Germline Variants in 32 Cancer-Related Genes among 700 Chinese Breast Cancer Patients by Next-Generation Sequencing: A Clinic-Based, Observational Study

Abstract

Breast cancer (BC) is associated with hereditary components, and some deleterious germline variants have been regarded as effective therapeutic targets. We conducted a clinic-based, observational study to better understand the distribution of deleterious germline variants and assess any clinicopathological predictors related to the variants among Chinese BC patients using a 32 cancer-related genes next-generation sequencing panel. Between November 2020 and February 2022, a total of 700 BC patients were recruited, and 13.1% (92/700) of them carried deleterious germline variants in 15 cancer-related genes, including 37 (37/700, 5.3%) in BRCA2, 29 (29/700, 4.1%) in BRCA1, 8 (8/700, 1.1%) in PALB2, 4 (4/700, 0.6%) in NBN, 3 (3/700, 0.4%) in MRE11A, 3 (3/700, 0.4%) in TP53 and 12 (12/700, 1.7%) in other genes. There were 28 novel variants detected: 5 in BRCA1, 14 in BRCA2, and 9 in non-BRCA1/2 genes. The variants in panel genes, HRR (homologous recombination repair)-related genes, and BRCA1/2 were significantly associated with the following clinicopathological factors: age at the initial diagnosis of BC, family history of any cancer, molecular subtype, Ki-67 index, and hereditary risk. In conclusion, we further expanded the spectrum of germline deleterious variants in Chinese BC patients, and the clinicopathological predictors of variants were identified to facilitate clinical genetic testing and counseling for appropriate individuals.

Role of Breast Cancer Risk Estimation Models to Identify Women Eligible for Genetic Testing and Risk-Reducing Surgery

“…Patients with early-onset BC have the highest probability of being carriers of BRCA1 or BRCA2 PGVs. Conversely, patients with later-onset BC have the highest probability of being carriers of non-BRCA1/BRCA2 PGVs [10]. In the case of a positive oncological family history, the prevalence of BRCA1/BRCA2 PGVs is comparable to the prevalence of PGVs in HBOC-related genes not including BRCA1/BRCA2.…”

“…On the other hand, in the absence of an oncological family history, PGVs in HBOC-related genes not including BRCA1/BRCA2 are prevalent and can cause oncological diseases less frequently due to their low penetrance. Therefore, these women may not develop tumors during their lifetime [10].…”