Two critical positions in zinc finger domains are heavily mutated in three human cancer types. Author Daniel Munro, Dario Ghersi, Mona Singh Publication Year 2018 Type Journal Article Abstract A major goal of cancer genomics is to identify somatic mutations that play a role in tumor initiation or progression. Somatic mutations within transcription factors are of particular interest, as gene expression dysregulation is widespread in cancers. The substantial gene expression variation evident across tumors suggests that numerous regulatory factors are likely to be involved and that somatic mutations within them may not occur at high frequencies across patient cohorts, thereby complicating efforts to uncover which ones are cancer-relevant. Here we analyze somatic mutations within the largest family of human transcription factors, namely those that bind DNA via Cys2His2 zinc finger domains. Specifically, to hone in on important mutations within these genes, we aggregated somatic mutations across all of them by their positions within Cys2His2 zinc finger domains. Remarkably, we found that for three classes of cancers profiled by The Cancer Genome Atlas (TCGA)-Uterine Corpus Endometrial Carcinoma, Colon and Rectal Adenocarcinomas, and Skin Cutaneous Melanoma-two specific, functionally important positions within zinc finger domains are mutated significantly more often than expected by chance, with alterations in 18%, 10% and 43% of tumors, respectively. Numerous zinc finger genes are affected, with those containing Krüppel-associated box (KRAB) repressor domains preferentially targeted by these mutations. Further, the genes with these mutations also have high overall missense mutation rates, are expressed at levels comparable to those of known cancer genes, and together have biological process annotations that are consistent with roles in cancers. Altogether, we introduce evidence broadly implicating mutations within a diverse set of zinc finger proteins as relevant for cancer, and propose that they contribute to the widespread transcriptional dysregulation observed in cancer cells. Keywords Repressor Proteins, Humans, Binding Sites, Transcription Factors, DNA, Amino Acid Sequence, Sequence Homology, Amino Acid, DNA-Binding Proteins, Female, Male, Neoplasms, Zinc Fingers, Adenomatous Polyposis Coli, CYS2-HIS2 Zinc Fingers, Skin Neoplasms, Uterine Neoplasms Journal PLoS Comput Biol Volume 14 Issue 6 Pages e1006290 Date Published 2018 Jun ISSN Number 1553-7358 DOI 10.1371/journal.pcbi.1006290 Alternate Journal PLoS Comput Biol PMCID PMC6040777 PMID 29953437 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML