Association of Genetic Variants in CDK6 and XRCC1 with the Risk of Dysplastic Nevi in Melanoma-Prone Families

Abstract

Dysplastic nevi (DN) is a strong risk factor for cutaneous malignant melanoma (CMM), and it frequently occurs in melanoma-prone families. To identify genetic variants for DN, we genotyped 677 tagSNPs in 38 melanoma candidate genes that are involved in pigmentation, DNA repair, cell cycle control, and melanocyte proliferation pathways in a total of 504 individuals (310 with DN, 194 without DN) from 53 melanoma-prone families (23 CDKN2A mutation positive and 30 negative). Conditional logistic regression, conditioning on families, was used to estimate the association between DN and each SNP separately, adjusted for age, sex, CMM and CDKN2A status. P-values for SNPs in the same gene were combined to yield gene-specific p-values. Two genes, CDK6 and XRCC1, were significantly associated with DN after Bonferroni correction for multiple testing (P=0.0001 and 0.00025, respectively), whereas neither gene was significantly associated with CMM. Associations for CDK6 SNPs were stronger in CDKN2A mutation positive families (rs2079147, Pinteraction=0.0033), whereas XRCC1 SNPs had similar effects in mutation-positive and negative families. The association for one of the associated SNPs in XRCC1 (rs25487) was replicated in two independent datasets (random effect meta-analysis: P<0.0001). Our findings suggest that some genetic variants may contribute to DN risk independently of their association with CMM in melanoma-prone families.

A meta-analysis on major risk factors of multiple primary cutaneous melanomas

“…Conversely, CDK6 and XRCC1 variants were shown to be associated with DN risk but not with melanoma development in melanoma families implying that other genetic or extrinsic factors (e.g. sun protection usage in risk individuals, solar exposure) might influence the transformation of DN into melanoma (31). Our findings on light hair color versus dark indicate a significant positive association with multiple melanoma, albeit to a lesser extent.…”

Genetic factors associated with naevus count and dermoscopic patterns: preliminary results from the Study of Nevi in Children ( SONIC )

“…The cell‐cycle regulator CDK6 was recently reported as the top gene associated with dysplastic naevi in melanoma‐prone families . In SONIC, the rs2079147 variant G is inversely associated with naevus count ( P < 0·05, Table ), and – with a marginal significance – with reticular‐patterned naevi ( P = 0·055).…”

“…48 We also found negative associations between SNPs in CDKN1B and MTAP with reticular-patterned naevi. CDKN1B was recently linked to dysplastic naevi in melanoma families; 16 it encodes the cell-cycle regulator p27, and its function is progressively lost in the transition from benign naevi to primary and metastatic melanomas. CDKN1B rs7330 is a tag SNP with unknown function; however, its location in the 3ʹ untranslated region may implicate a regulatory function.…”

“…10,15 Variants in DNA repair pathways, among others, were recently implicated in the development of dysplastic naevi. 16 The understanding of naevus development in childhood has been advanced with the use of dermoscopy, which allows a more detailed morphological assessment of individual naevi and has led to a new classification proposal. 17 We have previously distinguished two subsets of naevi with distinct dermoscopic patterns (i.e.…”

A distinct expression profile separates Turkish and Australian melanocytic naevi

“…Increases in CDK6 staining intensity and percentage of cells stained have been associated with a malignant phenotype . Interestingly, CDK6 single‐nucleotide polymorphisms have been shown to be strongly associated with the occurrence of dysplastic naevi, identifying CDK6 as a dysplastic naevus susceptibility gene . CDK6 positivity in this study was increased in the Turkish rather than in the Australian MNs.…”