Germline Mutations in 32 Cancer Susceptibility Genes by Next-Generation Sequencing among Breast Cancer Patients

BRCA1/2 germline mutations are the most well-known genetic determinants for breast cancer. However, the distribution of germline mutations in non-BRCA1/2 cancer susceptibility genes in Chinese breast cancer patients is unclear. The association between clinical characteristics and germline mutations remains to be explored.

Consecutive breast cancer patients from Peking University People's Hospital were enrolled. Clinical characteristics were collected, and next-generation sequencing was performed using blood samples of participants to identify pathogenic/likely pathogenic (P/LP) germline mutations in 32 cancer susceptibility genes including homologous recombination repair (HRR) genes.

A total of 885 breast cancer patients underwent the detection of germline mutations. 107 P/LP germline mutations of 17 genes were identified in 116 breast cancer patients including 79 (8.9%) in BRCA1/2 and 40 (4.5%) in 15 non-BRCA1/2 genes. PALB2 was the most frequently mutated gene other than BRCA1/2 but still relatively rare (1.1%). There were 38 novel P/LP germline variants detected. P/LP germline mutations in BRCA1/2 were significantly associated with onset age (p < 0.001), the family history of breast/ovarian cancer (p = 0.010), and molecular subtype (p < 0.001), while being correlated with onset age (p < 0.001), site of breast tumor (p = 0.028), and molecular subtype (p < 0.001) in HRR genes.

The multiple-gene panel prominently increased the detection rate of P/LP germline mutations in 32 cancer susceptibility genes compared to BRCA1/2 alone. Onset younger than or equal to 45 years of age, bilateral and triple-negative breast cancer patients may be more likely to be recommended for detecting P/LP germline mutations in HRR genes.