19p13.1 Is a Triple-Negative–Specific Breast Cancer Susceptibility Locus

Stevens, Kristen N.; Fredericksen, Zachary S.; Vachon, Celine M.; Wang, Xianshu; Margolin, Sara; Lindblom, Annika; Nevanlinna, Heli; Greco, Dario; Aittomäki, Kristiina; Blomqvist, Carl; Chang‐Claude, Jenny; Vrieling, Alina; Flesch-Janys, Dieter; Sinn, Hans‐Peter; Wang-Gohrke, Shan; Nickels, Stefan; Brauch, Hiltrud; Ko, Yon; Fischer, Hans Peter; Schmutzler, Rita K.; Meindl, Alfons; Bartram, Claus R.; Schott, Sarah; Engel, Christoph; Godwin, Andrew K.; Weaver, Jo Ellen; Pathak, Harsh B.; Sharma, Priyanka; Brenner, Hermann; Müller, Heiko; Arndt, Volker; Stegmaier, Christa; Miron, Penelope; Yannoukakos, Drakoulis; Stavropoulou, Alexandra; Fountzilas, George; Gogas, Helen; Swann, Ruth; Dwek, Miriam; Perkins, Annie; Milne, Roger L.; Benı́tez, Javier; Zamora, M. Pilar; Peŕez, José Ignacio Arias; Bojesen, Stig E.; Nielsen, Sune F.; Nordestgaard, Børge G.; Flyger, Henrik; Guénel, Pascal; Truong, Thérèse; Ménégaux, Florence; Cordina‐Duverger, Emilie; Burwinkel, Barbara; Marmé, F.; Schneeweiß, Andreas; Sohn, Christof; Sawyer, Elinor J.; Tomlinson, Ian; Kerin, Michael J.; Peto, Julian; Johnson, Nichola; Fletcher, Olivia; dos‐Santos‐Silva, Isabel; Fasching, Peter A.; Beckmann, Matthias W.; Hartmann, Arndt; Ekici, Arif B.; Lophatananon, Artitaya; Muir, Kenneth; Puttawibul, Puttisak; Wiangnon, Surapon; Schmidt, Marjanka K.; Broeks, Annegien; Braaf, Linde M.; Rosenberg, Efraim H.; Hopper, John L.; Apicella, Carmel; Park, Daniel J.; Southey, Melissa C.; Swerdlow, Anthony; Ashworth, Alan; Orr, Nicholas; Schoemaker, Minouk J.; Anton‐Culver, Hoda; Ziogas, Argyrios; Bernstein, Leslie; Dur, Christina Clarke; Shen, Chen; Yu, Jyh Cherng; Hsu, Huan Ming; Hsiung, Chia Ni; Hamann, Ute; Dünnebier, Thomas; Rüdiger, Thomas; Ulmer, Hans Ulrich; Pharoah, Paul; Dunning, Alison M.; Humphreys, Manjeet K.; Wang, Qin; Cox, Angela; Cross, Simon S.; Reed, Malcolm; Hall, Per; Czene, Kamila; Ambrosone, Christine B.; Ademuyiwa, Foluso O.; Hwang, Helena; Eccles, Diana; García-Closas, Montserrat; Figueroa, Jonine D.; Sherman, Mark E.; Lissowska, Jolanta; Devilee, Peter; Seynaeve, C.; Tollenaar, Rob A.E.M.; Hooning, Maartje J.; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Mulligan, Anna Marie; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; John, Esther M.; Miron, Alexander; Alnsæ, Grethe Grenaker; Kristensen, Vessela N.; Brøresen-Dale, Anne Lise; Giles, Graham G.; Baglietto, Laura; McLean, Catriona; Severi, Gianluca; Kosel, Matthew L.; Pankratz, V. Shane; Slager, Susan L.; Olson, Janet E.; Radice, Paolo; Peterlongo, Paolo; Manoukian, Siranoush; Barile, Mônica; Lambrechts, Diether; Hatse, Sigrid; Dieudonne, Anne Sophie; Christiaens, Marie Rose; Chenevix-Trench, Georgia; Beesley, Jonathan; Chen, Xiaoqing; Mannermaa, Arto; Kosma, Veli Matti; Hartikainen, Jaana M.; Soini, Ylermi; Easton, Douglas F.; Couch, Fergus J.

doi:10.1158/0008-5472.can-11-3364

Cited by 94 publications

(93 citation statements)

References 24 publications

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“…In the TNBCC [15], 6q25/ ESR1, 16q12/ TOX3 , 14q24/ RAD51L1 , and 19p13/ BABAM1 were significantly associated with the risk of TNBC. However, only two of them, 19p13/ BABAM1 and 16q12/ TOX3, were replicated in the BCAC [14,16]. In the present study, a similar, but non-significant association was observed with ORs (95% CI) of 1.19 (0.91–1.56) and 1.17 (0.86– 1.58) for 16q12/ TOX3 and 19p13/ BABAM1, respectively.…”

Section: Discussionsupporting

confidence: 64%

Evaluating 17 breast cancer susceptibility loci in the Nashville breast health study

et al. 2014

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Background Genome-wide association studies (GWAS) have discovered multiple genetic loci associated with breast cancer risk. Investigating these loci would be helpful to evaluate previous findings and identify causal variants for breast cancer. We evaluated index SNPs in17 of these loci in a study of 1,511 cases and 1,454 controls of European descent. Methods We investigated the overall association with breast cancer and among subtypes defined as ER+ (estrogen receptor positive), ER− (estrogen receptor negative) and TNBC (triple-negative breast cancer). Combined effects of SNPs on breast cancer risk were assessed via a genetic risk score (GRS). We evaluated the contribution of both genetic variants and traditional risk factors to a breast cancer risk assessment model. Results Five of the 17 SNPs were significantly associated (P ≤ 0.05) with overall breast cancer in the same direction as previously reported: rs13387042 (2q35/TNP1), rs4973768 (3p24/SLC4A7), rs2046210 (6q25/ESR1), rs1219648 (10q26/FGFR2), and rs4784227 (16q12/TOX3). When stratified by breast cancer subtype, all five SNPs were associated (P<0.05) with ER+ cancer, three with ER− cancer (rs13387042, rs1219648, and rs4784227), and one with TNBC (rs1219648). A GRS, based on those five significant SNPs, showed strong association with overall breast cancer with ORs (95% CI) of 1.48 (1.22–1.79), 1.85 (1.52–2.25) and 2.26 (1.82–2.80), respectively, for each quartile, (P = 2.0×10−15). Traditional risk factors, including previous benign breast disease, breast cancer family history and parity, were significantly associated with breast cancer risk in the present study. These factors, together with the GRS, were used to build a breast cancer risk assessment model with a c statistic of 0.6321 from receiver operating characteristic (ROC) analysis. The contribution of the GRS to the model was greater than prior benign breast disease, family history and parity with the c statistic change of 0.0374, 0.0324, 0.0103, 0.0012, respectively. Conclusions Our study demonstrates that five SNPs were associated with overall breast cancer, with stronger association for ER+ than ER− cancer as previously reported, and suggests that a risk assessment model incorporating the GRS from five loci is useful in identifying women at high risk of breast cancer.

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Section: Discussionsupporting

confidence: 64%

Evaluating 17 breast cancer susceptibility loci in the Nashville breast health study

et al. 2014

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“…Exceptions are three loci tagged by rs10069690 on chromosome 5p15 (ref. 5) (TERT-CLPTM1L), rs8170 at 19p13 (ref. 6) (BABAM1, also known as MERIT40) and rs2284378 at 20q11 (ref.…”

mentioning

confidence: 99%

“…Only seven loci identified so far, the four reported here and the three previously reported located at 5p15 (ref. 5), 19p13.1 (ref. 6) and 20q11 (ref.…”

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confidence: 99%

Genome-wide association studies identify four ER negative–specific breast cancer risk loci

García-Closas¹,

Couch²,

Lindström³

et al. 2013

Nat Genet

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309

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Estrogen receptor (ER)-negative tumors represent 20–30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry1. The etiology2 and clinical behavior3 of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition4. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10−12 and LGR6, P = 1.4 × 10−8), 2p24.1 (P = 4.6 × 10−8) and 16q12.2 (FTO, P = 4.0 × 10−8), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.

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“…Its MAF contributed to increased power to its detection over the rarer variants on the arrays. BABAM1 rs8170 is known to associate with EOC risk (10), with triple-negative breast cancer risk (34), and with risk of ovarian cancer and estrogen-negative subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers (16, 35). The estimated hazard ratio in meta-analysis was 1.16, which roughly translates to a 16% reduction in median survival time for patients with one copy of the minor allele compared to those with no copies (36).…”

Section: Discussionmentioning

confidence: 99%

Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer

Investigators

2016

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background While numerous susceptibility loci for epithelial ovarian cancer (EOC) have been identified, few associations have been reported with overall survival. In the absence of common prognostic genetic markers, we hypothesize that rare coding variants may be associated with overall EOC survival and assessed their contribution in two exome-based genotyping projects of the Ovarian Cancer Association Consortium (OCAC). Methods The primary patient set (Set 1) included 14 independent EOC studies (4293 patients) and 227,892 variants, and a secondary patient set (Set 2) included six additional EOC studies (1744 patients) and 114,620 variants. Because power to detect rare variants individually is reduced, gene-level tests were conducted. Sets were analyzed separately at individual variants and by gene, and then combined with meta-analyses (73,203 variants and 13,163 genes overlapped). Results No individual variant reached genome-wide statistical significance. A SNP previously implicated to be associated with EOC risk and, to a lesser extent, survival, rs8170, showed the strongest evidence of association with survival and similar effect size estimates across sets (Pmeta=1.1E-6, HRSet1=1.17, HRSet2=1.14). Rare variants in ATG2B, an autophagy gene important for apoptosis, were significantly associated with survival after multiple testing correction (Pmeta=1.1E-6; Pcorrected=0.01). Conclusions Common variant rs8170 and rare variants in ATG2B may be associated with EOC overall survival, although further study is needed. Impact This study represents the first exome-wide association study of EOC survival to include rare variant analyses, and suggests that complementary single variant and gene-level analyses in large studies are needed to identify rare variants that warrant follow-up study.

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19p13.1 Is a Triple-Negative–Specific Breast Cancer Susceptibility Locus

Cited by 94 publications

References 24 publications

Evaluating 17 breast cancer susceptibility loci in the Nashville breast health study

Evaluating 17 breast cancer susceptibility loci in the Nashville breast health study

Genome-wide association studies identify four ER negative–specific breast cancer risk loci

Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer

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