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Relationship of Chromosome Arm 10q Variants to Occurrence of Multiple Primary Melanoma in the Population-Based Genes, Environment, and Melanoma (GEM) Study

Open ArchivePublished:December 17, 2018DOI:https://doi.org/10.1016/j.jid.2018.11.030

      Abbreviations:

      CI (confidence interval), GEM (Genes), Environment (and Melanoma), MPM (multiple primary melanoma), OR (odds ratio), SNP (single nucleotide polymorphism), SPM (single primary melanoma)
      To the Editor
      Using a genome-wide association study of familial melanoma pedigrees (excluding CDKN2A+ pedigrees) and genetically matched controls,
      • Teerlink C.
      • Farnham J.
      • Allen-Brady K.
      • Camp N.J.
      • Thomas A.
      • Leachman S.
      • et al.
      A unique genome-wide association analysis in extended Utah high-risk pedigrees identifies a novel melanoma risk variant on chromosome arm 10q.
      identified three single nucleotide polymorphisms (SNPs) in close proximity and high linkage disequilibrium in the 10q25.1 region (rs17119434, rs17119461, and rs17119490) associated with melanoma (
      • Teerlink C.
      • Farnham J.
      • Allen-Brady K.
      • Camp N.J.
      • Thomas A.
      • Leachman S.
      • et al.
      A unique genome-wide association analysis in extended Utah high-risk pedigrees identifies a novel melanoma risk variant on chromosome arm 10q.
      ). These SNPs had low minor allele frequencies of 0.005 among controls utilized by
      • Teerlink C.
      • Farnham J.
      • Allen-Brady K.
      • Camp N.J.
      • Thomas A.
      • Leachman S.
      • et al.
      A unique genome-wide association analysis in extended Utah high-risk pedigrees identifies a novel melanoma risk variant on chromosome arm 10q.
      , making detection of associations via traditional case–control methods challenging. We sought to confirm the relationship between these SNPs and melanoma utilizing the population-based Genes, Environment, and Melanoma (GEM) Study, designed to detect associations of rare genetic variants with melanoma (
      • Begg C.B.
      • Hummer A.J.
      • Mujumdar U.
      • Armstrong B.K.
      • Kricker A.
      • Marrett L.D.
      • et al.
      A design for cancer case-control studies using only incident cases: experience with the GEM study of melanoma.
      ).
      The GEM Study is an international population-based case–control study of melanoma in which controls are those diagnosed with an invasive single primary melanoma (SPM) and cases are those diagnosed with multiple primary melanoma (MPM) ascertained between 1998 and 2003 in Australia, Canada, Italy, and the United States (
      • Begg C.B.
      • Hummer A.J.
      • Mujumdar U.
      • Armstrong B.K.
      • Kricker A.
      • Marrett L.D.
      • et al.
      A design for cancer case-control studies using only incident cases: experience with the GEM study of melanoma.
      ,
      • Millikan R.C.
      • Hummer A.
      • Begg C.
      • Player J.
      • de Cotret A.R.
      • Winkel S.
      • et al.
      Polymorphisms in nucleotide excision repair genes and risk of multiple primary melanoma: the Genes Environment and Melanoma Study.
      ). Per GEM protocol, in situ melanomas were considered to be incident melanomas if patients had prior invasive melanomas, in view of the careful surveillance that such patients would have received. The institutional review board at each participating recruitment site approved the study. Participants provided written informed consent. Patient characteristics were collected from phone interviews and self-completed questionnaires. DNA was collected from buccal brushes (
      • Begg C.B.
      • Orlow I.
      • Hummer A.J.
      • Armstrong B.K.
      • Kricker A.
      • Marrett L.D.
      • et al.
      Lifetime risk of melanoma in CDKN2A mutation carriers in a population-based sample.
      ). SNPs were genotyped using the MassArray iPLEX platform (Agena Bioscience, San Diego, CA) with quality-control measures described previously (
      • Orlow I.
      • Reiner A.S.
      • Thomas N.E.
      • Roy P.
      • Kanetsky P.A.
      • Luo L.
      • et al.
      Vitamin D receptor polymorphisms and survival in patients with cutaneous melanoma: a population-based study.
      ). The tumor characteristics were obtained from the diagnostic pathology reports or centralized pathology review as described previously (
      • Kricker A.
      • Armstrong B.K.
      • Goumas C.
      • Thomas N.E.
      • From L.
      • Busam K.
      • et al.
      Survival for patients with single and multiple primary melanomas: the Genes, Environment, and Melanoma Study.
      ,
      • Taylor N.J.
      • Busam K.J.
      • From L.
      • Groben P.A.
      • Anton-Culver H.
      • Cust A.E.
      • et al.
      Inherited variation at MC1R and histological characteristics of primary melanoma.
      ).
      Logistic regression models estimated the odds ratios (ORs) and 95% confidence intervals (CIs) for each SNP adjusted for study features (age, sex, and study center) and an age by sex interaction. Participants with SPM who developed MPM during the ascertainment period (n = 96) were included as both cases and controls. All tests were two-sided with P < 0.05 considered significant. All data were analyzed using Stata, version 15 (StataCorp, College Station, TX).
      The demographics and tumor characteristics of the 2,458 controls and 1,205 cases in GEM are in Supplementary Table S1 online, excluding 12 participants not of European descent. The SNPs were in high linkage disequilibrium with each other: D′ = 0.92 for rs17119434 and rs17119461, 0.95 for rs17119434 and rs17119490, and 1.00 for rs17119461 and rs17119490. Minor allele frequencies were between 0.012 and 0.013 for cases and 0.008 and 0.009 for controls, and the genotype frequency of homozygous minor allele carriage was zero for all three SNPs. The associations of these SNPs with MPM compared to SPM are in Table 1, and reported ORs reflect the comparison of heterozygous versus homozygous major allele genotypes. SNPs rs17119461 and rs17119490 were significantly associated with MPM (P < 0.05), and rs17119434 approached significance (P < 0.08). rs17119461 had the strongest independent association with MPM (OR = 1.77, 95% CI = 1.06–2.97).
