Detection of Germline Mutations in Breast Cancer Patients with Clinical Features of Hereditary Cancer Syndrome Using a Multi-Gene Panel Test

Abstract

Purpose: Hereditary cancer syndrome means that inherited genetic mutations can increase a person's risk of developing cancer. We assessed the frequency of germline mutations using an next-generation sequencing (NGS)-based multiple-gene panel containing 64 cancer-predisposing genes in Korean breast cancer patients with clinical features of hereditary breast and ovarian cancer syndrome (HBOC).

Materials and methods: A total of 64 genes associated with hereditary cancer syndrome were selected for development of an NGS-based multi-gene panel. Targeted sequencing using the multi-gene panel was performed to identify germline mutations in 496 breast cancer patients with clinical features of HBOC who underwent breast cancer surgery between January 2002 and December 2017.

Results: Of 496 patients, 95 patients (19.2%) were found to have 48 deleterious germline mutations in 16 cancer susceptibility genes. The deleterious mutations were found in 39 of 250 patients (15.6%) who had breast cancer and another primary cancer, 38 of 169 patients (22.5%) who had a family history of breast cancer (≥ 2 relatives), 16 of 57 patients (28.1%) who had bilateral breast cancer, and 29 of 84 patients (34.5%) who were diagnosed with breast cancer at younger than 40 years of age. Of the 95 patients with deleterious mutations, 60 patients (63.2%) had BRCA1/2 mutations and 38 patients (40.0%) had non-BRCA1/2 mutations. We detected two novel deleterious mutations in BRCA2 and MLH1.

Conclusion: NGS-based multiple-gene panel testing improved the detection rates of deleterious mutations and provided a cost-effective cancer risk assessment.

Keywords: Breast cancer; Germline mutation; Hereditary breast and ovarian cancer syndrome; Next-generation sequencing.

Fig. 1.

Summary of 48 deleterious mutations in 95 patients. Deleterious BRCA1 and BRCA2 mutations were detected in 30 patiensts and 31 patients, respectively. Non-BRCA1/2 germline mutations were found in 38 patients including CDH1, RAD51, SPINK1, TP53 and so on.

Fig. 2.

The proportion of deleterious mutations according to risk factors of hereditary cancer syndrome. The highest proportion of deleterious mutations were found in breast cancer patients who were diagnosed at < 40 years old and the lowest were found in breast cancer patient with another primary cancer. VUS, variants of unknown significance.

Fig. 3.

The distributions of the cancer susceptibility genes according to risk factors hereditary cancer syndrome. The proportion of BRCA1/2 mutations were relatively small in breast cancer patients with another primary cancer compared with patients with other risk factors.

Fig. 4.

Novel deleterious mutations mapped on corresponding protein structures. The impact of mutatinos were predicted in in silico analysis. (A) NM_000059.3:c.3096_3111del (p.Lys1032Asnfs*6) in BRCA2. (B) NM_000249.3:c.849T>A (p.Tyr283*) in MLH1.