Background: Morbidity and mortality associated with breast cancer (BC) had increased rapidly in China. Early screening and intervention could greatly reduce the risk of hereditary BC. Several risk models had been utilized over the last decades to predict individual BC risk, but most of them didn’t assess the polygenic risk of low-penetrant genes. A novel screening method integrating different penetrance susceptibility genes was eagerly needed.
Methods: Twenty-three variants of high and moderate penetrance susceptibility genes (HVs) and twenty loci of low penetrance susceptibility genes (LVs) were selected from previous studies. Genotyping of these mutations were conducted among 3777 healthy Chinese Han women and 401 BC subjects. Based on the mutation profiles, we raised a comprehensive screening strategy using HVs and LVs to evaluate the polygenic risk score (PRS) in healthy individuals.
Results: Three HVs in BRCA1, BRCA2 and PALB genes mutated in the study population, which suggests the necessity of applying genetic determination to healthy Han Chinese women. LVs were widely carried in objects and their frequencies differed greatly between Han Chinese females and the west population. After quality control and lasso dimension reduction, nineteen of twenty-three LVs were involved to construct a logistic regression model to evaluate the cumulative genetic risk score. The area under curve (AUC), sensitivity and specificity of the model is 0.993, 0.9676 and 0.9617 respectively, indicating that it is robust. Finally, a screening strategy using HVs and LVs was put forward to evaluate the risk of BC in normal objects.
Conclusions: The distribution of HVs and LVs differed greatly between Han Chinese females and the west population. A screening strategy combining HVs and LVs showed strong efficacy in distinguishing high risk individuals from healthy women.
Trial registration: ChiCTR, ChiCTR2000038558. Registered 24 September 2020 - Retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=60543