Universal patterns of selection in cancer and somatic tissues

Abstract

Cancer develops as a result of somatic mutation and clonal selection, but quantitative measures of selection in cancer evolution are lacking. We applied methods from evolutionary genomics to 7,664 human cancers across 29 tumor types. Unlike species evolution, positive selection outweighs negative selection during cancer development. On average, <1 coding base substitution/tumor is lost through negative selection, with purifying selection only detected for truncating mutations in essential genes in haploid regions. This allows exome-wide enumeration of all driver mutations, including outside known cancer genes. On average, tumors carry ~4 coding substitutions under positive selection, ranging from <1/tumor in thyroid and testicular cancers to >10/tumor in endometrial and colorectal cancers. Half of driver substitutions occur in yet-to-be-discovered cancer genes. With increasing mutation burden, numbers of driver mutations increase, but not linearly. We identify novel cancer genes and show that genes vary extensively in what proportion of mutations are drivers versus passengers. HIGHLIGHTS• Unlike the germline, somatic cells evolve predominantly by positive selection • Nearly all (~99%) coding mutations are tolerated and escape negative selection • First exome-wide estimates of the total number of driver coding mutations per tumor • 1-10 coding driver mutations per tumor; half occurring outside known cancer genes not peer-reviewed)

Filling the gap between chemical carcinogenesis and the hallmarks of cancer: A temporal perspective

“…Interestingly, a recent study involving next-generation sequencing of exomes in immortal human mammary epithelial cells showed that DNA repair genes were among the genes harbouring BaP-induced mutation with a potential functional impact, suggesting a potential impact on genome stability of the mutated cells. 26 Moreover, BaP increased the number of oxidatively induced clustered DNA lesions in normal primary breastderived cells which were correlated with the number of chromosomal aberrations. 67 These lesions were associated with a decrease in antioxidant defence capacity and an increased ROS and DNA repair gene transcription, 67 suggesting that oxidative stress and DNA damage and repair response are strictly correlated following BaP exposure.…”

“…Some mutations are just a byproduct of the increased genetic instability which characterizes the process of tumourigenesis. 26 In the causal framework we adopt, this means that mutations can provide different cues for the temporal reconstruction of cancer development. In other words, mutations may mark the cancer process at different salient points.…”

“…Studies have shown that a typical tumour contains 2-8 "driver gene" mutations, 26,27 but which specific genes will be mutated in different tumours might vary. In addition, cells from different sections of the same tumour tend to have a diverse mutational landscape, suggesting that different mutations may converge towards the same phenotypic result.…”

Guideline‐based and bioinformatic reassessment of lesion‐associated gene and variant pathogenicity in focal human epilepsies

“…We used the missense z conservation score when disease variants were reported to be missense variants in the brain lesion, pLI when disease variants were reported to be LoF variants, and both when missense and LoF variants were reported to play a role in the disease etiology. Additionally, as an alternative assessment of a gene's impact on diseases, we compared the neuropathology-associated gene set with cancer driver genes from Martincorena et al, 17 who studied the landscape of positive and negative selection in somatic evolution in cancer and systematically cataloged cancer genes.…”

“…Based on the literature, we categorized TSC1 and PTEN as intolerant for LoF, MTOR, PIK3CA, BRAF, and AKT3 as intolerant for missense, and NPRL2, NPRL3, TSC2, FGFR1, and DEPDC5 as intolerant for both (Table 1). Gene conservation scores (pLI and missense z) and gene positive selection classification in cancer genomes 17 indicated that only seven (AKT3, BRAF, DEPDC5, MTOR, PIK3CA, PTEN, and TSC1) of 11 genes showed support for association with a severe disease in early childhood for the reported disease mechanism by harboring significant less 16 or more 17 variants than expected under neutral evolution.…”