Genetics Study Points To Different Pathways For Melanoma Risk Interview with:

Nancy E. Thomas, MD PhD Department of Dermatology, University of North Carolina Chapel Hill, NC 27599

Dr. Nancy E. Thomas

Nancy E. Thomas, MD PhD
Department of Dermatology, University of North Carolina
Chapel Hill, NC 27599

Medical Research: What is the background for this study?

Dr. Thomas: Melanoma had been thought for some time to arise from at least two causal pathways, a ‘chronic sun exposure pathway’ and a ‘nevus pathway’. However, the role of inherited genetic variation in development of melanoma along these pathways had not previously been studied. Thus, we chose to examine the association of SNPs in putative low-penetrance melanoma susceptibility loci with histologic markers of divergent pathways.

Medical Research: What are the main findings?

Dr. Thomas: Within the large Genes, