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.

中文翻译：

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癌症易感基因的致病性变异易患乳腺导管原位癌


目的： 确定癌症易感基因中的种系致病性变异 （PVs） 与导管原位癌 （DCIS） 风险之间的关系。方法：比较乳腺癌易感基因 （ATM、BARD1、BRCA1、BRCA2、CDH1、CHEK2、PALB2、RAD51C 和 RAD51D） 在 DCIS 病例和未受影响的对照之间，以及来自临床检测队列 （n=9,887）、基于人群的队列 （n=3,876） 和英国生物样本库 （n=2421） 的 DCIS 和浸润性导管癌 （IDC） 病例。在基于人群的队列中估计了 PVs 的 DCIS 病例患对侧乳腺癌的风险。结果： 在临床检测和基于人群的队列中，分别在 6.5% 和 4.6% 的 DCIS 女性患者中观察到种系 PV。DCIS 女性患者的 BRCA1、BRCA2 和 PALB2 PVs 频率显著低于 IDC （临床队列：2.8% vs. 5.7%;基于人群的队列：1.7% vs. 3.7%），而 ATM 和 CHEK2 的 PV 频率相似。ATM、BRCA1、BRCA2、CHEK2 和 PALB2 PVs 与 DCIS 风险增加显著相关 （OR>2.0），但在两个队列中，只有 BRCA2 PVs 与高危 （OR>4） 相关。在 23 年内，DCIS 高外显率基因的 PVs 携带者对侧乳腺癌的累积发病率为 15%。结论： DCIS 女性 ATM 、 BRCA1 、 BRCA2 、 CHEK2 和 PALB2 中 PVs 的富集表明多基因面板检测可能适用于患有 DCIS 的女性。DCIS 高外显基因的 PV 携带者患对侧乳腺癌的风险升高证实了检测对手术决策的效用。