Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Abstract

The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts.

Somatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse

“…While these represent a plurality of newly diagnosed cases, it is unclear how these findings relate to other localized disease states. Finally, we cannot exclude the possibility of study-specific false-negative errors due to the use of unique analysis pipelines for each study cohort, although, the current study detected clinically relevant mutations in at least some driver genes across validated analysis pipelines 61 – 63 . For example, in localized disease, CNAs were called from either whole-genome sequencing (Gerhauser) or various microarray platforms (CPCG, TCGA, Baca, Barbieri, Taylor).…”

JWES: a new pipeline for whole genome/exome sequence data processing, management, and gene‐variant discovery, annotation, prediction, and genotyping

“…In the last several years, it has served as a powerful and cost‐effective tool for minutely dissect the genetic basis of diseases including the Mendelian disorders [58]. It has catapulted the speed of novel disease‐associated genes identification in intellectual disability [59], Parkinson's disease [60], and cancers [61]. Data generated from NGS technologies have led to a paradigm shift in the field of medical research and how clinical investigators practice the treatment of rare and more frequent human disorders [62].…”

Read depth correction for somatic mutations

“…In addition to undergoing exome sequencing, a certain number of TCGA samples also underwent genome sequencing as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. Recently the mutation calls between these two consortia were compared 10 . The comparison identified mutations which were only 3/6 called by the MC3 working group, mutations which were only called by the PCAWG working group, and called by both (Figure 2A).…”