A Systematic Literature Review of Whole Exome and Genome Sequencing Population Studies of Genetic Susceptibility to Cancer

Abstract

The application of next-generation sequencing (NGS) technologies in cancer research has accelerated the discovery of somatic mutations; however, progress in the identification of germline variation associated with cancer risk is less clear. We conducted a systematic literature review of cancer genetic susceptibility studies that used NGS technologies at an exome/genome-wide scale to obtain a fuller understanding of the research landscape to date and to inform future studies. The 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 review highlights the importance of establishing consensus on standards for the application and reporting of variants filtering strategies. It also describes the progress in the identification of cancer-related germline variation to date. These findings point to the untapped potential in conducting studies with appropriately sized and racially diverse families and populations, combining results across studies and expanding beyond a candidate analysis approach to advance the discovery of genetic variation that accounts for the unexplained cancer heritability.

Figure 1

Summary across the 186 reviewed articles of the methods used to conclude if a variant or gene was plausibly involved in a causal pathway to cancer. The y-axis displays the PMID of the 186 coded papers; the x-axis displays 29 broad categories of filtering criteria described in Table 1. White color indicates that the criterion was not used by the authors to identify a variant/gene as possibly linked to the cancer under investigation. Light blue indicates that the criterion was used as a selection filter. Dark blue indicates that the criterion was used as increased evidence of variant/gene-cancer association. Pink color indicates that the criterion was used as decreased evidence of variant/gene-cancer association. Dark red indicates that the information related to that criterion was unclear. The last category on the right “unclear” indicates that some other not clearly stated criteria were used. The order of the papers along the y-axis is based on a computed correlation between values 2 (for supporting evidence), 1 (for used selection criteria), 0 (for not used criteria), −1 (for unsupporting evidence) and −2 (for unclear), i.e., papers using similar filtering criteria sets are shown next to each other.