      Table 1Associations of genotypes from the 10q25.1 chromosomal region with multiple primary melanoma (n = 1,205) compared with single primary melanoma (n = 2458) patients in the Genes, Environment, and Melanoma Study
      Limited to participants of European origin.
      SNP (hg19)A/aGenotype Frequency, n (%)
      MAFSingle Primary Melanoma (n = 2,458)Multiple Primary Melanoma (n = 1,205)Aa Versus AA, OR (95% CI)
      We used logistic regression models to estimate the ORs and 95% CIs adjusted for study features (age at diagnosis [continuous], sex, and study center) and an age by sex interaction. The genotype frequency of homozygous minor allele carriage was zero for all three SNPs, and the ORs reflect the comparison of heterozygous versus homozygous major allele genotypes.
      P-Value
      ControlsCasesMissingAAAaMissingAAAa
      rs17119434 (107,505,161)A/G0.0090.01373 (3.0)2344 (95.4)41 (1.7)21 (1.7)1154 (95.8)30 (2.5)1.59 (0.94–2.67)0.08
      rs17119461 (107,516,352)T/C0.0090.01364 (2.0)2353 (95.7)41 (1.7)18 (1.5)1156 (95.9)31 (2.6)1.77 (1.06–2.97)0.03
      rs17119490 (107,522,927)G/A0.0080.01284 (3.4)2334 (95.0)40 (1.6)28 (2.3)1148 (95.3)29 (2.4)1.70 (1.00–2.88)0.05
      Bold type indicates the SNP with the strongest association.
      Abbreviations: A, major allele; a, minor allele; CI, confidence interval; hg19, human genome reference version 19; MAF, minor allele frequency; OR, odds ratio; SNP, single nucleotide polymorphism.
      1 Limited to participants of European origin.
      2 We used logistic regression models to estimate the ORs and 95% CIs adjusted for study features (age at diagnosis [continuous], sex, and study center) and an age by sex interaction. The genotype frequency of homozygous minor allele carriage was zero for all three SNPs, and the ORs reflect the comparison of heterozygous versus homozygous major allele genotypes.
      To our knowledge, we provide the first confirmation of associations between SNPs in the 10q25.1 region and melanoma occurrence. The ORs (1.6–1.8) for MPM versus SPM were lower in GEM than the ORs (6.8–8.4) for familial melanoma cases versus genetically matched controls in
      • Teerlink C.
      • Farnham J.
      • Allen-Brady K.
      • Camp N.J.
      • Thomas A.
      • Leachman S.
      • et al.
      A unique genome-wide association analysis in extended Utah high-risk pedigrees identifies a novel melanoma risk variant on chromosome arm 10q.
      . As previously found for CDKN2A mutations, melanoma risk variants in the general population can have a lower relative risk of melanoma than in a high-risk population (
      • Begg C.B.
      • Orlow I.
      • Hummer A.J.
      • Armstrong B.K.
      • Kricker A.
      • Marrett L.D.
      • et al.
      Lifetime risk of melanoma in CDKN2A mutation carriers in a population-based sample.
      ).
      • Teerlink C.
      • Farnham J.
      • Allen-Brady K.
      • Camp N.J.
      • Thomas A.
      • Leachman S.
      • et al.
      A unique genome-wide association analysis in extended Utah high-risk pedigrees identifies a novel melanoma risk variant on chromosome arm 10q.
      proposed a common ancestor to explain the high risk related to the 10q25.1 SNPs among their familial melanoma cases. A more plausible explanation, perhaps, is that the
      • Teerlink C.
      • Farnham J.
      • Allen-Brady K.
      • Camp N.J.
      • Thomas A.
      • Leachman S.
      • et al.
      A unique genome-wide association analysis in extended Utah high-risk pedigrees identifies a novel melanoma risk variant on chromosome arm 10q.
      estimate is simply an overestimate, a common feature of many initial epidemiologic discoveries (
      • Xiao R.
      • Boehnke M.
      Quantifying and correcting for the winner's curse in genetic association studies.
      ). An advantage of the GEM study is that low-frequency genetic variants are more likely to be observable in SPMs than normal controls (
      • Begg C.B.
      • Orlow I.
      • Hummer A.J.
      • Armstrong B.K.
      • Kricker A.
      • Marrett L.D.
      • et al.
      Lifetime risk of melanoma in CDKN2A mutation carriers in a population-based sample.
      ). Further, the ORs found in the GEM study are more likely to represent the impact of these SNPs in the general population than the ORs found for multiple case families.
      The 10q25.1 gene region lacks genes known to be associated with malignancy. A pseudogene, YWHAZP5, is the closest at 65 kb away. SORCS3 and SORCS1 genes, both involved with vacuolar protein production, fall within 1 Mb in either direction of the SNPs. Thus, the mechanism for these SNP associations with melanoma risk remains unknown. Notably, rs17119461 and rs17119490 were found to be nominally associated with pancreatic cancer, which shares genetic risk with familial melanoma (
      • Wu L.
      • Goldstein A.M.
      • Yu K.
      • Yang X.R.
      • Rabe K.G.
      • Arslan A.A.
      • et al.
      Variants associated with susceptibility to pancreatic cancer and melanoma do not reciprocally affect risk.
      ).
      Some melanoma genetic testing panels for patients meeting specific criteria include intermediate risk variants, such as MITF c.952 G>A that have a low minor allele frequency (∼0.0015) (
      • Delaunay J.
      • Martin L.
      • Bressac-de Paillerets B.
      • Duru G.
      • Ingster O.
      • Thomas L.
      Improvement of genetic testing for cutaneous melanoma in countries with low to moderate incidence: the rule of 2 vs the rule of 3.
      ). Thus, if validated in additional studies, rs17119461 may be a potential candidate for genetic testing in populations at high risk for melanoma. Further, additional studies investigating the mechanism for the 10q25.1 SNP associations with melanoma risk are warranted.

