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While there are small studies suggesting that this risk is associated with other malignancies (e.g. renal cell carcinoma), little is known about the role of this variant in specifying risk for other cancers. In this study, we perform a systematic review and meta-analysis of the published data as a backdrop to a whole-exome sequence(WES)-based characterization of MITF(E318K) risk for various cancers in sporadic samples from the TCGA and several genetically-enriched patient cohorts. We found minimal evidence of MITF(E318K)\u2019s contribution to non-melanoma cancer risk among individuals with low inherited risks of melanoma (OR 1.168; 95% CI 0.78\u20131.74; p\u2009=\u20090.454), suggesting that earlier reports of an association between this variant and other malignancies may be related to shared environmental or polygenic risk factors rather than MITF(E318K). Interestingly, an association was observed with uterine carcinosarcoma, (OR 9.24; 95% CI 2.08\u201337.17; p\u2009=\u20090.024), which was not previously described. While more research needs to be completed, this study will help update cancer screening recommendations for patients with the MITF(E318K) variant.<\/jats:p>","DOI":"10.1038\/s41598-020-74237-z","type":"journal-article","created":{"date-parts":[[2020,10,13]],"date-time":"2020-10-13T10:05:00Z","timestamp":1602583500000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Cancer risks associated with the germline MITF(E318K) variant"],"prefix":"10.1038","volume":"10","author":[{"given":"Samantha M.","family":"Guhan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mykyta","family":"Artomov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shelley","family":"McCormick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching -Ni","family":"Njauw","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander J.","family":"Stratigos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen","family":"Shannon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leif W.","family":"Ellisen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hensin","family":"Tsao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,10,13]]},"reference":[{"key":"74237_CR1","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1038\/nature10630","volume":"480","author":"S Yokoyama","year":"2011","unstructured":"Yokoyama, S. et al. A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma. Nature 480, 99\u2013103. https:\/\/doi.org\/10.1038\/nature10630 (2011).","journal-title":"Nature"},{"key":"74237_CR2","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1038\/nature10539","volume":"480","author":"C Bertolotto","year":"2011","unstructured":"Bertolotto, C. et al. A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature 480, 94\u201398. https:\/\/doi.org\/10.1038\/nature10539 (2011).","journal-title":"Nature"},{"key":"74237_CR3","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1111\/pcmr.12215","volume":"27","author":"M Berwick","year":"2014","unstructured":"Berwick, M. et al. MITF E318K\u2019s effect on melanoma risk independent of, but modified by, other risk factors. 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Cancer Genet. 207, 128\u2013132. https:\/\/doi.org\/10.1016\/j.cancergen.2014.03.003 (2014).","journal-title":"Cancer Genet."},{"key":"74237_CR6","doi-asserted-by":"publisher","first-page":"1030","DOI":"10.1111\/bjd.14897","volume":"175","author":"C Mangas","year":"2016","unstructured":"Mangas, C. et al. Genetic susceptibility to cutaneous melanoma in southern Switzerland: role of CDKN2A, MC1R and MITF. Br. J. Dermatol. 175, 1030\u20131037. https:\/\/doi.org\/10.1111\/bjd.14897 (2016).","journal-title":"Br. J. Dermatol."},{"key":"74237_CR7","doi-asserted-by":"publisher","DOI":"10.1111\/bjd.18777","author":"EK McMeniman","year":"2019","unstructured":"McMeniman, E. K. et al. The interplay of sun damage and genetic risk in Australian multiple and single primary melanoma cases and controls. Br. J. Dermatol. https:\/\/doi.org\/10.1111\/bjd.18777 (2019).","journal-title":"Br. J. 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