ratio (HR)=1.10, 95%CI=0.99-1.22), among serous cases (HR=1.12, 95%CI=0.99-1.28), or with progression-free survival in 540 cases treated with carboplatin and paclitaxel (HR=1.18, 95%CI=0.93-1.52).
Conclusions
These data exclude the possibility of an association between rs61764370 and a clinically significant risk of ovarian cancer or of familial ovarian cancer. Use of this SNP for ovarian cancer clinical risk prediction therefore appears unwarranted.
doi:10.1158/1078-0432.CCR-10-3405
PMCID: PMC3107901  PMID: 21385923
14.  No association between SNPs regulating TGF-β1 secretion and late radiotherapy toxicity to the breast: Results from the RAPPER study § 
Background and purpose
Several small studies have reported associations between TGFB1 single nucleotide polymorphisms (SNPs), considered to increase secretion of TGF-β1, and greater than 3-fold increases in incidence of fibrosis – an indicator of late toxicity after radiotherapy in breast cancer patients.
Materials and methods
Two SNPs in TGFB1, C-509T (rs1800469) and L10P (rs1800470), were genotyped in 778 breast cancer patients who had received radiotherapy to the breast. Late radiotherapy toxicity was assessed two years after radiotherapy using a validated photographic technique, clinical assessment and patient questionnaires.
Results
On photographic assessment, 210 (27%) patients showed some degree of breast shrinkage, whilst 45 (6%) patients showed marked breast shrinkage. There was no significant association of genotype at either of the TGFB1 SNPs with any measure of late radiation toxicity.
Conclusion
This adequately powered trial failed to confirm previously reported increases in fibrosis with TGFB1 genotype – any increase greater than 1.36 can be excluded with 95% confidence. Similar frequent failures to replicate associations with candidate genes have been resolved using genome-wide association scans: this methodology detects common, low risk alleles but requires even larger patient numbers for adequate statistical power.
doi:10.1016/j.radonc.2009.12.006
PMCID: PMC3120654  PMID: 20096948
Radiotherapy; Breast; Genetics; TGFB1; Breast cancer
15.  No association between TERT-CLPTM1L SNP rs401681 and mean telomere length or cancer risk 
Background
A recent study reported genetic variants in the TERT-CLPTM1L locus to be associated with mean telomere length, and with risk of multiple cancers.
Methods
We evaluated the association between SNP rs401681 [c>t] and mean telomere length, using quantitative Real Time PCR, in blood-extracted DNA collected from 11,314 cancer-free participants from the Sisters in Breast Screening (SIBS) study, the MAPLES melanoma family study, and the SEARCH Breast, Colorectal, Melanoma studies. We also examined the relationship between rs401618 genotype and susceptibility to breast cancer (6800 cases, 6608 controls), colorectal cancer (2259 cases, 2181 controls) and melanoma (787 cases, 999 controls).
Results
The ‘per t allele’ change in mean telomere length (ΔCt), adjusted for age, study plate, gender and family, was 0.001 (95%CI -0.01 – 0.02), p-trend=0.61. The ‘per t allele’ Odds Ratio (OR) for each cancer was: breast cancer OR=1.01 (95% Confidence Intervals 0.96-1.06), p-trend=0.64; colorectal cancer OR=1.02 (95%CI 0.94-1.11), p-trend=0.66; and melanoma OR=0.99 (95%CI 0.84-1.15), p-trend=0.87.
Conclusion
We found no evidence that this SNP is associated with mean telomere length, or with risk of breast cancer, colorectal cancer or melanoma.
Impact
Our results indicate that observed associations between rs401681 and several cancer types may be weaker than previously described. The lack of an association in our study between this SNP and mean telomere suggests that any association with cancer risk at this locus is not mediated through TERT.
doi:10.1158/1055-9965.EPI-10-0281
PMCID: PMC2901592  PMID: 20570912
16.  Telomere length in prospective and retrospective cancer case-control studies 
Cancer research  2010;70(8):3170-3176.
Previous studies have reported that shorter mean telomere length in lymphocytes is associated with increased susceptibility to common diseases of aging, and may be predictive of cancer risk. However, most analyses have examined retrospectively-collected case-control studies.
Mean telomere length was measured using high-throughput quantitative Real Time PCR. Blood for DNA extraction was collected after cancer diagnosis in the East Anglian SEARCH Breast (2243 cases, 2181 controls) and SEARCH Colorectal (2249 cases, 2161 controls) studies. Prospective case-control studies were conducted for breast cancer (199 cases) and colorectal cancer (185 cases), nested within the EPIC-Norfolk cohort. Blood has been collected at least 6 months prior to diagnosis, and was matched to DNA from two cancer-free controls per case.
In the retrospective, SEARCH studies, the age-adjusted Odds Ratios for shortest (Q4) vs. longest (Q1) quartile of mean telomere length was 15.5 (95%CI 11.6–20.8), p-het=5.7×10−75; with a ‘per quartile’ p-trend=2.1×10−80 for breast cancer, and 2.14 (95%CI 1.77–2.59), p-het=7.3×10−15; with a ‘per quartile’ p-trend=1.8×10−13 for colorectal cancer. In the prospective, EPIC study, the comparable Odds Ratios [Q4 vs. Q1] were 1.58 (95%CI 0.75–3.31), p-het=0.23 for breast cancer, and 1.13 (95%CI 0.54–2.36), p-het=0.75 for colorectal cancer risk.
Mean telomere length was shorter in retrospectively-collected cases than in controls but the equivalent association was markedly weaker in the prospective studies. This suggests that telomere shortening largely occurs after diagnosis, and may not, therefore, be of value in cancer prediction.
doi:10.1158/0008-5472.CAN-09-4595
PMCID: PMC2855947  PMID: 20395204
17.  A genome-wide association study of prognosis in breast cancer 
Background
Traditional clinicopathological features of breast cancer do not account for all the variation in survival. Germline genetic variation may provide additional prognostic information.
Materials and Methods
We conducted a GWAS study of survival after a diagnosis of breast cancer by obtaining follow-up data and genotyping information on 528,252 SNPs for 1,145 postmenopausal women with invasive breast cancer (7,711 person years at risk) from the Nurses’ Health Study scanned in the Cancer Genetic Markers of Susceptibility initiative. We genotyped the ten most statistically significant loci (most significant SNP located in ARHGAP10, p = 2.28 × 10−7) in 4,335 women diagnosed with invasive breast cancer (38,148 years at risk) in the SEARCH breast cancer study.
Results
None of the loci replicated in the SEARCH study (all p > 0.10). Assuming a minimum of ten associated loci, the power to detect at least one with a minor allele frequency of 0.2 conferring a relative hazard of 2.0 at genome-wide significance (5×10−8) was 99 percent.
Conclusions
We did not identify any common germline variants associated with breast cancer survival overall.
Impact
Our data suggest it is unlikely that there are common germline variants with large effect sizes for breast cancer survival overall (HR>2). Instead, it is plausible that common variants associated with survival could be specific to tumor subtypes or treatment approaches. New studies, sufficiently powered, are needed to discover new regions associated with survival overall or by subtype or treatment subgroups.
doi:10.1158/1055-9965.EPI-10-0085
PMCID: PMC2852476  PMID: 20332263
breast cancer; prognosis; genome-wide association study; molecular diagnosis and prognosis; single nucleotide polymorphism
18.  Prognostic Value of PAI1 in Invasive Breast Cancer: Evidence That Tumor-Specific Factors Are More Important Than Genetic Variation in Regulating PAI1 Expression 
Plasminogen activator inhibitor-1 (PAI1) can promote cancer progression, and its protein expression in tumors is an independent indicator of poor prognosis in many forms of cancer. Here, we show that high PAI1 mRNA levels also predict for shorter overall survival in two independent breast cancer data sets, highlighting the importance of its transcriptional regulation. The −675insG (4G/5G) single-nucleotide polymorphism in the PAI1 gene promoter has been shown to influence PAI1 transcription, with the 4G allele eliciting higher reporter gene expression in vitro and higher levels of circulating PAI1 in vivo. Nevertheless, its genotypic distribution in 2,539 British women with invasive breast cancer was virtually identical to that seen in 1,832 matched controls (P = 0.72), and annual mortality rates for 4G4G, 4G5G, and 5G5G cases were 2.6%, 2.8%, and 3.1% per year, respectively (P = 0.10). Thus, there was no association with breast cancer incidence or outcome, and in a separate set of breast cancers, the 4G/5G single-nucleotide polymorphism showed no association with PAI1 mRNA expression (P = 0.85). By contrast, connective tissue growth factor (CTGF), which can regulate PAI1 expression in culture, was associated with PAI1 expression in three independent cohorts (P ≪ 0.0001). In addition, PAI1 gene copy number differences in the tumors were correlated with PAI1 mRNA expression (P = 0.0005) and seemed to affect expression independently of CTGF. Thus, local factors, such as CTGF and genomic amplification, seem to be more important than germ line genetic variation in influencing PAI1 expression and its untoward effects in breast cancer.
