Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer

Purrington, Kristen; Slager, Susan L.; Eccles, Diana; Yannoukakos, Drakoulis; Fasching, Peter A.; Miron, Penelope; Carpenter, Jane; Chang‐Claude, Jenny; Martin, Nicholas G.; Montgomery, Grant W.; Kristensen, Vessela N.; Anton‐Culver, Hoda; Goodfellow, Paul J.; Tapper, William; Rafiq, Sajjad; Gerty, Susan M.; Durcan, Lorraine; Konstantopoulou, Irene; Fostira, Florentia; Vratimos, Athanassios; Apostolou, Paraskevi; Konstanta, Irene; Kotoula, Vassiliki; Lakis, Sotiris; Dimopoulos, Meletios Α.; Skarlos, Dimosthenis; Pectasides, Dimitrios; Fountzilas, George; Beckmann, Matthias W.; Hein, Alexander; Ruebner, Matthias; Ekici, Arif B.; Hartmann, Arndt; Schulz-Wendtland, R.; Renner, Stefan P.; Janni, Wolfgang; Rack, Brigitte; Scholz, Christoph; J, Neugebauer; Andergassen, Ulrich; Lux, Michael P.; Haeberle, Lothar; Clarke, Christine L.; Pathmanathan, Nirmala; Rudolph, Anja; Flesch-Janys, Dieter; Nickels, Stefan; Olson, Janet E.; Ingle, James N.; Olswold, Curtis; Slettedahl, Seth W.; Eckel‐Passow, Jeanette E.; Anderson, S. Keith; Visscher, Daniel W.; Cafourek, Victoria; Sicotte, Hugues; Prodduturi, Naresh; Weiderpass, Elisabete; Bernstein, Leslie; Ziogas, Argyrios; Ivanovich, Jennifer; Giles, Graham G.; Baglietto, Laura; Southey, Melissa C.; Kosma, Veli Matti; Fischer, Hans Peter; Reed, Malcolm; Cross, Simon S.; Deming-Halverson, Sandra; Shrubsole, Martha J.; Cai, Qiuyin; Shu, Xiao Ou; Daly, Mary B.; Weaver, Jo Ellen; Ross, Eric A.; Klemp, Jennifer R.; Sharma, Priyanka; Torres, Diana; Rüdiger, Thomas; Wölfing, Heidrun; Ulmer, Hans Ulrich; Försti, Asta; Khoury, Thaer; Kumar, Shicha; Pilarski, Robert; Shapiro, Charles L.; Greco, Dario; Heikkilä, Päivi; Aittomäki, Kristiina; Blomqvist, Carl; Irwanto, Astrid; Liu, Jing; Pankratz, V. Shane; Wang, Xianshu; Severi, Gianluca; Mannermaa, Arto; Easton, Douglas F.; Hall, Per; Brauch, Hiltrud; Cox, Angela; Wang, Zheng; Godwin, Andrew K.; Hamann, Ute; Ambrosone, Christine B.; Toland, Amanda E.; Nevanlinna, Heli; Vachon, Celine M.; Couch, Fergus J.

doi:10.1093/carcin/bgt404

Cited by 152 publications

(120 citation statements)

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“…Specifically, mutations in the breast cancer predisposing genes BRCA1 and BRCA2 have been observed in as many as 15% of TNBC cases, and 70% of BRCA1-associated breast tumors exhibit TN characteristics. In addition, three known TNBC-specific low-risk loci (TERT, MERIT40, and MDM4) contain genes that participate in DNA repair and maintenance of genome stability (24,25). Our findings suggest that FANCM is a breast cancer susceptibility gene, mutations in which confer a particularly strong predisposition for TNBC.…”

Section: Discussionmentioning

confidence: 68%

Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer

Kiiski

Pelttari

Khan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Inherited predisposition to breast cancer is known to be caused by loss-of-function mutations in BRCA1, BRCA2, PALB2, CHEK2, and other genes involved in DNA repair. However, most families severely affected by breast cancer do not harbor mutations in any of these genes. In Finland, founder mutations have been observed in each of these genes, suggesting that the Finnish population may be an excellent resource for the identification of other such genes. To this end, we carried out exome sequencing of constitutional genomic DNA from 24 breast cancer patients from 11 Finnish breast cancer families. From all rare damaging variants, 22 variants in 21 DNA repair genes were genotyped in 3,166 breast cancer patients, 569 ovarian cancer patients, and 2,090 controls, all from the Helsinki or Tampere regions of Finland. In Fanconi anemia complementation gene M (FANCM), nonsense mutation c.5101C>T (p.Q1701X) was significantly more frequent among breast cancer patients than among controls [odds ratio (OR) = 1.86, 95% CI = 1.26-2.75; P = 0.0018], with particular enrichment among patients with triplenegative breast cancer (TNBC; OR = 3.56, 95% CI = 1.81-6.98, P = 0.0002). In the Helsinki and Tampere regions, respectively, carrier frequencies of FANCM p.Q1701X were 2.9% and 4.0% of breast cancer patients, 5.6% and 6.6% of TNBC patients, 2.2% of ovarian cancer patients (from Helsinki), and 1.4% and 2.5% of controls. These findings identify FANCM as a breast cancer susceptibility gene, mutations in which confer a particularly strong predisposition for TNBC.breast cancer | DNA repair | FANCM | exome sequencing | triple-negative breast cancer B reast cancer is the most common cancer affecting women worldwide. It is also the principal cause of death from cancer among women globally, accounting for 14% of all cancer deaths (1). The etiology of breast cancer is multifactorial, and the risk depends on various factors like age, family history, and reproductive, hormonal, or dietary factors. The majority of breast cancers are sporadic, but approximately 15% of cases show familial aggregation (2, 3). Since the identification of the first breast and ovarian cancer susceptibility genes breast cancer 1 and 2 (BRCA1 and BRCA2, respectively) by linkage analysis and positional cloning, several breast cancer susceptibility genes and alleles with different levels of risk and prevalence in the population have been recognized. BRCA1 and BRCA2 mutation carriers have more than 10-fold increased risk of breast cancer compared with women in

