Abstract 1600: A literature review of whole exome and genome sequencing population studies for identifying novel germline mutations in relation to cancer risk
Authors: Barajas Rolando , Hoover Elise , Clyne Mindy , Lam Tram , Mechanic Leah , Goldstein Alisa , Gillanders Elizabeth , Rotunno Melissa 
Published: August 2019

Abstract
The application of Next Generation Sequencing (NGS) technologies in cancer research has accelerated the discovery of somatic mutations; however, it has not mirrored the same progress in the identification of cancer associated germline variation. With the goal to inform future studies on commonly used methods and their degree of success and limitations in identifying germline variants associated with cancer, we performed a review of the English literature for genome-wide germline sequencing studies aimed at identifying new cancer susceptibility genes or variants. A key words search in 2005-April 2017 PubMed yielded 7,349 articles which were checked against the following exclusion criteria: non-cancer (1852), somatic mutations (1764), methods (905), reviews (872), non-human (735), expression (272), targeted sequencing (224), commentaries (170), epigenetic (135), non-English (89), functional (85), clinical studies (51), others (44). The remaining 151 publications were examined in-depth and coded in an Access database according to ~60 fields, capturing information on: publication (journal, year, author, title, abstract), study design (goal; cancer type; population and ethnicity; discovery, technical validation, and replication phases; numbers and characteristics of cases, controls, families used in each phase), sequencing technique (center, technology, coverage, reads aligner, variants caller, QCs), data analysis (variants annotation, candidate genes, filtering strategy, association test), in silico and experimental functional assessment, and key conclusions (main results, challenges, next steps). The discovery phase of the examined papers was largely based on familial cases (77%), exome/genome sequencing of one single family (31%), and restricted to the analysis of candidate genes lists. The distribution of ethnicity for the sequenced cancer patients was 38% European, 11% Asian, 10% African, 5% multi-ethnic, 4% African American, 3% Latino/Hispanic, 3% Middle Eastern, 1% Jewish, and 25% unreported. Breast, prostate, colorectal, and lung cancer represented ~40% of the assessed articles, and the remaining 60% a diverse group of rare cancer types. Most studies (~80%) included a technical validation phase, but without clear success rate. Only 60% of studies included a replication phase in an independent population. Although most studies (~80%) described the identification of multiple germline variants and genes thought to have a role in cancer susceptibility, the supporting evidence was often disparate or not clearly stated. Our findings underscore the importance of establishing standards for reporting filtering strategies and rational for variant identification. We identified untapped potentials in the utilization of more/larger families, the harmonization of results across studies, and the expansion beyond candidate genes.
Citation Format: Rolando Barajas, Elise Hoover, Mindy Clyne, Tram Lam, Leah Mechanic, Alisa Goldstein, Elizabeth Gillanders, Melissa Rotunno. A literature review of whole exome and genome sequencing population studies for identifying novel germline mutations in relation to cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1600.