doi:10.1158/1055-9965.EPI-06-0351
PMCID: PMC2731792  PMID: 17119035
19.  Genome-wide association study identifies novel breast cancer susceptibility loci 
Easton, Douglas F. | Pooley, Karen A. | Dunning, Alison M. | Pharoah, Paul D. P. | Thompson, Deborah | Ballinger, Dennis G. | Struewing, Jeffery P. | Morrison, Jonathan | Field, Helen | Luben, Robert | Wareham, Nicholas | Ahmed, Shahana | Healey, Catherine S. | Bowman, Richard | Meyer, Kerstin B. | Haiman, Christopher A. | Kolonel, Laurence K. | Henderson, Brian E. | Marchand, Loic Le | Brennan, Paul | Sangrajrang, Suleeporn | Gaborieau, Valerie | Odefrey, Fabrice | Shen, Chen-Yang | Wu, Pei-Ei | Wang, Hui-Chun | Eccles, Diana | Evans, D. Gareth | Peto, Julian | Fletcher, Olivia | Johnson, Nichola | Seal, Sheila | Stratton, Michael R. | Rahman, Nazneen | Chenevix-Trench, Georgia | Bojesen, Stig E. | Nordestgaard, Børge G. | Axelsson, Christen K. | Garcia-Closas, Montserrat | Brinton, Louise | Chanock, Stephen | Lissowska, Jolanta | Peplonska, Beata | Nevanlinna, Heli | Fagerholm, Rainer | Eerola, Hannaleena | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Ahn, Sei-Hyun | Hunter, David J. | Hankinson, Susan E. | Cox, David G. | Hall, Per | Wedren, Sara | Liu, Jianjun | Low, Yen-Ling | Bogdanova, Natalia | Schürmann, Peter | Dörk, Thilo | Tollenaar, Rob A. E. M. | Jacobi, Catharina E. | Devilee, Peter | Klijn, Jan G. M. | Sigurdson, Alice J. | Doody, Michele M. | Alexander, Bruce H. | Zhang, Jinghui | Cox, Angela | Brock, Ian W. | MacPherson, Gordon | Reed, Malcolm W. R. | Couch, Fergus J. | Goode, Ellen L. | Olson, Janet E. | Meijers-Heijboer, Hanne | van den Ouweland, Ans | Uitterlinden, André | Rivadeneira, Fernando | Milne, Roger L. | Ribas, Gloria | Gonzalez-Neira, Anna | Benitez, Javier | Hopper, John L. | McCredie, Margaret | Southey, Melissa | Giles, Graham G. | Schroen, Chris | Justenhoven, Christina | Brauch, Hiltrud | Hamann, Ute | Ko, Yon-Dschun | Spurdle, Amanda B. | Beesley, Jonathan | Chen, Xiaoqing | Mannermaa, Arto | Kosma, Veli-Matti | Kataja, Vesa | Hartikainen, Jaana | Day, Nicholas E. | Cox, David R. | Ponder, Bruce A. J. | Luccarini, Craig | Conroy, Don | Shah, Mitul | Munday, Hannah | Jordan, Clare | Perkins, Barbara | West, Judy | Redman, Karen | Driver, Kristy | Aghmesheh, Morteza | Amor, David | Andrews, Lesley | Antill, Yoland | Armes, Jane | Armitage, Shane | Arnold, Leanne | Balleine, Rosemary | Begley, Glenn | Beilby, John | Bennett, Ian | Bennett, Barbara | Berry, Geoffrey | Blackburn, Anneke | Brennan, Meagan | Brown, Melissa | Buckley, Michael | Burke, Jo | Butow, Phyllis | Byron, Keith | Callen, David | Campbell, Ian | Chenevix-Trench, Georgia | Clarke, Christine | Colley, Alison | Cotton, Dick | Cui, Jisheng | Culling, Bronwyn | Cummings, Margaret | Dawson, Sarah-Jane | Dixon, Joanne | Dobrovic, Alexander | Dudding, Tracy | Edkins, Ted | Eisenbruch, Maurice | Farshid, Gelareh | Fawcett, Susan | Field, Michael | Firgaira, Frank | Fleming, Jean | Forbes, John | Friedlander, Michael | Gaff, Clara | Gardner, Mac | Gattas, Mike | George, Peter | Giles, Graham | Gill, Grantley | Goldblatt, Jack | Greening, Sian | Grist, Scott | Haan, Eric | Harris, Marion | Hart, Stewart | Hayward, Nick | Hopper, John | Humphrey, Evelyn | Jenkins, Mark | Jones, Alison | Kefford, Rick | Kirk, Judy | Kollias, James | Kovalenko, Sergey | Lakhani, Sunil | Leary, Jennifer | Lim, Jacqueline | Lindeman, Geoff | Lipton, Lara | Lobb, Liz | Maclurcan, Mariette | Mann, Graham | Marsh, Deborah | McCredie, Margaret | McKay, Michael | McLachlan, Sue Anne | Meiser, Bettina | Milne, Roger | Mitchell, Gillian | Newman, Beth | O'Loughlin, Imelda | Osborne, Richard | Peters, Lester | Phillips, Kelly | Price, Melanie | Reeve, Jeanne | Reeve, Tony | Richards, Robert | Rinehart, Gina | Robinson, Bridget | Rudzki, Barney | Salisbury, Elizabeth | Sambrook, Joe | Saunders, Christobel | Scott, Clare | Scott, Elizabeth | Scott, Rodney | Seshadri, Ram | Shelling, Andrew | Southey, Melissa | Spurdle, Amanda | Suthers, Graeme | Taylor, Donna | Tennant, Christopher | Thorne, Heather | Townshend, Sharron | Tucker, Kathy | Tyler, Janet | Venter, Deon | Visvader, Jane | Walpole, Ian | Ward, Robin | Waring, Paul | Warner, Bev | Warren, Graham | Watson, Elizabeth | Williams, Rachael | Wilson, Judy | Winship, Ingrid | Young, Mary Ann | Bowtell, David | Green, Adele | deFazio, Anna | Chenevix-Trench, Georgia | Gertig, Dorota | Webb, Penny
Nature  2007;447(7148):1087-1093.
Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r2>0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P<10−7). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P<0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach.
doi:10.1038/nature05887
PMCID: PMC2714974  PMID: 17529967
20.  Consortium analysis of 7 candidate SNPs for ovarian cancer 
The Ovarian Cancer Association Consortium selected 7 candidate single nucleotide polymorphisms (SNPs), for which there is evidence from previous studies of an association with variation in ovarian cancer or breast cancer risks. The SNPs selected for analysis were F31I (rs2273535) in AURKA, N372H (rs144848) in BRCA2, rs2854344 in intron 17 of RB1, rs2811712 5′ flanking CDKN2A, rs523349 in the 3′ UTR of SRD5A2, D302H (rs1045485) in CASP8 and L10P (rs1982073) in TGFB1. Fourteen studies genotyped 4,624 invasive epithelial ovarian cancer cases and 8,113 controls of white non-Hispanic origin. A marginally significant association was found for RB1 when all studies were included [ordinal odds ratio (OR) 0.88 (95% confidence interval (CI) 0.79-1.00) p = 0.041 and dominant OR 0.87 (95% CI 0.76-0.98) p = 0.025]; when the studies that originally suggested an association were excluded, the result was suggestive although no longer statistically significant (ordinal OR 0.92, 95% CI 0.79-1.06). This SNP has also been shown to have an association with decreased risk in breast cancer. There was a suggestion of an association for AURKA, when one study that caused significant study heterogeneity was excluded [ordinal OR 1.10 (95% CI 1.01-1.20) p = 0.027; dominant OR 1.12 (95% CI 1.01-1.24) p = 0.03]. The other 5 SNPs in BRCA2, CDKN2A, SRD5A2, CASP8 and TGFB1 showed no association with ovarian cancer risk; given the large sample size, these results can also be considered to be informative. These null results for SNPs identified from relatively large initial studies shows the importance of replicating associations by a consortium approach.
