Germline variants in cancer susceptibility genes among patients with mucosal melanoma
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.
Authors
- Priyadharsini Nagarajan (ORCID: https://orcid.org/0000-0002-5346-2669)
- Devarati Mitra (ORCID: https://orcid.org/0000-0002-2225-164X)
- Isabella C. Glitza Oliva (ORCID: https://orcid.org/0000-0002-4530-7765)
- Afsaneh Amouzegar (ORCID: https://orcid.org/0009-0005-3651-3777)
- Justin Wong (ORCID: https://orcid.org/0000-0002-6803-1060)
- Roi Weiser (ORCID: https://orcid.org/0000-0002-4522-6404)
- Xiaogang Wu (ORCID: https://orcid.org/0000-0003-4373-6926)
- Travis T. Sims (ORCID: https://orcid.org/0000-0003-1975-0795)
- James P. Long
- Jeffrey E. Gershenwald (ORCID: https://orcid.org/0000-0003-4519-5369)
- Neus Bota
- Sabitha Prabhakaran
- PA Futreal
- Alexandra Ikeguchi
- Jennifer Wargo
- Paul Scheet (ORCID: https://orcid.org/0000-0002-5173-7497)
- Chad Huff (ORCID: https://orcid.org/0000-0002-1100-9364)
- Jared Malke
- Michael A. Davies
- Curtis Gumbs
- Yao Yu
- Brian Bednarski
- Jennifer L. McQuade
- Jianhua Zhang
- Hussein Tawbi
- Latasha Little
- Shirley Su
- Julie Simon
- Ehab Y. Hanna
- Rodabe N. Amaria
- Gabriela W. Chen
- Kelly C. Nelson
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- Healthcentric Advisors (US)
- UCSF Helen Diller Family Comprehensive Cancer Center (US)
Publication Details
- Journal
- npj Genomic Medicine
- Published
- 2026-05-23
- DOI
- https://doi.org/10.1038/s41525-026-00583-y
- Primary Topic
- Cutaneous Melanoma Detection and Management
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- U.S. Department of Defense
- American Cancer Society
- Melanoma Research Foundation
- Melanoma Research Alliance
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- AIM at Melanoma
- Andrew Sabin Family Foundation
- National Institutes of Health
- University of Texas MD Anderson Cancer Center
- National Cancer Institute
- National Center for Advancing Translational Sciences