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Section: Discussionmentioning

confidence: 68%

Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer

Kiiski

Pelttari

Khan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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159

170

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“…It appears that most risk loci increase the risk for ERpositive BC, such as FGFR2 (Broeks et al, 2011), but a panel of 25 single-nucleotide polymorphisms has been associated with TNBC (Purrington et al, 2014). Some of these genes are known to be involved in homologous repair as well, such as BRCA2 and RAD51B.…”

Section: Discussionmentioning

confidence: 99%

“…Most studies have tended to investigate hormone receptor positivity or negativity, or grading, rather than triple negativity or HER2 positivity (Sherman et al, 2007;Purrington et al, 2014). In addition, almost no studies have used more sophisticated approaches than hormone receptors or HER2 to differentiate between molecular subtypes, although other factors have been described as being helpful here -such as Ki-67, which is believed to be able to distinguish luminal A-like tumors from luminal B-like tumors (Sotiriou et al, 2006;Cheang et al, 2009;Sotiriou and Pusztai, 2009).…”

Section: Introductionmentioning

confidence: 99%

Association of molecular subtypes with breast cancer risk factors

Rauh¹,

Gaß²,

Haeberle³

et al. 2015

European Journal of Cancer Prevention

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As breast cancer (BC) screening identifies many BCs with a good prognosis, which might be overdiagnosed and therefore overtreated, the identification of subgroups with a high risk for aggressive subtypes might be helpful. The aim of this case-case analysis was to investigate the association between epidemiological risk factors and molecular subtypes in a cohort of BC patients. Epidemiological risk factors for 2587 BC patients were obtained using a structured questionnaire and from the patients' charts. The histopathological information (estrogen and progesterone receptor, HER2 and Ki-67) used in the analysis was retrieved from the original pathology reports. Analyses using conditional inference regression trees were carried out on these data. The strongest influence factor on the distribution of the molecular subtypes was age at first diagnosis of BC. An influence of BMI was also identified in patients aged either more than 42 years or 49.6 years or less. Older patients aged more than 49.6 years and perimenopausal women with a BMI of 32.4 kg/m or less were most likely to develop luminal A-like BC. Young patients aged 42 years or less and perimenopausal patients with a BMI more than 32.4 kg/m more often developed triple-negative BC. The study confirmed that age at diagnosis is an important factor influencing the distribution of molecular subtypes. In the perimenopausal group, it may be postulated that BMI plays a critical role in the pathogenesis of BC, defining a subgroup that is more likely to develop triple-negative BC or luminal B-like disease and another group in which there is a more postmenopausal distribution pattern.

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“…Presently, the disease will affect 12% of all women and about 30-40% of patients will die from metastatic disease despite radical surgery (Brown et al, 2011). And several risk factors have been recognized, such as early menarche, late menopause, nulliparity, and positive family history (Purrington et al, 2014). However, there are at present no realistic options for primary prevention in patients, except hereditary breast cancer related genes, such as BRCA1 and BRCA2 (Marcus et al, 1996), PTEN (Cowden's disease) (Eng et al, 1994), and p53 (Li Fraumeni syndrome) (Magnusson et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Hiwi Promotes Growth of Human Breast Cancer Cells

Wang¹,

Wang²,

Wang³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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The Piwi subfamily comprises two argonaute (Ago) family proteins, which are defined by the presence of PAZ and Piwi domains, with well known roles in RNA silencing. Hiwi, a human Piwi subfamily member, has been shown to play essential roles in stem cell self-renewal and gametogenesis. Recently, accumulating reports have indicated that abnormal hiwi expression is associated with poorer prognosis of multiple types of human cancers, including examples in the breast. However, little is known about details of the oncogenic role of hiwi in breast cancers. In present study, we confirmed overexpression of hiwi in breast cancer specimens and breast cancer cell lines at both mRNA and protein levels. Thus both RT-qPCR and Western blot data revealed significantly higher hiwi in intratumor than peritumor specimens, overexpression being associated with tumor size, lymph node metastasis and histological grade. Hiwi overexpression was also identified in breast cancer cell lines, MDA-MB-231 and MCF-7, and gain-of-function and loss-of-function strategies were adopted to identify the role of hiwi in the MCF-7 cell growth. Results demonstrated that hiwi expression in MCF-7 cells was significantly up-or down-regulated by the two strategies. We next evaluated the influence of hiwi overexpression or knockdown on the growth of breast cancer cells. Both cell count and colony formation assays confirmed promoting roles of hiwi in MCF-7 cells, which could be inhibited by hiwi specific blockage by siRNAs. In summary, the present study confirmed overexpression of hiwi in breast cancer specimens and breast cancer cell lines, and provided evidence of promotion by hiwi of cell growth. The results imply an oncogenic role of hiwi in breast cancers.

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Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer

Cited by 152 publications

References 28 publications

Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer

Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer

Association of molecular subtypes with breast cancer risk factors

Overexpression of Hiwi Promotes Growth of Human Breast Cancer Cells

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