Two critical positions in zinc finger domains are heavily mutated in three human cancer types

摘要

Author summary Recent large-scale cancer genomics initiatives have revealed that tumor cells typically have numerous genetic alterations, only a small subset of which play a functional role in cancer. Thus, discovering cancer-relevant mutations from tumor sequencing data is a major goal of cancer genomics. Here, we aimed to uncover functional mutations occurring in transcription factors, as gene expression dysregulation is frequently observed in human cancers. In particular, we analyzed Cys2His2 zinc finger genes, as they comprise the largest family of transcription factors in human. We aggregated somatic mutations within these genes by their positions within zinc finger domains, and found that two specific positions within zinc finger domains are recurrently mutated in three cancer types—Uterine Corpus Endometrial Carcinoma, Colon and Rectal Adenocarcinomas, and Skin Cutaneous Melanoma. The two heavily altered positions are known to influence whether and how the domains bind DNA, and thus mutations within them can substantially alter gene function. Further, these mutations, observed across a wide range of transcription factors, converge on at least two processes—chromatin remodeling and dysregulation of retroelements—that are increasingly being linked to human cancers. More generally, we propose that these uncovered mutations contribute to the widespread transcriptional dysregulation commonly observed in cancer cells.