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

<div><p>Cyclin D1 (<i>CCND1</i>) 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 <i>CCND1</i> gene that result in nuclear retention and constitutive activation of CDK4/6 kinases are oncogenic drivers in cancer. However, the spectrum of <i>CCND1</i> 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 <i>CCND1</i> 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), <i>CCND1</i> 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. <i>CCND1</i> 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 <i>CCND1</i> in the pathogenesis of a subset of human cancers and provide a key resource to guide future preclinical and clinical investigations.</p>