BACKGROUND
Cutaneous melanoma is rare in Patients of Color (POC), and the genomics are not well understood.
OBJECTIVE
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.
METHODS
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.
RESULTS
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).
LIMITATIONS
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.
CONCLUSION
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.
J. Ross, Vanessa R. Weir, Leore Lavin et al.· Journal of American Academy...· 0 citations
Chemokine (CK) and chemokine receptors (CKR) regulate cell growth, tumor immunity, migration, angiogenesis, and metastasis. We evaluated associations of inherited CK/CKR variants with subsequent primary melanomas among patients with a previous melanoma. Our population-based cohort included 2,458 incident single primary and 1,205 multiple primary melanoma (MPM) cases. We examined 215 a priori candidate polymorphisms selected based on prior evidence and predicted functional relevance, along with nine haplotype blocks. Logistic regression estimated odds ratios and 95% confidence intervals, adjusting for age at diagnosis, sex, age by sex interaction, and study center. Thirty variants across fourteen genes were nominally associated with MPM (p<0.05), with effect sizes ranging from 16% to 80%. Five haplotypes in CXCL12, CCL18, CXCR2, and CCR9 were significantly associated with MPM (pglobal<0.03) with stronger effects than individual effect-alleles. Functional annotation identified 160 associated index variants and linkage disequilibrium (LD) proxies acting as skin expression Quantitative Trait Loci (eQTLs) for CXCR2, XCR1, BCL9L, FYCO1, PNKD, RUFY4, and RP11–378A13.1 (p-value <1.06E-05 to 4.3E-34). These variants were classified functionally as candidate causal variants based on convergent regulatory annotation and skin-specific eQTL evidence, linking CK/CKR variants and haplotypes to downstream genes involved in epithelial–mesenchymal–like transition, matrix remodeling, and other tumorigenic processes, thereby implicating immune regulatory mechanisms in melanoma development. To our knowledge, this is the first study to demonstrate an association of a priori CK/CKR variants with subsequent melanoma risk. Validation and evaluation of associations with tumor characteristics and survival are warranted.
I. Orlow, L. Luo, Isidora Autuori et al.· Melanoma research· 0 citations
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