![]() ![]() Also, proliferation assays performed in cancer cells demonstrated that losing most genes would have a detrimental fitness effect 11. This indicates that general housekeeping functions (which should be important in somatic lineages too) are protected from mutations. E.g., globally expressed genes are under negative selection in the germline 20, 23. This is surprising given that many of the functions under negative selection in germline evolution affect general processes that should be important in every cell of the body, in particular in fast-dividing cancer cells. First, most mutations might have deleterious effects only on the development of an organism (germline evolution) but are instead tolerated in differentiated tissues or tumors (somatic evolution). Typically, two complementary answers are given to this question. These observations raise the question of how cancers can tolerate many deleterious mutations. This contrasts with negative selection during germline (organismal) evolution, where the majority of genes are under negative selection and thereby protected from mutations 20, 21, 22. While the extent of negative selection acting on cancer genomes is still under debate 3, 4, 5, 6, 15, 16, 17, 18, 19, common measures of selection – such as the ratio of non-synonymous to synonymous substitution rates (dN/dS) – indicate that most protein-coding genes lack detectable signals of negative selection in cancer genomes: as a matter of fact, 99% of coding mutations appear to be tolerated 5, 16. Specifically, among point mutations in coding regions, more than 75% are non-synonymous 12, and those mildly or strongly deleterious for cellular fitness are predicted to be within a range of about 65% 13 to >70% 14. ![]() However, in many systems – including cancer cells – the majority of coding mutations have been observed to have a deleterious role on cellular fitness: e.g., in silico evolutionary simulations 7, in vitro and in vivo proliferation assays 8, 9, 10, and whole-genome CRISPR-KO screens within different species and many tumor cell lines 11, showed a reduced in vitro proliferative fitness and a slower in vivo tumor growth, demonstrating the deleterious role of most coding passenger mutations. A small fraction of these thousands of aberrations 1, 2 is considered beneficial from the tumor perspective (driver events), while the vast majority is not undergoing detectable selection 3, 4, 5, 6 (passenger events). ![]() Ultimately, our work paves the way for the detection of novel cancer vulnerabilities by revealing genes that fall within amplifications likely selected during evolution to mitigate the effect of mutations.Ĭancer genomes evolve through the acquisition of multiple types of somatic aberrations – these include somatic single nucleotide variants (SNVs or mutations) and copy number alterations (CNAs). We show how cancer type-specific mutation landscapes drive copy number alteration patterns across cancer types. Our findings demonstrate that these potential buffering events are highly influenced by gene functions, essentiality, and mutation impact and that they occur early during tumor evolution. This could increase tolerance towards the deleterious impact of mutations by creating safe copies of wild-type regions and, hence, protecting the genes therein. Using 8,690 tumor samples from The Cancer Genome Atlas, we demonstrate that copy number amplifications frequently cover haploinsufficient genes in mutation-prone regions. This raises the question of how tumors tolerate such large amounts of deleterious mutations. While most coding mutations are deleterious, almost all protein-coding genes lack detectable signals of negative selection. Note: Because Article and Regulation numbers are not reassigned when Regulations are deleted, there may be gaps in numbering.Cancers evolve under the accumulation of thousands of somatic mutations and chromosomal aberrations. Website of World Cube Association: Original source of the WCA Regulations: WCA Regulations in PDF formatĭevelopment of the WCA Regulations and Guidelines is public on GitHub and the discussion is public on the WCA Forum.įor questions and feedback, please contact the WCA Regulations Committee (WRC). Uses of the words "must", "must not", "should", "should not" and "may" match RFC 2119. The Regulations should be considered a complete document, but the Guidelines contain additional clarifications and explanations. The WCA Regulations are also supplemented by the WCA Guidelines. The WCA Regulations contain the full set of Regulations that apply to all official competitions sanctioned by the World Cube Association. Version: Febru Notes WCA Regulations and Guidelines ![]()
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