Abstract
Mucosal melanoma (MM) is a rare and aggressive melanoma subtype with poor outcomes and poorly understood risk factors, including the contribution of germline pathogenic variants (PVs). In this study, 346 MM patients treated at MD Anderson Cancer Center underwent germline sequencing of 322 known cancer susceptibility genes, with PV frequencies compared to population controls (gnomAD and TOPMed) using Fisher’s exact test. The cohort had a median age at diagnosis of 64 years and was predominantly female (62%) and White (84.0%). Anatomical subtypes of MM included gastrointestinal (36%), head and neck (33%), and genitourinary (31%). Among patients with somatic testing results (n = 303), KIT mutations (26%) were most common, followed by NRAS (17%), BRAFNon-V600 (6.6%), and BRAFV600 (2.6%). Germline PVs were identified in 37 patients (10.7%), most frequently in CHEK2 (n = 9, 23.0%), ATM (n = 8, 20.5%), and MITF (n = 6, 15.4%). MITF p.E318K (OR 6.0; 95% CI 2.2–13.2) and CHEK2 c.1100delC (OR 6.7; 95% CI 1.8–17.5) were significantly enriched compared to population control rates. Patients with germline PVs were more likely to have two or more affected first-degree relatives (49.0% vs. 29.1%, p = 0.019). These findings highlight a meaningful germline contribution to MM risk and support the incorporation of genetic testing in this population.
Acknowledgements
This study received funding support from DOD grant W81XWH2210975, Melanoma Research Foundation, Andrew Sabin Family Foundation, Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the AIM at Melanoma Foundation, the NIH/NCI P50CA221703, the NIH/NCI P30CA016672, SPORE in Melanoma at University of Texas MD Anderson Cancer, the American Cancer Society and the Melanoma Research Alliance, Cancer Fighters of Houston, the Anne and John Mendelsohn Chair for Cancer Research, the Andrew M. McDougall Brain Metastasis Clinic and Research Program, philanthropic contributions to the MD Anderson Melanoma Moon Shots Program, the MD Anderson Patient Mosaic Program, Young Investigator Award from Melanoma Research Alliance (#570806), and National Cancer Institute and the National Center for Advancing Translational Sciences of the NIH (CCSG P30CA016672-46 and CCTS UM1TR004906).
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Authors A.A., X.W., J.P.L., G.W.C., J.W.W., S.P., L.L., C.G., N.B., J.M., J.S., J.Z., P.N., Y.Y., C.H., H.T., R.N.A., I.C.G., A.P.I., S.S., E.Y.H., R.W., B.B., T.T.S., D.M., J.W., J.E.G., P.S., and K.C.N. declare no financial or non-financial competing interests. Author M.A.D. has been a consultant to Replimmune, Nurix, Roche/Genentech, Array, Pfizer, Novartis, BMS, GSK, Sanofi-Aventis, Vaccinex, Apexigen, Eisai, Iovance, Merck, and ABM Therapeutics. M.A.D. is also a scientific advisory board member for THERAtRAME, and he has been the PI of research grants to MD Anderson by Roche/Genentech, GSK, Sanofi-Aventis, Merck, Myriad, Oncothyreon, Pfizer, ABM Therapeutics, and LEAD Pharma. Author J.L.M. has received honoraria from BMS, Merck and Replimmune. Author A.F. is a scientific advisory board member for Scorpion Therapeutics.
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Amouzegar, A., Wu, X., Long, J.P. et al. Germline variants in cancer susceptibility genes among patients with mucosal melanoma. npj Genom. Med. (2026). https://doi.org/10.1038/s41525-026-00583-y
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DOI: https://doi.org/10.1038/s41525-026-00583-y
