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

Aamir Ahmad,Jia Xu,Douglas I Lin

doi:10.1371/journal.pone.0199688

Abstract

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.

Highlights

Cyclin D1, encoded by the CCND1 gene, is a core cell cycle regulator that promotes cellular proliferation and is frequently overexpressed in human cancers
In mantle cell lymphoma and multiple myeloma, the majority of CCND1 mutations occurred within the amino terminal domain of cyclin D1 (S2 Table and Fig 1B), while in endometrial adenocarcinomas, and less frequently in colorectal carcinoma and melanoma, CCND1 mutations centered on the carboxy terminal domain (Fig 1C and 1D and S1 Fig)
CCND1 mutations inhibiting Thr286 phosphorylation, nuclear export and ubiquitin-mediated degradation by the Oncogenic CCND1 mutations in endometrial cancer proteasome have been shown to result in constitutive activation of CDK4/6 complexes, thereby promoting cellular proliferation and malignant transformation both in vitro and in vivo [6][7] [8]

Summary

Introduction

Cyclin D1, encoded by the CCND1 gene, is a core cell cycle regulator that promotes cellular proliferation and is frequently overexpressed in human cancers. Alterations of cyclin D1 resulting in nuclear protein expression is thought to promote tumorigenesis in various types of cancers[1][2], often as a result of CCND1 gene amplification, such as in breast, lung, bladder carcinomas [3][4], or as a result of CCND1 translocation in mantle cell lymphoma [5]. Accumulating evidence suggests that mutations of the CCND1 gene that result in nuclear.

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