doi:10.1002/ijc.23448
PMCID: PMC2667795  PMID: 18431743
association study; neoplasms; ovarian cancer; replication; single nucleotide polymorphism
21.  Effects of Common Germ-Line Genetic Variation in Cell Cycle Genes on Ovarian Cancer Survival 
Purpose:
Somatic alterations have been shown to correlate with ovarian cancer prognosis and survival, but less is known about the effects on survival of common inherited genetic variation. Of particular interest are genes involved in cell cycle pathways, which regulate cell division and could plausibly influence clinical characteristics of multiple tumors types.
Experimental Design:
We examined associations between common germ-line genetic variation in 14 genes involved in cell cycle pathway (CCND1, CCND2, CCND3, CCNE1, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, CDKN2D, CDK2, CDK4, CDK6, and RB1) and survival among women with invasive ovarian cancer participating in a multicenter case-control study from United Kingdom, Denmark, and United States. DNAs from up to 1,499 women were genotyped for 97 single-nucleotide polymorphisms that tagged the known common variants (minor allele frequency ≥0.05) in these genes. The genotypes of each polymorphism were tested for association with survival by Cox regression analysis.
Results:
A nominally statistically significant association between genotype and ovarian cancer survival was observed for polymorphisms in CCND2 and CCNE1. The per-allele hazard ratios (95% confidence intervals) were 1.16 (1.03-1.31; P = 0.02) for rs3217933, 1.14 (1.02-1.27; P = 0.024) for rs3217901, and 0.85 (0.73-1.00; P = 0.043) for rs3217862 in CCND2 and 1.39 (1.04-1.85; P = 0.033) for rs3218038 in CCNE1. However, these were not significant after adjusting for multiple hypothesis tests.
Conclusion:
It is unlikely that common variants in cell cycle pathways examined above associated with moderate effect in survival after diagnosis of ovarian cancer. Much larger studies will be needed to exclude common variants with small effects.
doi:10.1158/1078-0432.CCR-07-1195
PMCID: PMC2430032  PMID: 18281541
22.  Somatically acquired hypomethylation of IGF2 in breast and colorectal cancer 
Human Molecular Genetics  2008;17(17):2633-2643.
The imprinted insulin-like growth factor 2 (IGF2) gene is expressed predominantly from the paternal allele. Loss of imprinting (LOI) associated with hypomethylation at the promoter proximal sequence (DMR0) of the IGF2 gene was proposed as a predisposing constitutive risk biomarker for colorectal cancer. We used pyrosequencing to assess whether IGF2 DMR0 methylation is either present constitutively prior to cancer or whether it is acquired tissue-specifically after the onset of cancer. DNA samples from tumour tissues and matched non-tumour tissues from 22 breast and 42 colorectal cancer patients as well as peripheral blood samples obtained from colorectal cancer patients [SEARCH (n=case 192, controls 96)], breast cancer patients [ABC (n=case 364, controls 96)] and the European Prospective Investigation of Cancer [EPIC-Norfolk (n=breast 228, colorectal 225, controls 895)] were analysed. The EPIC samples were collected 2–5 years prior to diagnosis of breast or colorectal cancer. IGF2 DMR0 methylation levels in tumours were lower than matched non-tumour tissue. Hypomethylation of DMR0 was detected in breast (33%) and colorectal (80%) tumour tissues with a higher frequency than LOI indicating that methylation levels are a better indicator of cancer than LOI. In the EPIC population, the prevalence of IGF2 DMR0 hypomethylation was 9.5% and this correlated with increased age not cancer risk. Thus, IGF2 DMR0 hypomethylation occurs as an acquired tissue-specific somatic event rather than a constitutive innate epimutation. These results indicate that IGF2 DMR0 hypomethylation has diagnostic potential for colon cancer rather than value as a surrogate biomarker for constitutive LOI.
doi:10.1093/hmg/ddn163
PMCID: PMC2515372  PMID: 18541649
23.  Association of single-nucleotide polymorphisms in the cell cycle genes with breast cancer in the British population 
Carcinogenesis  2008;29(2):333-341.
