This extensive review [see attached] describes the use of both whole-exome sequencing [WES; i.e. protein-coding genes only; spanning ~30 Mb (megabases, million bases)], plus whole-genome sequencing (WGS; 30,000+ Mb, i.e. the entire haploid genome). The application of NGS technologies has been successful in revealing complex somatic mutational signatures associated with different types of cancer — a disease that is (by definition) a result of somatic mutations. The estimated cancer heritability is ~33% for overall cancer, and its unexplained component has remained high (e.g. 91% of cancer cases tested negative for known mutations in a large gene-panel testing study). In addition to the heritability hidden in current array-based studies and likely detectability in using larger sample sizes — it has been postulated that the missing familial heritability may reside in rare variants of high or moderate/low penetrance, which are now potentially detectable by NGS technologies.
Authors [see attached review] therefore conducted a systematic literature review, evaluating the degree of success and limitations in identifying germline cancer susceptibility variants using WES and WGS. Given the transition of genomic discovery research from candidate genes (historically of limited success), the high cost of WES/WGS methods, and their specific challenge with sifting through millions of variants — this review focuses on the effectiveness of WES/WGS studies (and not on other NGS gene-targeted approaches) to identify novel variants and genes involved in cancer risk.
This review provides selected study-related characteristics, technologies, and methodologic details for 186 WES/WGS-related publications (out of a total of 6,339 unique articles) with the goal of informing the design of future studies. Authors also discussed the research needs and opportunities that could further advance the discovery of cancer susceptibility genes or variants. It should be noted that — although the 186 selected articles were not chosen on the basis of their focus on rare versus common variants, nor on their focus on low versus moderate/high penetrant variants, because more cost-efficient approaches (based on genome-wide genotyping assays) exist to study common variants, whereas NGS technologies are necessary to study rare variants. These GEITP pages believe the list of genes and genetic pathways shown in Table 3 was most informative. 😊
Authors found that variability across studies — on methodologies and reporting — was considerable; most studies sequenced few high-risk (mainly European) families, used a candidate-analysis approach, and identified potential cancer-related germline variants or genes in a small fraction of the sequenced cancer cases. This analysis, however, does highlight the importance of establishing consensus on standards for the application and reporting of variants filtering strategies. Authors also describe the progress in identification of cancer-related germline variation to date. Authors believe that their findings point to the untapped potential in conducting studies with appropriately-sized and ethnically-diverse families and populations, in which results across studies can be combined and expanded — beyond a candidate-analysis approach — to advance the discovery of genetic variation that accounts for unexplained cancer heritability. This overview should be a valuable resource for anyone interested in the heritability of cancer susceptibility. 😊
Cancer Epidemiol Biomarkers Prev Aug 2020; 29: 1519-1534