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. 2025 Jan 6;31(1):130-138.
doi: 10.1158/1078-0432.CCR-24-1884.

Pathogenic Variants in Cancer Susceptibility Genes Predispose to Ductal Carcinoma In Situ of the Breast

Huaizhi Huang  1 , Ronan E Couch  1 , Rachid Karam  2 , Chunling Hu  1 , Nicholas Boddicker  3 , Eric C Polley  4 , Jie Na  3 , Christine B Ambrosone  5 , Song Yao  5 , Amy Trentham-Dietz  6 , A Heather Eliassen  7 , Kathryn Penney  7 , Kristen Brantley  7 , Clara Bodelon  8 , Lauren R Teras  8 , James Hodge  8 , Alpa Patel  8 , Christopher A Haiman  9 , Esther M John  10 , Susan L Neuhausen  11 , Elena Martinez  12 , James V Lacey  11 , Katie M O'Brien  13 , Dale P Sandler  13 , Clarice R Weinberg  13 , Julie R Palmer  14 , Kimberly A Bertrand  14 , Celine M Vachon  3 , Janet E Olson  3 , Kathryn E Ruddy  15 , Hoda Anton-Culver  16 , Argyrios Ziogas  16 , David E Goldgar  17 , Katherine L Nathanson  18 , Susan M Domchek  18 , Jeffrey N Weitzel  19 , Peter Kraft  20 , Jill S Dolinsky  2 , Tina Pesaran  2 , Marcy E Richardson  2 , Siddhartha Yadav  1 , Fergus J Couch  1   3
Affiliations

Pathogenic Variants in Cancer Susceptibility Genes Predispose to Ductal Carcinoma In Situ of the Breast

Huaizhi Huang et al. Clin Cancer Res. .

Abstract

Purpose: To determine the relationship between germline pathogenic variants (PV) in cancer predisposition genes and the risk of ductal carcinoma in situ (DCIS).

Experimental design: 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 invasive ductal breast cancer (IDC) cases from a clinical testing cohort (n = 9,887), a population-based cohort (n = 3,876), and the UK Biobank (n = 2,421). The risk of contralateral breast cancer (CBC) for DCIS cases with PV was estimated in the population-based cohort.

Results: Germline PV 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 PV frequencies were significantly lower among women with DCIS than those with 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 PV were significantly associated with an increased risk of DCIS (OR > 2.0), but only BRCA2 PV were associated with high risk (OR > 4) in both cohorts. The cumulative incidence of CBC among carriers of PV in high-penetrance genes with DCIS was 23% over 15 years.

Conclusions: The enrichment of PV 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 CBC in carriers of PV in high-penetrance genes with DCIS confirmed the utility of testing for surgical decision-making.

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Conflict of interest statement

R. Karam reports other support from Ambry Genetics outside the submitted work. A. Trentham-Dietz reports grants from NCI during the conduct of the study. A.H. Eliassen reports grants from NIH during the conduct of the study. J.R. Palmer reports grants from NIH during the conduct of the study. C.M. Vachon reports grants from NCI during the conduct of the study, as well as grants from GRAIL outside the submitted work. J.N. Weitzel reports grants from Breast Cancer Research Foundation during the conduct of the study, as well as personal fees from Natera, MyOme, CancerIQ, and AstraZeneca and other support from Natera outside the submitted work. P. Kraft reports grants from NIH during the conduct of the study. J.S. Dolinsky reports personal fees from Ambry Genetics outside the submitted work. M.E. Richardson reports personal fees from Ambry Genetics outside the submitted work. S. Yadav reports other support from AstraZeneca and Repare Therapeutics outside the submitted work. F.J. Couch reports grants from NIH and Breast Cancer Research Foundation during the conduct of the study, as well as grants from GRAIL and personal fees from AstraZeneca outside the submitted work. No disclosures were reported by the other authors.

Figures

Figure 1.
Figure 1.
Estimated risks of DCIS associated with PV in breast cancer predisposition genes. ORs and 95% CIs (bars) for associations of PV in predisposition genes with breast cancer are shown for the population-based CARRIERS and clinical testing cohorts in combination with gnomAD reference controls.
Figure 2.
Figure 2.
CBC in BRCA1 and BRCA2 PV carriers with DCIS in the population-based cohort. Kaplan–Meier plots for CBC events over 20 years are shown for carriers of PV in BRCA1/BRCA2 (red) and noncarriers (blue). Number of events by time period is indicated below the graph.
See this image and copyright information in PMC

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