Mutational heterogeneity in cancer and the search for new cancer-associated genes

Abstract

Major international projects are now underway aimed at creating a comprehensive catalog of all genes responsible for the initiation and progression of cancer. These studies involve sequencing of matched tumor–normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here, we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false positive findings that overshadow true driver events. Here, we show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumor-normal pairs and discover extraordinary variation in (i) mutation frequency and spectrum within cancer types, which shed light on mutational processes and disease etiology, and (ii) mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and allow true cancer genes to rise to attention.

NF1‐mutated melanoma tumors harbor distinct clinical and biological characteristics

“…Screening for significantly mutated genes was performed using the MutSigCV algorithm (Lawrence et al ., 2013). Fisher's exact test was used to evaluate correlations between clinical variables in the total cohort, or stratified upon the genomic groups, and finally to further examine the prevalence of mutated genes or mutated signaling pathways across the genomic subtypes.…”

Enhanced inflammation and attenuated tumor suppressor pathways are associated with oncogene‐induced lung tumors in aged mice

“…As early as the 1950s, it was hypothesized that cancers were a product of a multistep genetic lesions arising somatically in specific cells (Nordling, 1953; Armitage & Doll, 1954). Cancer genome sequencing has confirmed that the vast majority of individual cancers display mutations in multiple genes known functionally to be cancer driver genes (Lawrence et al ., 2013). Thus, the age dependence of cancer is likely driven in large measure by the statistical likelihood over time that a given set of complementary driver mutations occurs within a single normal cell that transforms it into a malignant cancer cell.…”

Germline genetic variants were interactively associated with somatic alterations in gastric cancer

“…Gastric cancer driver genes were obtained from 3 sources: (1) 16 gastric cancer‐related driver genes from Catalogue of Somatic Mutations in Cancer (COSMIC) Cancer Gene Census(v78)31; (2) 175 driver genes of gastric cancer from the Integrative Onco Genomics (IntOGen) database32; (3) 108 significantly mutated genes (SMGs) and 26 somatic copy number alteration genes from previously published Whole Genome Sequencing (WGS) or Whole Exome Sequencing (WES) articles 4, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22…”

“…These studies have identified many driver genes, whose mutations confer selective growth advantage to tumor 11. Some of these driver genes are previously known cancer genes (eg, TP53 , ARID1A, and CDH1 ), while the others are new‐found significantly mutated genes in gastric cancer (eg, MUC6 , CTNNA2 , GLI3, and RNF43 ) 4, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22. Moreover, the copy number changes and characteristic mutational signatures also play important roles in gastric cancer development 4, 16, 17, 18, 19…”