Triple-Negative Breast Cancer Risk Genes Identified by Multigene Hereditary Cancer Panel Testing

Shimelis, Hermela; LaDuca, Holly; Hu, Chunling; Hart, Steven N.; Na, Jie; Thomas, Abigail; Akinhanmi, Margaret; Moore, Raymond M.; Brauch, Hiltrud; Cox, Angela; Eccles, Diana; Toland, Amanda E.; Fasching, Peter A.; Fostira, Florentia; Garber, Judy E.; Godwin, Andrew K.; Konstantopoulou, Irene; Nevanlinna, Heli; Sharma, Priyanka; Yannoukakos, Drakoulis; Yao, Song; Feng, Bing; Davis, Brigette Tippin; Lilyquist, Jenna; Pesaran, Tina; Goldgar, David E.; Polley, Eric C.; Dolinsky, Jill S.; Couch, Fergus J.

doi:10.1093/jnci/djy106

Cited by 240 publications

(278 citation statements)

References 25 publications

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“…More recently, a study of 8753 TNBC subjects found a mutation rate of 14.4% through a 17-gene panel test. 20 In our current analysis, the overall prevalence of germline mutations was also higher in the TN (24%) and ER-and PR-positive/HER2-negative subtypes (13%), but the prevalence was lower in IBC subjects with HER2-positive disease (5.6%).…”

Section: Discussionsupporting

confidence: 38%

“…In Tung et al’s study, the prevalence of germline mutations varied according to the breast cancer subtype: 17.2% in TN disease, 8.6% in ER‐ and PR‐positive/HER2‐negative disease, and 10.8% to 11.1% in HER2‐positive disease. More recently, a study of 8753 TNBC subjects found a mutation rate of 14.4% through a 17‐gene panel test . In our current analysis, the overall prevalence of germline mutations was also higher in the TN (24%) and ER‐ and PR‐positive/HER2‐negative subtypes (13%), but the prevalence was lower in IBC subjects with HER2‐positive disease (5.6%).…”

Section: Discussionmentioning

confidence: 69%

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Prevalence of germline variants in inflammatory breast cancer

Rana

Sacca

Drogan

et al. 2019

Cancer

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Background Inflammatory breast cancer (IBC) is an uncommon and aggressive subtype of breast cancer associated with early disease recurrence and short survival. The prevalence of germline variants in cancer predisposition genes has not been systematically evaluated in women with IBC. Methods Among 301 women enrolled in the clinical IBC registry at a single institution between 2010 and 2017, 168 had documented genetic testing. A second cohort of 200 IBC cases who had panel‐based germline testing performed through a commercial testing laboratory from 2012 to 2017 was added to the analyses. Personal and family cancer histories and genetic testing results were evaluated when they were available for both cohorts. Results Among 501 IBC cases, 368 had documented genetic testing. Germline mutations (56 total) were identified in 53 cases (14.4%). BRCA1 or BRCA2 mutations were found in 7.3% of the subjects, 6.3% had a mutation in other breast cancer genes (PALB2, CHEK2, ATM, and BARD1), and 1.6% had mutations in genes not associated with breast cancer. The prevalence of mutations was 24% (22 of 92) among women with triple‐negative IBC, 13% (13 of 99) among women with estrogen receptor– and/or progesterone receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative disease, and 9.3% (10 of 108) among women with HER2‐positive IBC. Conclusions The prevalence and diversity of germline genetic mutations among patients with IBC suggest that further studies should be performed to assess the role of inherited mutations in IBC carcinogenesis in comparison with non‐IBC breast cancer. Since IBC has a high metastatic potential associated with poor prognostic outcomes, proposed future studies may also inform targeted treatment options.

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Section: Discussionsupporting

confidence: 38%

Section: Discussionmentioning

confidence: 69%

Prevalence of germline variants in inflammatory breast cancer

Rana

Sacca

Drogan

et al. 2019

Cancer

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“…history of the disease. 8 RAD51C and RAD51D have recently been suggested as risk genes for triple-negative BC, 19 while their contribution to OC with a fiveto sixfold increased risk has been acknowledged longer. [16][17][18] We have previously identified FANCM as a BC predisposing gene in the Finnish population with approximately twofold increased risk of BC.…”

Section: Discussionmentioning

confidence: 99%

“…[9][10][11][12][13][14][15] RAD51C and RAD51D have been identified primarily as OC susceptibility genes, but have recently been linked also to triple-negative BC. [16][17][18][19] In addition, genome-wide association studies have reported numerous common risk-modifying alleles. 20 In the Finnish population, the history of geographic isolation and genetic bottlenecks has led to reduced variation and enrichment of deleterious alleles.…”

