Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
Oncogenetics Unit, Sheba Medical Center, Tel Hashomer, Israel.
BMC Cancer. 2022 Jun 27;22(1):706. doi: 10.1186/s12885-022-09780-1.
BACKGROUND: Clinical management of women carrying a germline pathogenic variant (PV) in the BRCA1/2 genes demands for accurate age-dependent estimators of breast cancer (BC) risks, which were found to be affected by a variety of intrinsic and extrinsic factors. Here we assess the contribution of polygenic risk scores (PRSs) to the occurrence of extreme phenotypes with respect to age at onset, namely, primary BC diagnosis before the age of 35 years (early diagnosis, ED) and cancer-free survival until the age of 60 years (late/no diagnosis, LD) in female BRCA1/2 PV carriers. METHODS: Overall, estrogen receptor (ER)-positive, and ER-negative BC PRSs as developed by Kuchenbaecker et al. for BC risk discrimination in female BRCA1/2 PV carriers were employed for PRS computation in a curated sample of 295 women of European descent carrying PVs in the BRCA1 (n=183) or the BRCA2 gene (n=112), and did either fulfill the ED criteria (n=162, mean age at diagnosis: 28.3 years, range: 20 to 34 years) or the LD criteria (n=133). Binomial logistic regression was applied to assess the association of standardized PRSs with either ED or LD under adjustment for patient recruitment criteria for germline testing and localization of BRCA1/2 PVs in the corresponding BC or ovarian cancer (OC) cluster regions. RESULTS: For BRCA1 PV carriers, the standardized overall BC PRS displayed the strongest association with ED (odds ratio (OR) = 1.62; 95% confidence interval (CI): 1.16-2.31, p<0.01). Additionally, statistically significant associations of selection for the patient recruitment criteria for germline testing and localization of pathogenic PVs outside the BRCA1 OC cluster region with ED were observed. For BRCA2 PV carriers, the standardized PRS for ER-negative BC displayed the strongest association (OR = 2.27, 95% CI: 1.45-3.78, p<0.001). CONCLUSIONS: PRSs contribute to the development of extreme phenotypes of female BRCA1/2 PV carriers with respect to age at primary BC diagnosis. Construction of optimized PRS SNP sets for BC risk stratification in BRCA1/2 PV carriers should be the task of future studies with larger, well-defined study samples. Furthermore, our results provide further evidence, that localization of PVs in BC/OC cluster regions might be considered in BC risk calculations for unaffected BRCA1/2 PV carriers.
背景：携带 BRCA1/2 基因种系致病性变异（PV）的女性的临床管理需要准确的年龄依赖性乳腺癌（BC）风险估计，这些风险估计受到多种内在和外在因素的影响。在这里，我们评估多基因风险评分（PRSs）对发病年龄极端表型的贡献，即 BRCA1/2 PV 携带者的原发性 BC 诊断年龄早于 35 岁（早期诊断，ED）和癌症无生存年龄早于 60 岁（晚期/无诊断，LD）。
方法：总体而言，Kuchenbaecker 等人开发的用于 BRCA1/2 PV 携带者中 BC 风险区分的雌激素受体（ER）阳性和 ER 阴性 BC PRS 用于计算 295 名欧洲血统的 BRCA1（n=183）或 BRCA2 基因（n=112）携带 PV 的女性的 PRS 计算，并满足 ED 标准（n=162，平均诊断年龄：28.3 岁，范围：20 至 34 岁）或 LD 标准（n=133）。应用二项逻辑回归评估标准化 PRS 与 ED 或 LD 的关联，调整种系检测的患者招募标准和 BRCA1/2 PV 在相应 BC 或卵巢癌（OC）簇区域的定位。
结果：对于 BRCA1 PV 携带者，整体 BC PRS 与 ED 关联最强（比值比（OR）=1.62；95%置信区间（CI）：1.16-2.31，p<0.01）。此外，还观察到患者招募标准和致病性 PV 定位于 BRCA1 OC 簇区域外与 ED 相关的选择与 ED 显著相关。对于 BRCA2 PV 携带者，ER 阴性 BC 的标准化 PRS 与 ED 关联最强（OR=2.27，95%CI：1.45-3.78，p<0.001）。
结论：PRSs 有助于 BRCA1/2 PV 携带者原发性 BC 诊断年龄的极端表型的发展。用于 BRCA1/2 PV 携带者的 BC 风险分层的优化 PRS SNP 集的构建应是未来具有更大、定义明确的研究样本的研究任务。此外，我们的结果提供了进一步的证据，即 PV 在 BC/OC 簇区域的定位可以在未受影响的 BRCA1/2 PV 携带者的 BC 风险计算中得到考虑。
J Natl Cancer Inst. 2022-1-11
JAMA Netw Open. 2024-4-1
NPJ Genom Med. 2024-3-14
Breast Care (Basel). 2023-12
Int J Mol Sci. 2023-11-30
Breast Care (Basel). 2021-4
J Natl Cancer Inst. 2021-7-1
Am J Hum Genet. 2018-12-13
Breast Care (Basel). 2018-4
Zotero 插件