      Conflict of Interest

      KJB has received minor royalties from editing a textbook with Elsevier. The remaining authors state no conflict of interest.

      Acknowledgments

      This work was supported by the National Cancer Institute (P01CA206980 to NET and MB, R01CA112243 to NET, U01CA83180 and R01CA112524 to MB, R01CA098438 to CBB, R03CA125829 and R03CA173806 to IO, P30CA016086 (to Henry Shelton Earp), P30CA014089 (to SBG), and P30CA008748 (to Craig B. Thompson); National Institute of Environmental Health Sciences (P30ES010126 to James A. Swenberg). AEC was supported by Career Development Fellowships from the National Health and Medical Research Council is (1147843) and Cancer Institute of New South Wales (15/CDF/1-14).
      GEM Study Group: Coordinating Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA: Marianne Berwick (principal investigator [PI], currently at the University of New Mexico, Albuquerque, NM, USA), Colin Begg (co-PI), Irene Orlow (co-investigator), Klaus J. Busam (dermatopathologist), Pampa Roy (senior laboratory technician), Siok Leong (research assistant), Sergio Corrales-Guerrero (senior research technician), Keimya Sadeghi (senior laboratory technician), Anne Reiner (biostatistician). University of New Mexico, Albuquerque, NM, USA: Marianne Berwick (PI), Li Luo (biostatistician), Tawny W. Boyce (data manager). Study centers: The University of Sydney and The Cancer Council New South Wales, Sydney, Australia: Anne E. Cust (PI), Bruce K. Armstrong (former PI), Anne Kricker (former co-PI); Menzies Institute for Medical Research University of Tasmania, Hobart, Australia: Alison Venn (current PI), Terence Dwyer (PI, currently at University of Oxford, Oxford, UK), Paul Tucker (dermatopathologist); British Columbia Cancer Research Centre, Vancouver, Canada: Richard P. Gallagher (PI), Agnes Lai, Research Coordinator, Cancer Care Ontario, Toronto, Canada: Loraine D. Marrett (PI), Lynn From (dermatopathologist); CPO, Center for Cancer Prevention, Torino, Italy: Roberto Zanetti, M.D (PI), Stefano Rosso (co-PI); University of California, Irvine, CA, USA: Hoda Anton-Culver (PI); University of Michigan, Ann Arbor, MI, USA: University of Michigan, Ann Arbor, MI, USA: Stephen B. Gruber (PI, currently at University of Southern California, Los Angeles, CA, USA), Shu-Chen Huang (co-investigator, joint at University of Southern California–University of Michigan); University of North Carolina, Chapel Hill, NC, USA: Nancy E. Thomas (PI), Kathleen Conway (co-investigator), David W. Ollila (co-Investigator), Pamela A. Groben (dermatopathologist), Sharon N. Edmiston (research analyst), Honglin Hao (laboratory specialist), Eloise Parrish (laboratory specialist), Jill S. Frank (Research Assistant), David C. Gibbs (Research Assistant, Emory University, Atlanta, GA, USA); University of Pennsylvania, Philadelphia, PA, USA: Timothy R. Rebbeck (former PI), Peter A. Kanetsky (PI, currently at H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA); UV data consultants: Julia Lee Taylor and Sasha Madronich, National Centre for Atmospheric Research, Boulder, CO, USA.

      Supplementary Material

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