Using a large-scale case–control study, we examined whether common single-nucleotide polymorphisms (SNPs) within 13 genes involved in the cell cycle pathway are associated with breast cancer risk. Seventy-nine tag SNPs were used to evaluate 240 common SNPs found in the genes: CCND1, CCND2, CCND3, CCNE1, CDK2, CDK4, CDK6, CDKN1A, CDKNIB, CDKN2A/CDKN2B, CDKN2C and CDKN2D. These were genotyped in 2270 cases and 2280 controls from the Studies in Epidemiology and Risks of Cancer Heredity (SEARCH) study. Tag SNPs showing evidence of statistically significant differences between cases and controls (P < 0.1) were genotyped in a further 2200 cases and 2280 controls from the same population. This approach found evidence for breast cancer-associated SNPs in four of the cell cycle genes: the cyclin CCNE1 rs997669 had an odds ratio (OR) (GG/AA) of 1.18 [95% confidence interval (95% CI) 1.04–1.34] P = 0.003 and the cyclin-dependent kinase inhibitors—CDKN1A rs3176336: OR (TT/AA) = 1.25 (95% CI 1.11–1.42) P = 0.0026; CDKN1B rs34330: OR (TT/CC) = 1.22 (95% CI 1.02–1.47) P = 0.013 and the region of CDKN2A/2B rs3731239: OR (CC/TT) = 0.90 (95% CI 0.79–1.03) P = 0.013 and rs3218005 OR (GG/AA) = 1.55 (95% CI 1.02–2.37) P = 0.013 (P-values unadjusted for multiple testing). We were able to exclude the D-type cyclins, cyclin-dependent kinases, CDKN2C and CDKN2D from having any significantly associated risk with breast cancer in our study population. The combined effects of the cell cycle genes considered here provide evidence for a significant association with breast cancer risk in a global test (P-heterogeneity = 0.010, P-trend = 0.048). Further large-scale studies are needed to confirm these results.
doi:10.1093/carcin/bgm284
PMCID: PMC2346546  PMID: 18174243
24.  Association between Common Variation in 120 Candidate Genes and Breast Cancer Risk 
PLoS Genetics  2007;3(3):e42.
Association studies in candidate genes have been widely used to search for common low penetrance susceptibility alleles, but few definite associations have been established. We have conducted association studies in breast cancer using an empirical single nucleotide polymorphism (SNP) tagging approach to capture common genetic variation in genes that are candidates for breast cancer based on their known function. We genotyped 710 SNPs in 120 candidate genes in up to 4,400 breast cancer cases and 4,400 controls using a staged design. Correction for population stratification was done using the genomic control method, on the basis of data from 280 genomic control SNPs. Evidence for association with each SNP was assessed using a Cochran–Armitage trend test (p-trend) and a two-degrees of freedom χ2 test for heterogeneity (p-het). The most significant single SNP (p-trend = 8 × 10−5) was not significant at a nominal 5% level after adjusting for population stratification and multiple testing. To evaluate the overall evidence for an excess of positive associations over the proportion expected by chance, we applied two global tests: the admixture maximum likelihood (AML) test and the rank truncated product (RTP) test corrected for population stratification. The admixture maximum likelihood experiment-wise test for association was significant for both the heterogeneity test (p = 0.0031) and the trend test (p = 0.017), but no association was observed using the rank truncated product method for either the heterogeneity test or the trend test (p = 0.12 and p = 0.24, respectively). Genes in the cell-cycle control pathway and genes involved in steroid hormone metabolism and signalling were the main contributors to the association. These results suggest that a proportion of SNPs in these candidate genes are associated with breast cancer risk, but that the effects of individual SNPs is likely to be small. Large sample sizes from multicentre collaboration will be needed to identify associated SNPs with certainty.
