Molecular Alterations in Patients of Color with Advanced Cutaneous and Unknown Primary Melanomas

Cutaneous melanoma is rare in Patients of Color (POC), and the genomics are not well understood.

Describe MAPK drivers and tumor mutational burden (TMB) of cutaneous and unknown primary (CUP) melanoma in POC and compare them to non-Hispanic White (NHW) patients.

We analyzed a retrospective convenience cohort of 676 patients with advanced CUP melanoma undergoing clinically-warranted multigene sequencing with MSK-IMPACT. Self-identified (self-ID) POC were defined as non-White race and/or Hispanic ethnicity; this cohort was also analyzed by genetically inferred ancestry and skin tone using Monk scale.

Self-ID POC (n=35) had frequent BRAF V600E mutations (43%) and, compared to NHW (N=641) patients, more "pan-wildtype" tumors of unknown driver (14% vs 4%, p=0.010). Among self-ID POC, skin tone and inferred ancestry showed moderate overlap, but did not consistently predict genomic features. Median TMB was higher for patients with light (N=185) vs medium/dark (N=8) skin tone (15.8 vs 2.6, p<0.0001).

Skin tone assessments were only available for a subset of patients (N=193). BRAF mutations are underestimated given molecular testing preferentially sent in patients with BRAF-wildtype disease.

CUP melanomas in self-ID POC had lower median TMB and were more likely to be pan-wildtype, reflecting differences in pathogenesis. Larger scale studies are needed to validate these findings.