Section: Introductionmentioning

confidence: 99%

Recurrent moderate‐risk mutations in Finnish breast and ovarian cancer patients

Nurmi

Muranen

Pelttari

et al. 2019

Intl Journal of Cancer

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Mutations in BRCA1 and BRCA2 genes predispose to breast and ovarian cancer (BC/OC) with a high lifetime risk, whereas mutations in PALB2, CHEK2, ATM, FANCM, RAD51C and RAD51D genes cause a moderately elevated risk. In the Finnish population, recurrent mutations have been identified in all of these genes, the latest being CHEK2 c.319+2T>A and c.444+1G>A. By genotyping 3,156 cases and 2,089 controls, we estimated the frequencies of CHEK2 c.319+2T>A and c.444+1G>A in Finnish BC patients. CHEK2 c.319+2T>A was detected in 0.7% of the patients, and it was associated with a high risk of BC in the unselected patient group (OR = 5.40 [95% CI 1.58–18.45], p = 0.007) and similarly in the familial patient group. CHEK2 c.444+1G>A was identified in 0.1% of all patients. Additionally, we evaluated the combined prevalence of recurrent moderate‐risk gene mutations in 2,487 BC patients, 556 OC patients and 261 BRCA1/2 carriers from 109 families. The overall frequency of the mutations was 13.3% in 1,141 BRCA1/2‐negative familial BC patients, 7.5% in 1,727 unselected BC patients and 7.2% in 556 unselected OC patients. At least one moderate‐risk gene mutation was found in 12.5% of BRCA1 families and 7.1% of BRCA1 index patients, as well as in 17.0% of BRCA2 families and 11.3% of BRCA2 index patients, and the mutations were associated with an additional risk in the BRCA1/2 index patients (OR = 2.63 [1.15–5.48], p = 0.011). These results support gene panel testing of even multiple members of BC families where several mutations may segregate in different individuals.

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“…PVs in CHEK2 , ATM and PALB2 were also identified in 0.5% of patients, but a cost–benefit analysis would be needed before including them as opportunistic testing beyond the patient's phenotype. Regarding BARD1 , the role of this gene in BC susceptibility is currently being investigated with a potential significant association with triple negative BC. It is not clear if a relative risk of 3–4 for triple negative BC will be clinically relevant due to the lower prevalence of triple negative BC and, therefore, a lower absolute risk.…”

Section: Discussionmentioning

confidence: 99%

Opportunistic testing of BRCA1, BRCA2 and mismatch repair genes improves the yield of phenotype driven hereditary cancer gene panels

Feliubadaló

López‐Fernández

Pineda

et al. 2019

Intl Journal of Cancer

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Multigene panels provide a powerful tool for analyzing several genes simultaneously. We evaluated the frequency of pathogenic variants (PV) in customized predefined panels according to clinical suspicion by phenotype and compared it to the yield obtained in the analysis of our clinical research gene panel. We also investigated mutational yield of opportunistic testing of BRCA1/2 and mismatch repair (MMR) genes in all patients. A total of 1,205 unrelated probands with clinical suspicion of hereditary cancer were screened for germline mutations using panel testing. Overall, 1,048 females and 157 males were analyzed, mean age at cancer diagnosis was 48; 883 had hereditary breast/ovarian cancer‐suspicion, 205 hereditary nonpolyposis colorectal cancer (HNPCC)‐suspicion, 73 adenomatous‐polyposis‐suspicion and 44 with other/multiple clinical criteria. At least one PV was found in 150 probands (12%) analyzed by our customized phenotype‐driven panel. Tumoral MMR deficiency predicted for the presence of germline MMR gene mutations in patients with HNPCC‐suspicion (46/136 vs. 0/56 in patients with and without MMR deficiency, respectively). Opportunistic testing additionally identified five MSH6, one BRCA1 and one BRCA2 carriers (0.6%). The analysis of the extended 24‐gene panel provided 25 additional PVs (2%), including in 4 out of 51 individuals harboring MMR‐proficient colorectal tumors (2 CHEK2 and 2 ATM). Phenotype‐based panels provide a notable rate of PVs with clinical actionability. Opportunistic testing of MMR and BRCA genes leads to a significant straightforward identification of MSH6, BRCA1 and BRCA2 mutation carriers, and endorses the model of opportunistic testing of genes with clinical utility within a standard genetic counseling framework.

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Triple-Negative Breast Cancer Risk Genes Identified by Multigene Hereditary Cancer Panel Testing

Cited by 240 publications

References 25 publications

Prevalence of germline variants in inflammatory breast cancer

Prevalence of germline variants in inflammatory breast cancer

Recurrent moderate‐risk mutations in Finnish breast and ovarian cancer patients

Opportunistic testing of BRCA1, BRCA2 and mismatch repair genes improves the yield of phenotype driven hereditary cancer gene panels

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