Prognostic and Clinicopathological Significance of CCND1/Cyclin D1 Upregulation in Melanomas: A Systematic Review and Comprehensive Meta-Analysis González-Ruiz, Lucía González Moles, Miguel Ángel González-Ruiz, Isabel Ruiz Ávila, María Isabel Ramos García, Pablo Melanoma Cyclin D1 CCND1 Systematic review Meta-analysis We would like to thank the research group CTS-392 (Plan Andaluz de Investigación, Junta de Andalucía, Spain). Simple Summary The incidence of cutaneous melanoma is increasing worldwide, currently responsible for 287,723 new cases and 60,712 deaths per year (GLOBOCAN, IARC, WHO). It should be also highlighted that some less frequent subtypes of melanomas-i.e., acral, uveal, and mucous melanoma-are responsible for significant morbidity associated with metastasis, responding typically worse to newer therapies. Therefore, new biomarkers are needed to improve the prognosis in individual patients. In this sense, the present study showed that CCND1/cyclin D1 upregulation is a common molecular oncogenic alteration in melanomas that probably favors the growth and expansion on cutaneous primary melanomas. Furthermore, immunohistochemical cyclin D1 overexpression strongly predicted a higher Breslow thickness, currently considered the most relevant prognostic factor in individual patients with melanomas. Finally, special attention should be paid to the CCND1/cyclin D1 complex in mucosal melanomas, whose upregulation was strikingly altered. Our objective was to evaluate the prognostic and clinicopathological significance of cyclin D1 (CD1) overexpression/CCND1 amplification in melanomas. We searched studies published before September 2019 (PubMed, Embase, Web of Science, Scopus). We evaluated the quality of the studies included (QUIPS tool). The impact of CD1 overexpression/CCND1 amplification on overall survival and relevant clinicopathological characteristic were meta-analyzed. We performed heterogeneity, sensitivity, small-study effects, and subgroup analyses. Forty-one studies and 3451 patients met inclusion criteria. Qualitative evaluation demonstrated that not all studies were performed with the same rigor, finding the greatest risk of bias in the study confounding domain. Quantitative evaluation showed that immunohistochemical CD1 overexpression had a statistical association with Breslow thickness (p = 0.007; OR = 2.09,95% CI = 1.23-3.57), significantly higher frequency of CCND1/cyclin D1 abnormalities has been observed in the primary tumor compared to distant metastases (p = 0.004), revealed also by immunohistochemical overexpression of the protein (p < 0.001; OR = 0.53,95% CI = 0.40-0.71), while the CCND1 gene amplification does not show association (p = 0.43); while gene amplification, on the contrary, appeared more frequently in distant metastases (p = 0.04; OR = 1.70,95% CI = 1.01-2.85) and not in the primary tumor. In conclusion, CCND1/cyclin D1 upregulation is a common molecular oncogenic alteration in melanomas that probably favors the growth and expansion of the primary tumor. This upregulation is mainly consequence to the overexpression of the cyclin D1 protein, and not to gene amplification. 2021-04-23T10:11:39Z 2021-04-23T10:11:39Z 2021-03-15 info:eu-repo/semantics/article González-Ruiz, L.; González-Moles, M.Á.; González-Ruiz, I.; Ruiz-Ávila, I.; Ramos-García, P. Prognostic and Clinicopathological Significance of CCND1/Cyclin D1 Upregulation in Melanomas: A Systematic Review and Comprehensive Meta-Analysis. Cancers 2021, 13, 1314. [https://doi.org/10.3390/cancers13061314] http://hdl.handle.net/10481/68070 10.3390/cancers13061314 eng http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess Atribución 3.0 España MDPI