What question did this study set out to answer?

This study aims to assess the prevalence of germline pathogenic variants in known cancer susceptibility genes among patients with mucosal melanoma.

May 25, 2026Open Access

Germline variants in cancer susceptibility genes among patients with mucosal melanoma

Puntos clave

This study aims to assess the prevalence of germline pathogenic variants in known cancer susceptibility genes among patients with mucosal melanoma.
Germline sequencing was performed on 346 mucosal melanoma patients at MD Anderson Cancer Center.
Variant frequencies were compared to population controls using Fisher’s exact test.
Anatomical subtypes included gastrointestinal, head and neck, and genitourinary regions.
Germline pathogenic variants were found in 37 patients (10.7%), with CHEK2 and ATM being the most frequent.
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 controls.
49.0% of patients with germline variants had two or more affected first-degree relatives versus 29.1% in the control group (p = 0.019).

Resumen

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.

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