Author Summary
The polygenic model of cancer susceptibility suggests that multiple alleles contribute to the excess familial risk of most common cancers. Candidate gene association studies have been a commonly used approach in the search for such alleles. We have investigated over 700 common variants in genes that are candidates for breast cancer susceptibility in a large case-control study of breast cancer, but no single variant was identified at an appropriate level of statistical significance. The purpose of this study was to consider these data as a whole, using a novel method, the admixture maximum likelihood test, to test the hypothesis that a proportion (unknown) of the variants we investigated are associated with breast cancer. After adjusting for population substructure, we found evidence for association that was robust to all but the most extreme assumptions about the degree of population stratification. Genes in the cell-cycle control and steroid hormone metabolism and signalling pathways were the main contributors. These results suggest that a proportion of single nucleotide polymorphisms (SNPs) in these candidate genes are associated with breast cancer risk, but that the effects of individual SNPs are likely to be small. Large sample sizes from multicentre collaboration will be needed to identify associated SNPs with certainty.
doi:10.1371/journal.pgen.0030042
PMCID: PMC1828694  PMID: 17367212
25.  Association between Common Variation in 120 Candidate Genes and Breast Cancer Risk 
PLoS Genetics  2007;3(3):e42.
Association studies in candidate genes have been widely used to search for common low penetrance susceptibility alleles, but few definite associations have been established. We have conducted association studies in breast cancer using an empirical single nucleotide polymorphism (SNP) tagging approach to capture common genetic variation in genes that are candidates for breast cancer based on their known function. We genotyped 710 SNPs in 120 candidate genes in up to 4,400 breast cancer cases and 4,400 controls using a staged design. Correction for population stratification was done using the genomic control method, on the basis of data from 280 genomic control SNPs. Evidence for association with each SNP was assessed using a Cochran–Armitage trend test (p-trend) and a two-degrees of freedom χ2 test for heterogeneity (p-het). The most significant single SNP (p-trend = 8 × 10−5) was not significant at a nominal 5% level after adjusting for population stratification and multiple testing. To evaluate the overall evidence for an excess of positive associations over the proportion expected by chance, we applied two global tests: the admixture maximum likelihood (AML) test and the rank truncated product (RTP) test corrected for population stratification. The admixture maximum likelihood experiment-wise test for association was significant for both the heterogeneity test (p = 0.0031) and the trend test (p = 0.017), but no association was observed using the rank truncated product method for either the heterogeneity test or the trend test (p = 0.12 and p = 0.24, respectively). Genes in the cell-cycle control pathway and genes involved in steroid hormone metabolism and signalling were the main contributors to the association. These results suggest that a proportion of SNPs in these candidate genes are associated with breast cancer risk, but that the effects of individual SNPs is likely to be small. Large sample sizes from multicentre collaboration will be needed to identify associated SNPs with certainty.
Author Summary
The polygenic model of cancer susceptibility suggests that multiple alleles contribute to the excess familial risk of most common cancers. Candidate gene association studies have been a commonly used approach in the search for such alleles. We have investigated over 700 common variants in genes that are candidates for breast cancer susceptibility in a large case-control study of breast cancer, but no single variant was identified at an appropriate level of statistical significance. The purpose of this study was to consider these data as a whole, using a novel method, the admixture maximum likelihood test, to test the hypothesis that a proportion (unknown) of the variants we investigated are associated with breast cancer. After adjusting for population substructure, we found evidence for association that was robust to all but the most extreme assumptions about the degree of population stratification. Genes in the cell-cycle control and steroid hormone metabolism and signalling pathways were the main contributors. These results suggest that a proportion of single nucleotide polymorphisms (SNPs) in these candidate genes are associated with breast cancer risk, but that the effects of individual SNPs are likely to be small. Large sample sizes from multicentre collaboration will be needed to identify associated SNPs with certainty.
doi:10.1371/journal.pgen.0030042
PMCID: PMC1828694  PMID: 17367212

Results 1-25 (48)