Somatic Mutation Patterns in Hemizygous Genomic Regions Unveil Purifying Selection during Tumor Evolution

Abstract

Identification of cancer driver genes using somatic mutation patterns indicative of positive selection has become a major goal in cancer genomics. However, cancer cells additionally depend on a large number of genes involved in basic cellular processes. While such genes should in theory be subject to strong purifying (negative) selection against damaging somatic mutations, these patterns have been elusive and purifying selection remains inadequately explored in cancer. Here, we hypothesized that purifying selection should be evident in hemizygous genomic regions, where damaging mutations cannot be compensated for by healthy alleles. Using a 7,781-sample pan-cancer dataset, we first confirmed this in POLR2A, an essential gene where hemizygous deletions are known to confer elevated sensitivity to pharmacological suppression. We next used this principle to identify several genes and pathways that show patterns indicative of purifying selection to avoid deleterious mutations. These include the POLR2A interacting protein INTS10 as well as genes involved in mRNA splicing, nonsense-mediated mRNA decay and other RNA processing pathways. Many of these genes belong to large protein complexes, and strong overlaps were observed with recent functional screens for gene essentiality in human cells. Our analysis supports that purifying selection acts to preserve the remaining function of many hemizygously deleted essential genes in tumors, indicating vulnerabilities that might be exploited by future therapeutic strategies.

Searching for essential genes in cancer genomes

“…Так, согласно [41], только 0,14% генов находятся под отрицательным отбором, для небольшой доли генов (2,2%) характерен положительный отбор, в то время как подавляющее большинство генов аккумулирует мутации нейтрально -соответствующие величины dN/dS приблизительно равны единице. Единственной категорией, для которой удалось показать связь между пониженным значением величины dN/dS и эссенциальностью гена -это нонсенс-мутации в гемизиготных участках генома, что согласуется с данными работы [46].…”

“…Подводя итог, следует отметить крайне незначительный уровень отрицательного отбора в раковом геноме [41,45,46]. Частично это можно объяснить недостатком имеющихся данных по соматическим мутациям.…”

Lack of detectable neoantigen depletion in the untreated cancer genome

“…Our results indicate that signals of neoantigen depletion are overall weak to absent in the untreated cancer genome. While we cannot exclude that this is related to poor accuracy to predict HLA affinities and neoantigen formation, it is remarkable that signals of negative selection in general are weak in cancer mutation data (22,23,36,37). As neoantigen depletion results from a specific form of negative selection, it should in the end also be detectable as a reduction in overall mutation rates in cancers that are known to be influenced by the immune system, even without considering HLA affinities.…”

Whole Genome Doubling mitigates Muller’s Ratchet in Cancer Evolution

“…Indeed, the extent of negative selection during somatic evolution has been subject to debate. For example, while negative selection has been reported in transcription factor binding motifs (Vorontsov et al, 2016), hemizygous regions (van den Eynden et al, 2016;Martincorena et al, 2017) and splicing-associated sequences (Hurst et al, 2017), conflicting reports regarding the extent to which the immune system results in negative selection and mutation loss have been presented (Zapata et al, 2018;Martincorena et al, 2017;Van den Eynden et al, 2018).…”