Journal Article

Oncogenic c-terminal cyclin D1 (CCND1) mutations are enriched in endometrioid endometrial adenocarcinomas

Xu, Jia, Lin, Douglas I.

2018

Overview

Cyclin D1 (CCND1) is a core cell cycle regulator and is frequently overexpressed in human cancers, often via amplification, translocation or post-transcription regulation. Accumulating evidence suggests that mutations of the CCND1 gene that result in nuclear retention and constitutive activation of CDK4/6 kinases are oncogenic drivers in cancer. However, the spectrum of CCND1 mutations across human cancers has not been systematically investigated. Here, we retrospectively mined whole-exome sequencing data from 124 published studies representing up to 29,432 cases from diverse cancer types and sites of origin, including carcinoma, melanoma, sarcoma and lymphoma/leukemia, via online tools to determine the frequency and spectrum of CCND1 mutations in human cancers and their associated clinico-pathological characteristics. Overall, in contrast to gene amplification, which occurred at a frequency of 4.8% (1,419 of 28,769 cases), CCND1 mutations were of very low frequency (0.5%, 151 of 29,432 cases) across all cancers, but were predominantly enriched in uterine endometrioid-type adenocarcinoma (6.5%, 30 of 458 cases) in both primary tumors and in advanced, metastatic endometrial cancer samples. CCND1 mutations in endometrial endometrioid adenocarcinoma occurred most commonly in the c-terminus of cyclin D1, as putative driver mutations, in a region thought to result in oncogenic activation of cyclin D1 via inhibition of Thr-286 phosphorylation and nuclear export, thereby resulting in nuclear retention and protein overexpression. Our findings implicate oncogenic c-terminal mutations of CCND1 in the pathogenesis of a subset of human cancers and provide a key resource to guide future preclinical and clinical investigations.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Activation / Adenocarcinoma / Adenocarcinoma - genetics / Adenocarcinoma - pathology / Amplification / Analysis / Biology and Life Sciences / Biomarkers, Tumor - genetics / C-Terminus / Cancer / Carcinogenesis / CCND1 gene / Cell cycle / Cell proliferation / Cyclin D1 / Cyclin D1 - genetics / Cyclin-dependent kinase 4 / Databases, Factual / Datasets / Endometrial cancer / Endometrial Neoplasms - genetics / Endometrial Neoplasms - pathology / Endometrium / Female / Gene amplification / Gene expression / Gene regulation / Genomes / Genomics / Humans / Kinases / Leukemia / Lymphoma / Medicine and Health Sciences / Melanoma / Metastases / Metastasis / Mutation / Nuclear transport / Pathogenesis / Pathology / Phosphorylation / Post-transcription / Proteins / Retention / Retrospective Studies / Sarcoma / Studies / Translocation / Tumorigenesis / Tumors / Uterine cancer / Uterus