Rozenblit Mariya, Qing Tao, Ye Yixuan, Zhao Hongyu, Hofstatter Erin, Singh Vinit, Reisenbichler Emily, Murray Michael, Pusztai Lajos
Breast Medical Oncology, School of Medicine, Yale University, New Haven, CT, USA.
Computation Biology and Bioinformatics Program, Yale University, New Haven, CT, USA.
Breast Cancer Res Treat. 2025 Jan;209(1):21-26. doi: 10.1007/s10549-024-07560-y. Epub 2024 Nov 27.
It is incompletely understood why some women develop breast cancer 15-20 years earlier than the majority of women. We hypothesize that women with early-onset breast cancer and high-risk family history without germline pathogenic variants in cancer-predisposing genes (CPGs, n = 83) have a higher load of germline high functional impact variants (gHFI) in cancer hallmark genes (n = 1508) compared to healthy controls.
Germline whole exome sequencing data were analyzed from 5818 breast cancer cases from UKBiobank and from 94 young women with breast cancer without CPG pathogenic variants from the Yale Cancer Prevention Clinic, and compared to 149 controls from Yale GENERATIONS project and 56,917 controls from UKBiobank. Rare gHFI variants were compared between cases and controls using the burden test and the optimal unified SNP-set Kernel Association Test (SKAT-O). We assessed germline versus somatic origins of pathway level alterations in the TCGA and Yale data.
In UKBiobank, higher gHFI variant load was seen in CPGs in cancer cases regardless of family history (p < 8.78 × 10), and in hallmark genes in cases with family history vs controls (p = 0.0093). Similarly, numerically higher rare gHFI burden was seen in hallmark genes in the Yale cohort vs controls, but this difference was not statistically significant. Pathway level alterations were dominated by somatic events. These results suggest that rare germline variants in cancer biology-related genes partly mediate the contribution of family history to cancer risk in individuals without germline alterations in high penetrance CPGs.
目前尚不完全清楚为何有些女性患乳腺癌的时间比大多数女性早15至20年。我们推测，与健康对照相比，患有早发性乳腺癌且有高危家族史但癌症易感基因（CPGs，n = 83）中无胚系致病变异的女性，其癌症特征基因（n = 1508）中的胚系高功能影响变异（gHFI）负荷更高。
分析了来自英国生物银行的5818例乳腺癌病例以及来自耶鲁癌症预防诊所的94例无CPG致病变异的年轻乳腺癌女性的胚系全外显子测序数据，并与来自耶鲁世代项目的149例对照以及来自英国生物银行的56917例对照进行比较。使用负担检验和最优统一单核苷酸多态性集核关联检验（SKAT-O）比较病例组和对照组之间的罕见gHFI变异。我们在TCGA和耶鲁的数据中评估了通路水平改变的胚系与体细胞起源。
在英国生物银行中，无论家族史如何，癌症病例中CPGs的gHFI变异负荷均较高（p < 8.78×10），有家族史的病例与对照相比，特征基因中的gHFI变异负荷也较高（p = 0.0093）。同样，在耶鲁队列中，特征基因中的罕见gHFI负担在数值上高于对照组，但这种差异无统计学意义。通路水平的改变以体细胞事件为主。这些结果表明，癌症生物学相关基因中的罕见胚系变异部分介导了家族史对无高外显率CPG胚系改变个体癌症风险的影响。
