Abstract
Next generation sequencing (NGS) provides a powerful tool in the field of medical genetics, allowing one to perform multi-gene analysis and to sequence entire exomes (WES), transcriptomes or genomes (WGS). The generated high-throughput data are particularly suitable for enhancing the understanding of the genetic bases of complex, multi-gene diseases, such as cancer. Among the various types of tumors, those with a familial predisposition are of great interest for the isolation of novel genes or gene variants, detectable at the germline level and involved in cancer pathogenesis. The identification of novel genetic factors would have great translational value, helping clinicians in defining risk and prevention strategies. In this regard, it is known that the majority of breast/ovarian cases with familial predisposition, lacking variants in the highly penetrant BRCA1 and BRCA2 genes (non-BRCA), remains unexplained, although several less penetrant genes (e.g., ATM, PALB2) have been identified. In this scenario, NGS technologies offer a powerful tool for the discovery of novel factors involved in familial breast/ovarian cancer. In this review, we summarize and discuss the state of the art applications of NGS gene panels, WES and WGS in the context of familial breast/ovarian cancer.
Highlights
Inherited genetic defective variants significantly contribute to familial cancers
The study of hereditary cancer was based on the linkage analysis of numerous pedigrees, which led, in 1994, to the isolation of BRCA1 and BRCA2, the main predisposing genes for hereditary breast/ovarian cancer (BC/OC) syndrome [1,2]
Only 20%–25% of Breast cancer (BC)/OC cases are due to inheritance of the highly penetrant cancer susceptibility genes BRCA1 and BRCA2, involved in DNA repair mechanisms [7]
Summary
Inherited genetic defective variants significantly contribute to familial cancers. The extensive use of Sanger DNA sequencing, often associated with upstream prescreening techniques (e.g., single stranded conformational polymorphism or DHPLC) [3], allowed the detection and the characterization of germ-line gene mutations responsible for cancer susceptibility. Technologies, able to perform multi-gene analysis or sequencing of entire exomes, corresponding to the DNA protein-coding regions, transcriptomes, including coding and/or non-coding RNA transcripts, or genomes, consisting of both exon and non-coding intron DNA regions [4,5]. This review is focused on describing the applications and potentiality of NGS technologies for the detection of variants in genes already known as responsible for familial breast and ovarian cancer, and novel susceptibility genes/variants as well
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