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

Funder: NCI U24CA211006Abstract: 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

Allowable variability: a preliminary investigation of word recognition in Navajo

Because speakers do not produce uninflected or 'base' forms, and listeners do not hear them, the shape of the word lexicon in languages with highly productive word formation processes directly addresses the conflict between morphological theories which assume the primacy of word formation processes (Anderson 1992, Bybee and Moder 1983,) and theories of word recognition such as the Cohort theory (Caramaza, Laudana and Romani 1988, Marslen-Wilson 1978) which assume words are stored. How does a relationship between inflected forms, or between inflected forms and their more abstract base, get established? One (common) assumption is that less fluent speakers have less complete grammars and their mistakes reflect their less complete or 'imperfect' knowledge of structure. Since the productive morphology indicates a more complex word processing device and presumably a more complex word lexicon, these errors may reasonably reflect the principles that underlie the organization of the lexical system. In this study, designed to test the feasibility of this strategy, we produced a list of 100 Navajo forms, half of which were 'correct' Navajo words and half were 'incorrect', containing mistakes that less fluent Navajo speakers actually made. The Navajo verbs were categorized into 5 groups, reflecting five types of commonly occurring errors. We found that all speakers accommodated ‘errors’, with differences in the kinds of errors more and less fluent speakers tolerated. The results bear on the issue of the role context, fluency and morphological structure in the recognition of morphologically complex words

Sex differences in oncogenic mutational processes

Funder: Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada (NSERC Canadian Network for Research and Innovation in Machining Technology); doi: https://doi.org/10.13039/501100002790Funder: Genome Canada (Génome Canada); doi: https://doi.org/10.13039/100008762Funder: Canada Foundation for Innovation (Fondation canadienne pour l'innovation); doi: https://doi.org/10.13039/501100000196Funder: Terry Fox Research Institute (Institut de Recherche Terry Fox); doi: https://doi.org/10.13039/501100004376Abstract: Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research