Gene Panel Testing in Hereditary Breast Cancer

Area of Science:

• Genetics
• Oncology

Background:

• Breast cancer (BC) is a leading cause of cancer mortality in women, with hereditary factors playing a significant role.
• While BRCA1/2 mutations account for a small percentage of hereditary breast cancer, other genetic mutations are implicated.
• Investigating additional BC genes is crucial for understanding familial BC, particularly in diverse populations like the Iranian population.

Purpose of the Study:

• To investigate the role of other breast cancer (BC) susceptibility genes in familial BC among the Iranian population.
• To identify mutations in known BC genes among patients with hereditary BC who are wild-type for BRCA1/2 mutations.

Main Methods:

• Selected 61 hereditary breast cancer (BC) patients negative for BRCA1/2 mutations based on ACMG/NCCN guidelines.
• Performed targeted sequencing of 130 cancer susceptibility genes using next-generation sequencing (NGS).
• Confirmed identified mutations via Sanger sequencing and RT-PCR for splice variants, with in silico pathogenicity prediction.

Main Results:

• Identified seven mutations in seven known BC susceptibility genes (RAD50, PTEN, TP53, POLH, DKC1, WRN, CHEK2) in seven patients.
• Detected pathogenic variants including frameshift, missense, and splice donor mutations.
• Confirmed pathogenicity through Sanger sequencing, RT-PCR, and in silico analysis.

Conclusions:

• Panel testing for BC patients with hereditary criteria but negative BRCA1/2 results provides valuable clinical information in ~11.5% of families.
• Next-generation sequencing (NGS) is an effective tool for identifying pathogenic variants in hereditary BC patients with negative BRCA1/2 testing.
• This study expands the understanding of genetic underpinnings of familial breast cancer in the Iranian population.