Use of signals of positive and negative selection to distinguish cancer genes and passenger genes

Abstract

A major goal of cancer genomics is to identify all genes that play critical roles in carcinogenesis. Most approaches focused on genes positively selected for mutations that drive carcinogenesis and neglected the role of negative selection. Some studies have actually concluded that negative selection has no role in cancer evolution. We have re-examined the role of negative selection in tumor evolution through the analysis of the patterns of somatic mutations affecting the coding sequences of human genes. Our analyses have confirmed that tumor suppressor genes are positively selected for inactivating mutations, oncogenes, however, were found to display signals of both negative selection for inactivating mutations and positive selection for activating mutations. Significantly, we have identified numerous human genes that show signs of strong negative selection during tumor evolution, suggesting that their functional integrity is essential for the growth and survival of tumor cells.

Genetic Variants in Transcription Factor Binding Sites in Humans: Triggered by Natural Selection and Triggers of Diseases

“…Interestingly, previous studies suggest that there is some selection pressure in these comorbidities (body mass index [82], chronic kidney disease [83], diabetes [84], altered LDL/HDL/triglyceride levels [74,85], coronary artery disease/ischemic heart disease [86], hypertension [87], hyperuricemia [74], osteoporosis [88], and prostate cancer [89]) related to gout [74]. Accordingly, in the following section we focus on examples of mechanistic investigations of the regulatory elements of TFBSs related to transcription factors, affected genes, and disease phenotypes in gout and its associated comorbidities which exhibit selection signatures in susceptibility loci.…”

“…Gout is associated with prostate cancer [81], and prostate cancer risk genes display the signature of selection pressure [89]. Several studies have also identified the transcription factor and downstream effector genes involved with the prostate cancer-associated TFBS variant.…”

Inhibition of Polo-like Kinase 1 by HMN-214 Blocks Cell Cycle Progression and Inhibits Neuroblastoma Growth

“…Tumorigenesis mainly depends on the activation of oncogenes and the inactivation of tumor suppressor genes [ 4 ]. Most of these proto-oncogenes and tumor suppressor genes play an important role in regulating the cell cycle progression, and dysregulation of these genes contributes to cancer progression [ 4 ].…”

“…Tumorigenesis mainly depends on the activation of oncogenes and the inactivation of tumor suppressor genes [ 4 ]. Most of these proto-oncogenes and tumor suppressor genes play an important role in regulating the cell cycle progression, and dysregulation of these genes contributes to cancer progression [ 4 ]. PLK1 (Polo-like kinase 1) is a member of the polo-like kinase family of serine/threonine protein kinases and plays an important role in regulating the cell cycle.…”

Use of Publication Dynamics to Distinguish Cancer Genes and Bystander Genes

“…The overall conclusion of de Magalhães (conveyed by the title of his paper) is that “every gene can (and possibly will) be associated with cancer” and that “if a gene has not been associated with cancer yet, it probably means it has not been studied enough and will most likely be associated with cancer in the future” [ 1 ]. The author is correct in pointing out that this conclusion would have important implications for analyzing and interpreting large-scale analyses in cancer genomics, especially as it contradicts the dominant view that cancer is driven by a few hundred cancer genes, whereas the vast majority of genes are just bystanders (or passengers) in carcinogenesis (ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium, 2020; [ 2 , 3 , 4 ]).…”