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Associations of 9p21 variants with cutaneous malignant melanoma, nevi, and pigmentation phenotypes in melanoma-prone families with and without CDKN2A mutations

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Abstract

Chromosome 9p21 has been implicated in the pathogenesis of cutaneous malignant melanoma (CMM). In addition to CDKN2A, the major known high-risk susceptibility gene for CMM, recent studies suggest that other 9p21 genes may be involved in melanoma/nevi development. To identify 9p21 variants that influence susceptibility to CMM and number of nevi in CMM-prone families with and without CDKN2A mutations, we analyzed 562 individuals (183 CMM) from 53 families (23 CDKN2A+, 30 CDKN2A−) for 233 tagging SNPs in 21 genes at 9p21. Single SNP- and gene-based regression analyses were used to assess the risk of CMM, nevi count, skin complexion, and tanning ability associated with these SNPs and genes. We found that SNP rs7023329 in the MTAP gene was associated with number of nevi (P trend = 0.003) confirming a recent finding by a genome-wide association study. In addition, three SNPs in the ACO1 gene, rs7855483 (P trend = 0.002), rs17288067 (P trend = 0.0009), and rs10813813 (P trend = 0.005), showed the strongest associations with CMM risk. None of the examined 9p21 SNPs was associated with skin complexion, whereas two SNPs, rs10964862 in IFNW1 (P trend = 0.003), and rs13290968 in TUSC1 (P trend = 0.0006), were associated with tanning ability. Gene-based analyses suggested that the ACO1 gene was significantly associated with CMM (P = 0.0004); genes IFNW1 (P = 0.002) and ACO1 (P = 0.0002) were significantly associated with tanning ability. Our findings are consistent with recent proposals that additional 9p21 genes may contribute to CMM susceptibility in CMM-prone families. These genetic variants may, at least partially, exert their effects through nevi and tanning ability.

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Abbreviations

CMM:

Cutaneous malignant melanoma

SNP:

Single nucleotide polymorphism

GWAS:

Genome-wide association study

MAF:

Minimum minor allele frequency

OR:

Odds ratio

95% CI:

95% Confidence interval

GEE:

Generalized estimating equations

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Acknowledgments

We are indebted to the participating families, whose generosity and cooperation have made this study possible. We also acknowledge the contributions to this work that were made by Virginia Pichler, Deborah Zametkin, and Mary Fraser. This research was supported by the Intramural Research Program of the NIH, NCI, DCEG.

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Authors and Affiliations

  1. Division of Cancer Epidemiology & Genetics, NCI/NIH/DHHS, Bethesda, MD, USA

    Xiaohong Rose Yang, Xueying Liang, Ruth M. Pfeiffer, Dennis Maeder, Stephen Chanock, Margaret A. Tucker & Alisa M. Goldstein

  2. Information Management Services, Inc., Rockville, MD, USA

    William Wheeler

  3. Core Genotyping Facility, SAIC-Frederick, Inc., NCI-Frederick, Frederick, MD, USA

    Laurie Burdette & Meredith Yeager

  4. Genetic Epidemiology Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, NIH, DHHS, 6120 Executive Blvd., Rockville, MD, 20852, USA

    Xiaohong Rose Yang

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  1. Xiaohong Rose Yang
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Correspondence to Xiaohong Rose Yang.

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Yang, X.R., Liang, X., Pfeiffer, R.M. et al. Associations of 9p21 variants with cutaneous malignant melanoma, nevi, and pigmentation phenotypes in melanoma-prone families with and without CDKN2A mutations. Familial Cancer 9, 625–633 (2010). https://doi.org/10.1007/s10689-010-9356-3

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