Associations of MC1R Genotype and Patient Phenotypes with BRAF and NRAS Mutations in Melanoma

Abstract

Associations of MC1R with BRAF mutations in melanoma have been inconsistent between studies. We sought to determine for 1227 participants in the international population-based Genes, Environment and Melanoma (GEM) study whether MC1R and phenotypes were associated with melanoma BRAF/NRAS subtypes. We used logistic regression adjusted by age, sex, and study design features and examined effect modifications. BRAF+ were associated with younger age, blond/light brown hair, increased nevi, and less freckling and NRAS+ with older age relative to WT (BRAF−/NRAS−) melanomas (all P<0.05). Comparing specific BRAF subtypes to WT, BRAF V600E was associated with younger age, blond/light brown hair, and increased nevi and V600K with increased nevi and less freckling (all P<0.05). MC1R was positively associated with BRAF V600E cases but only among individuals with darker phototypes or darker hair (Pinteraction<0.05), but inversely associated with BRAF V600K (Ptrend=0.006) with no significant effect modification by phenotypes. These results support distinct etiologies for BRAF V600E, BRAF V600K, NRAS+, and WT melanomas. MC1R’s associations with BRAF V600E cases limited to individuals with darker phenotypes indicate that MC1R genotypes specifically provide information about BRAF V600E melanoma risk in those not considered high risk based on phenotype. Our results also suggest melanin pathways deserve further study in BRAF V600E melanomagenesis.

Inherited Genetic Variants Associated with Melanoma BRAF/NRAS Subtypes

“…Many of these variants are in gene regions associated with pigmentation, such as TYRP1, TYR, HERC2/OCA2, SLC45A2 , and ASIP ; nevi, such as PLA2G6, MTAP , and NID1 ; or both, such as IRF4 , while others are in genes, including ATM, MX2, PARP1, ARNT , and CASP8 , not associated with melanoma-risk phenotypes (Amos et al, 2011, Barrett et al, 2011, Bishop et al, 2009, Fernandez et al, 2008, Gudbjartsson et al, 2008, Han et al, 2008, Jannot et al, 2005, Law et al, 2012, Macgregor et al, 2011, Nan et al, 2011, Zhang et al, 2012). In parallel but separate studies, we and Hacker et al found that increased number of nevi was associated with melanoma BRAF V600E and V600K subtypes (Hacker et al, 2016, Thomas et al, 2007, Thomas et al, 2017), and we found that BRAF V600E was associated with blond/light brown hair and BRAF V600K with less freckling (Thomas et al, 2017). MC1R has been inconsistently associated with BRAF V600E cases (Fargnoli et al, 2008, Hacker et al, 2010, Hacker et al, 2013, Hacker et al, 2016, Landi et al, 2006, Thomas et al, 2010a).…”

“…We, like others (Duffy et al, 2010a, Duffy et al, 2010b, Han et al, 2008, Zhang et al, 2013), found rs12203592*T to be associated with fewer nevi, darker hair color, and increased freckles. Previously, we reported increased nevi were associated with BRAF V600E and V600K; lighter hair color with BRAF V600E and decreased freckling with BRAF V600K compared to WT melanoma (Thomas et al, 2017). Hacker et al also found increased nevi to be associated with BRAF V600E and V600K vs. WT melanoma (Hacker et al, 2016).…”

“…We had previously found that number of back nevi, hair color, and freckling were associated with BRAF/NRAS subtype (Thomas et al, 2017), indicating that these phenotypes could be mediators of genotype associations with BRAF/NRAS subtype. To further explore this possibility, we examined, in participants with tumor BRAF/NRAS subtype analyzed, whether IRF4 rs12203592 or PLA2G6 rs132985 genotypes were associated with these phenotypes in models adjusted for study features (Supplementary Tables S3, available online).…”

“…Falchi et al explored whether nevus count mediated the association between rs132985 and melanoma and reported attenuation of the melanoma odds ratio when adding nevus count to their model (Falchi et al, 2009). Because of these findings and BRAF V600’s known association with increased nevi (Hacker et al, 2016, Thomas et al, 2007, Thomas et al, 2017), it might have been expected that the PLA2G6 rs132985*C would have been positively associated with BRAF subtypes. However, instead, we found a positive association with rs132985*T. Also, the associations of rs132985 with BRAF subtypes reported here in GEM were overall independent of number of nevi, hair color, and freckling.…”

“…MC1R has been inconsistently associated with BRAF V600E cases (Fargnoli et al, 2008, Hacker et al, 2010, Hacker et al, 2013, Hacker et al, 2016, Landi et al, 2006, Thomas et al, 2010a). Our recent work indicates MC1R variants are positively associated with BRAF V600E cases in people with darker phenotypes, but inversely associated with BRAF V600K cases with no significant effect modification by phenotype (Thomas et al, 2017). To our knowledge, the associations between melanoma BRAF/NRAS subtypes and other low-penetrant genetic variants besides MC1R have not been investigated.…”