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PLoS One. 2018 Jul 3;13(7):e0199688. doi: 10.1371/journal.pone.0199688. eCollection 2018.

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

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Beth Israel Deaconess Medical Center, Department of Pathology, Boston, MA, United States of America.


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.

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Conflict of interest statement

Author DIL recently became a molecular tumor board consultant for Foundation Medicine, Inc, in Cambridge, MA. However, DIL has not received any funding or payments from Foundation Medicine for this study. Furthermore, this does not alter our adherence to PLOS ONE policies on sharing data and materials.

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