Targeted Sequencing of Germline Breast Cancer Susceptibility Genes for Discovering Pathogenic/Likely Pathogenic Variants in the Jakarta Population

Abstract

Germline predisposition plays an important role in breast cancer. Different ethnic populations need respective studies on cancer risks pertinent to germline variants. We aimed to discover the pathogenic and likely pathogenic variants (P/LP-Vs) of germline breast cancer susceptibility genes and to evaluate their correlation with the clinical characteristics in Jakarta populations. The pure DNA was extracted from the blood buffy coat, using reagents from the QIAamp DNA Mini Kit® (Qiagen, Hilden, Germany). The DNA libraries were prepared using the TargetRich™ Hereditary Cancer Panel (Kailos Genetics®, Huntsville, AL, USA). The barcoded DNA libraries were sequenced using the Illumina NextSeq 500 platform. In-house bioinformatics pipelines were used to analyze the gene variants. We identified 35 pathogenic and likely pathogenic (P/LP-Vs) variants (28 frameshift, 5 nonsense, and 2 splice-site variants). The P/LP-Vs group was statistically significantly different in luminal B status (p < 0.05) compared with the non-P/LP-Vs group. The P/LP-Vs found both in BRCA1/2 genes and non-BRCA genes may increase the risk of breast cancer and alter drug responses. The screening of multigene variants is suggested, rather than BRCA testing only. Prior knowledge of the germline variants status is important for optimal breast cancer diagnosis and optimal therapy.

Keywords

• breast cancer
• germline variants
• NGS
• sequencing
• young women