TitleTwo critical positions in zinc finger domains are heavily mutated in three human cancer types.
Publication TypeJournal Article
Year of Publication2018
AuthorsMunro, D, Ghersi, D, Singh, M
JournalPLoS Comput Biol
Volume14
Issue6
Paginatione1006290
Date Published2018 06
ISSN1553-7358
KeywordsAdenomatous Polyposis Coli, Amino Acid Sequence, Binding Sites, CYS2-HIS2 Zinc Fingers, DNA, DNA-Binding Proteins, Female, Humans, Male, Neoplasms, Repressor Proteins, Sequence Homology, Amino Acid, Skin Neoplasms, Transcription Factors, Uterine Neoplasms, Zinc Fingers
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 Kr├╝ppel-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.

DOI10.1371/journal.pcbi.1006290
Alternate JournalPLoS Comput. Biol.
PubMed ID29953437
PubMed Central IDPMC6040777
Grant ListR01 CA208148 / CA / NCI NIH HHS / United States
R01 GM076275 / GM / NIGMS NIH HHS / United States