Background Associations between germline alterations in women and cancer risks among their relatives are largely unknown. Methods We used women from two Swedish cohorts (KARMA and pKARMA), including 28,362 women with genotyping data and 13,226 with sequencing data. Using Swedish Multi-Generation Register, we linked these women to 133,389 first-degree relatives. Associations between protein-truncating variants (PTVs) in 8 risk genes and breast cancer polygenic risk score (PRS) in index women and cancer risks among their relatives were modeled via Cox regression. Results Female relatives of index women who were PTV carriers in any of the 8 risk genes had an increased breast cancer risk compared to those of non-carriers (HR 1.85, 95% CI: 1.52-2.27), with the strongest association found for PTVs in BRCA1/2. These relatives had a statistically higher risk of early-onset than late-onset breast cancer (P = .001). Elevated breast cancer risk was also observed in female relatives of index women with higher PRS (HR per SD: 1.28, 95% CI: 1.23-1.32). The estimated lifetime risk was 22.3% for female relatives of PTV carriers and 14.4% for those related to women in the top PRS quartile. Moreover, relatives of index women with PTV presence (HR: 1.30, 95% CI: 1.06-1.59) or higher PRS (HR per SD: 1.04, 95% CI: 1.01-1.07) were also at higher risk of non-breast-HBOC cancers, including prostate, ovarian, pancreatic cancer, and melanoma. Conclusions Both PTVs of risk genes and higher PRS in index women are associated with an increased risk of breast and other HBOC-related cancers among relatives.

中文翻译：

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具有乳腺癌遗传倾向的女性的一级亲属的癌症风险

背景 女性种系改变与其亲属癌症风险之间的关联在很大程度上尚不清楚。方法 我们使用了来自两个瑞典队列（KARMA 和 pKARMA）的女性，其中包括 28,362 名拥有基因分型数据的女性和 13,226 名拥有测序数据的女性。使用瑞典多代登记系统，我们将这些女性与 133,389 名一级亲属联系起来。通过 Cox 回归对 8 个风险基因的蛋白质截短变异 (PTV) 与指数女性的乳腺癌多基因风险评分 (PRS) 及其亲属的癌症风险之间的关联进行建模。结果 与非携带者相比，8 个风险基因中任何一个 PTV 携带者的指标女性的女性亲属患乳腺癌的风险增加（HR 1.85，95% CI：1.52-2.27），其中与 PTV 的关联性最强在 BRCA1/2 中。从统计上看，这些亲属患早发性乳腺癌的风险高于晚发性乳腺癌 (P = .001)。 PRS 较高的指标女性的女性亲属中也观察到乳腺癌风险升高（HR/SD：1.28，95% CI：1.23-1.32）。 PTV 携带者的女性亲属的估计终生风险为 22.3%，与 PRS 前四分位数的女性亲属的估计终生风险为 14.4%。此外，存在 PTV（HR：1.30，95% CI：1.06-1.59）或更高 PRS（HR per SD：1.04，95% CI：1.01-1.07）的指标女性的亲属也有较高的非乳腺癌风险。 HBOC 癌症，包括前列腺癌、卵巢癌、胰腺癌和黑色素瘤。结论 指数女性的风险基因 PTV 和较高的 PRS 均与亲属中乳腺癌和其他 HBOC 相关癌症的风险增加相关。