Huaizhi Huang, Ronan E. Couch, Rachid Karam, Chunling Hu, Nicholas Boddicker, Eric C. Polley, Jie Na, Christine B. Ambrosone, Song Yao, Amy Trentham-Dietz, A. Heather Eliassen, Kathryn Penney, Kristen Brantley, Clara Bodelon, Lauren R. Teras, James Hodge, Alpa Patel, Christopher A. Haiman, Esther M. John, Susan L. Neuhausen, Elena Martinez, James V. Lacey, Katie M. O'Brien, Dale P. Sandler, Clarice R. Weinberg, Julie R. Palmer, Kimberly A. Bertrand, Celine M. Vachon, Janet E. Olson, Kathryn E. Ruddy, Hoda Anton-Culver, Argyrios Ziogas, David E. Goldgar, Katherine L. Nathanson, Susan M. Domchek, Jeffrey N. Weitzel, Peter Kraft, Jill S. Dolinsky, Tina Pesaran, Marcy E. Richardson, Siddhartha Yadav, Fergus J. Couch
{"title":"Pathogenic variants in cancer susceptibility genes predispose to Ductal Carcinoma In situ of the breast","authors":"Huaizhi Huang, Ronan E. Couch, Rachid Karam, Chunling Hu, Nicholas Boddicker, Eric C. Polley, Jie Na, Christine B. Ambrosone, Song Yao, Amy Trentham-Dietz, A. Heather Eliassen, Kathryn Penney, Kristen Brantley, Clara Bodelon, Lauren R. Teras, James Hodge, Alpa Patel, Christopher A. Haiman, Esther M. John, Susan L. Neuhausen, Elena Martinez, James V. Lacey, Katie M. O'Brien, Dale P. Sandler, Clarice R. Weinberg, Julie R. Palmer, Kimberly A. Bertrand, Celine M. Vachon, Janet E. Olson, Kathryn E. Ruddy, Hoda Anton-Culver, Argyrios Ziogas, David E. Goldgar, Katherine L. Nathanson, Susan M. Domchek, Jeffrey N. Weitzel, Peter Kraft, Jill S. Dolinsky, Tina Pesaran, Marcy E. Richardson, Siddhartha Yadav, Fergus J. Couch","doi":"10.1158/1078-0432.ccr-24-1884","DOIUrl":null,"url":null,"abstract":"Purpose: To determine the relationship between germline pathogenic variants (PVs) in cancer predisposition genes and the risk of ductal carcinoma in situ (DCIS). Methods: Germline PV frequencies in breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, PALB2, RAD51C, and RAD51D) were compared between DCIS cases and unaffected controls, and between DCIS and infiltrating ductal carcinoma (IDC) cases from a clinical-testing cohort (n=9,887), a population-based cohort (n=3,876) and the UK Biobank (n=2421). The risk of contralateral breast cancer for DCIS cases with PVs was estimated in the population-based cohort. Results: Germline PVs were observed in 6.5% and 4.6% of women with DCIS in the clinical-testing and population-based cohorts, respectively. BRCA1, BRCA2, and PALB2 PVs frequencies were significantly lower among women with DCIS than IDC (clinical cohort: 2.8% vs. 5.7%; population-based cohort: 1.7% vs. 3.7%), whereas the PV frequencies for ATM and CHEK2 were similar. ATM, BRCA1, BRCA2, CHEK2, and PALB2 PVs were significantly associated with an increased risk of DCIS (OR>2.0), but only BRCA2 PVs were associated with high-risk (OR>4) in both cohorts. The cumulative incidence of contralateral breast cancer among carriers of PVs in high penetrance genes with DCIS was 23% over 15 years. Conclusions: The enrichment of PVs in ATM, BRCA1, BRCA2, CHEK2 and PALB2 among women with DCIS suggests that multigene panel testing may be appropriate for women with DCIS. Elevated risks of contralateral breast cancer in carriers of PVs in high penetrance genes with DCIS confirmed the utility of testing for surgical decision-making.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0000,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Cancer Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/1078-0432.ccr-24-1884","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Purpose: To determine the relationship between germline pathogenic variants (PVs) in cancer predisposition genes and the risk of ductal carcinoma in situ (DCIS). Methods: Germline PV frequencies in breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, PALB2, RAD51C, and RAD51D) were compared between DCIS cases and unaffected controls, and between DCIS and infiltrating ductal carcinoma (IDC) cases from a clinical-testing cohort (n=9,887), a population-based cohort (n=3,876) and the UK Biobank (n=2421). The risk of contralateral breast cancer for DCIS cases with PVs was estimated in the population-based cohort. Results: Germline PVs were observed in 6.5% and 4.6% of women with DCIS in the clinical-testing and population-based cohorts, respectively. BRCA1, BRCA2, and PALB2 PVs frequencies were significantly lower among women with DCIS than IDC (clinical cohort: 2.8% vs. 5.7%; population-based cohort: 1.7% vs. 3.7%), whereas the PV frequencies for ATM and CHEK2 were similar. ATM, BRCA1, BRCA2, CHEK2, and PALB2 PVs were significantly associated with an increased risk of DCIS (OR>2.0), but only BRCA2 PVs were associated with high-risk (OR>4) in both cohorts. The cumulative incidence of contralateral breast cancer among carriers of PVs in high penetrance genes with DCIS was 23% over 15 years. Conclusions: The enrichment of PVs in ATM, BRCA1, BRCA2, CHEK2 and PALB2 among women with DCIS suggests that multigene panel testing may be appropriate for women with DCIS. Elevated risks of contralateral breast cancer in carriers of PVs in high penetrance genes with DCIS confirmed the utility of testing for surgical decision-making.
期刊介绍:
Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.