Identification of novel hereditary cancer genes by whole exome sequencing

Abstract

Whole exome sequencing (WES) provides a powerful tool for medical genetic research. Several dozens of WES studies involving patients with hereditary cancer syndromes have already been reported. WES led to breakthrough in understanding of the genetic basis of some exceptionally rare syndromes; for example, identification of germ-line SMARCA4 mutations in patients with ovarian hypercalcemic small cell carcinomas indeed explains a noticeable share of familial aggregation of this disease. However, studies on common cancer types turned out to be more difficult. In particular, there is almost a dozen of reports describing WES analysis of breast cancer patients, but none of them yet succeeded to reveal a gene responsible for the significant share of missing heritability. Virtually all components of WES studies require substantial improvement, e.g. technical performance of WES, interpretation of WES results, mode of patient selection, etc. Most of contemporary investigations focus on genes with autosomal dominant mechanism of inheritance; however, recessive and oligogenic models of transmission of cancer susceptibility also need to be considered. It is expected that the list of medically relevant tumor-predisposing genes will be rapidly expanding in the next few years.

Cytotoxic and targeted therapy for hereditary cancers

“…The number of known hereditary cancer syndromes will rapidly grow within next several years, thanks to the invention of whole exome sequencing [131]. Many of already identified hereditary cancer types are represented by exceptionally rare instances of the disease, and future investigations are likely to reveal even more uncommon cancer syndromes.…”

“…There are multiple types of hereditary colon cancer [131], with the so-called hereditary non-polyposis colorectal cancer (HNPCC) syndrome being the most studied type of this disease. HNPCC is caused by germ-line mutations in DNA mismatch repair genes; HNPCC-related tumors are characterized by a unique phenotypic feature, i.e.…”

Molecular Diagnostics in Clinical Oncology

“…In contrast to non-cancer genetic diseases, where significant knowledge is accumulated with regard to pathogenic role of aminoacid substitutions, the spectrum of tumor-predisposing alleles is almost entirely represented by protein-truncating variants (Sokolenko et al, 2015). It is beyond any reasonable doubt that many missense mutations, which are currently classified as “variants of unknown significance,” are actually disease-predisposing.…”

“…Only a minor part of the heritability of cancer risk has been dissected so far, and forthcoming whole exome sequencing studies are expected to significantly increase the number of known hereditary cancer genes. The existence of medically relevant interethnic genetic variations needs to be considered while planning these activities (Sokolenko et al, 2015). …”

“…This table does not include severe multiorgan maladies, in which cancer serves only as part of clinical manifestation, i.e., some primary immune deficiencies, DNA repair abnormalities etc. The list of cancer syndromes is constantly expanding due to discovery of novel causative genes (Sokolenko et al, 2015). The catalog of cancer syndromes can be found in the OMIM database (https://www.ncbi.nlm.nih.gov/omim/) .…”