| Title: | Pathogenic Variants in Cancer Susceptibility Genes Predispose to Ductal Carcinoma In Situ of the Breast |
| Journal: | Clinical Cancer Research |
| Published: | 8 Nov 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39513960/ |
| DOI: | https://doi.org/10.1158/1078-0432.ccr-24-1884 |
| URL: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11701432 |
Publication 14590
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Abstract
PURPOSE: To determine the relationship between germline pathogenic variants (PV) in cancer predisposition genes and the risk of ductal carcinoma in situ (DCIS).</p>
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.</p>
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.</p>
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.</p>
10 Keywords
- Adult
- Aged
- Breast Neoplasms
- Carcinoma, Ductal, Breast
- Carcinoma, Intraductal, Noninfiltrating
- Female
- Genetic Predisposition to Disease
- Germ-Line Mutation
- Humans
- Middle Aged
42 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
Enabling scientific discoveries that improve human health