Survey for Activating Oncogenic Mutation Variants in Metazoan Germline Genes.

Autor: Krueger KE; National Cancer Institute, 9609 Medical Center Drive, 5E-132, Rockville, MD, 20850, USA. karl.krueger@nih.gov.
Jazyk: angličtina
Zdroj: Journal of molecular evolution [J Mol Evol] 2024 Dec; Vol. 92 (6), pp. 930-943. Date of Electronic Publication: 2024 Nov 26.
DOI: 10.1007/s00239-024-10218-4
Abstrakt: Most cancers present with mutations or amplifications in distinctive tumor promoter genes that activate principal cell-signaling cascades promoting cell proliferation, dedifferentiation, cell survival, and replicative immortality. Somatic mutations found in this these driver proto-oncogenes invariably result in constitutive activation of the encoded protein. A salient feature of the activating mutations observed throughout many thousands of clinical tumor specimens reveals these driver missense mutations are recurrent and restricted to just one or very few codons of the entire gene, suggesting they have been positively selected during the course of tumor development. The purpose of this study is to investigate whether these characteristic oncogenic driver mutations are observed in the germline genes of any metazoan species. Six well-known tumor promoter genes were chosen for this survey including BRAF, KRAS, JAK2, PIK3CA, EGFR, and IDH1/2. The sites of all driver mutations were found to occur in highly conserved regions of each gene comparing protein sequences throughout diverse phyla of metazoan species. None of the oncogenic missense mutations were found in germlines of any species of current genome and protein databases. Despite many tumors readily selecting these somatic mutations, the conclusion drawn from this study is that these variants are negatively rejected if encountered as a germline mutation. While cancer expansion ensues from dysregulated growth elicited by these mutations, this effect is likely detrimental to embryonic development and/or survival of multicellular organisms. Although all oncogenic mutations considered here are gain-of-function where five of the six increase activity of the encoded proteins, clonal advancement promotes tumor growth by these genomic changes without conferring selection advantages benefiting the organism or species.
Competing Interests: Declarations. Conflict of interest: The author did not receive support from any organization for the submitted work. The author has no competing interests to declare that are relevant to the content of this article.
(© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE