Risk and protective factors for acral, mucosal, and uveal melanoma in a multi-institutional cohort of veterans and civilians.

9555 Background: Melanoma is the 4th most common cancer among US Veterans. Non-acral cutaneous melanoma has well-established risk factors including history of sunburn, ultraviolet (UV) exposure, fair skin and features. Risk factors for acral (AM), mucosal (MM), or uveal melanoma (UM), are less understood. Methods: We conducted a nested case-control study (2000-2024) identifying cases of acral (N=1,292, Veterans only), mucosal (N=520, combined Veteran and civilian cohort), and uveal (N=2,010, combined Veteran and civilian cohort) melanoma using the Veterans Affairs (VA) Cancer Registry, natural language processing applied to pathology reports, and Mass General Brigham Research Patient Data Repository. Results: For AM, current smoking was associated with reduced odds, while Agent Orange Exposure (AOE) was associated with increased odds compared to both control populations. Compared to non-melanoma controls, prior nevus, keratinocyte carcinoma (KC), and actinic keratosis (AK) were associated with increased odds of AM. For MM, prior KC was associated with higher odds of MM compared to non-melanoma controls, consistent across anogenital, sinonasal, and upper aerodigestive tract sites. Smoking status was associated with reduced MM odds in the sinonasal cohort. For UM, we conducted a case-control study using data from 3 academic medical centers and the VA. Prior cutaneous and systemic immune disease were protective of UM development compared to CM. Smoking status and prior nevi had higher odds of UM compared to CM and non-cancer controls. Conclusions: To our knowledge, this is the largest cohort of AM, MM, and UM cases to date. Our study identified unique factors associated with risk of, or protection from, AM, MM, or UM, compared to CM or non-cancer controls. These findings provide novel insights into potential risks for rare melanomas and can help guide future biologically driven studies. Risk and protective factor associations across rare melanomas. Melanoma type Factor type Both cohorts CM only Non-cancer only Acral High risk association factors Younger age, female sex, Black race, Hispanic ethnicity, AOE Asian race Prior nevus, prior KC, prior AK Protective factors Current smoking ≥2 comorbidities, AUDIT-C positive, prior KC, prior AK Former smoking No associations BMI Mucosal High risk association factors Younger age, female sex Black race, Hispanic ethnicity Prior KC Protective factors Former smoking Current smoking, ≥2 comorbidities No associations Prior nevus, BMI Uveal High risk association factors Older age, former smoking, current smoking, prior nevus Black race, American Indian/Alaska Native race, obesity Protective factors ≥1 comorbidities, prior photosensitizing medication use, prior cutaneous autoimmune disease, prior systemic autoimmune disease Prior non-melanoma skin cancer Hispanic ethnicity, normal or underweight BMI No associations Sex