Inherited Genetic Variants Associated with Melanoma BRAF/NRAS Subtypes

Abstract

BRAF and NRAS mutations arise early in melanoma development, but their associations with low-penetrance melanoma susceptibility loci remain unknown. In the Genes, Environment and Melanoma Study, 1,223 European-origin participants had their incident invasive primary melanomas screened for BRAF/NRAS mutations and germline DNA genotyped for 47 single-nucleotide polymorphisms identified as low-penetrant melanoma-risk variants. We used multinomial logistic regression to simultaneously examine each single-nucleotide polymorphism's relationship to BRAF V600E, BRAF V600K, BRAF other, and NRAS+ relative to BRAF-/NRAS- melanoma adjusted for study features. IRF4 rs12203592*T was associated with BRAF V600E (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.43-0.79) and V600K (OR = 0.65, 95% CI = 0.41-1.03), but not BRAF other or NRAS+ melanoma. A global test of etiologic heterogeneity (P = 0.001) passed false discovery (P = 0.0026). PLA2G6 rs132985*T was associated with BRAF V600E (OR = 1.32, 95% CI = 1.05-1.67) and BRAF other (OR = 1.82, 95% CI = 1.11-2.98), but not BRAF V600K or NRAS+ melanoma. The test for etiologic heterogeneity (P) was 0.005. The IRF4 rs12203592 associations were slightly attenuated after adjustment for melanoma-risk phenotypes. The PLA2G6 rs132985 associations were independent of phenotypes. IRF4 and PLA2G6 inherited genotypes may influence melanoma BRAF/NRAS subtype development.

Genome‐wide association studies and polygenic risk scores for skin cancer: clinically useful yet?

“…Evidence suggests that histological factors may affect tumour aggressiveness and patient prognosis in melanoma and KCs . One study, for example, found that two SNVs in IRF4 and PLA2G6 were associated with BRAF / NRAS melanoma subtypes . However, PRS studies to date have combined histological subtypes together, which could lead to confounding.…”

Germline Variants Impact Somatic Events during Tumorigenesis

“…Cutaneous melanomas are categorized byfourgenomicsubtypes: mutant BRAF, mutant RAS(mainly NRAS), mutant NF1, and triple-wild-type. In one study, germline DNAfrom 1,223 participantswas genotyped for 47 SNVs previously associated with melanoma risk [53]. Melanomas were also interrogated for BRAFand NRASmutations.…”

“…The rs12203592(T)alleleof IRF4was associated with decreased risk of BRAF V600E and BRAF V600K mutations, but an increased likelihood ofother BRAFexon 15 mutations (Table 2). The rs132985(T) allele of PLA2G6was associated with increased likelihood of BRAF V600E and other BRAFexon 15 mutations(Table 2) [53] Germline MC1Rvariantsalso influence the somaticmutational landscape of melanoma. These variants are associated with red hair, freckling, and sun sensitivity.…”

The combination of mutations in BRAF and NRAS genes within a one tumor in patients with cutaneous melanoma

“…Около 25% всех злокачественных опухолей имеют нарушения регуляции сигнального каскада MAPK, связанные с увеличением продукции активирующих лигандов, а также наличием активирующих мутаций в генах семейств RTKs, RAS и RAF [3]. При меланоме кожи нарушения в MAPK сигнальном каскаде связаны, как правило, с активирующей мутацией в гене BRAF в 50% случаев или с мутацией в гене NRAS в 15% случаев [4]. Данный факт демонстрирует важность контроля регуляции MAPK в гомеостазе меланоцитов.…”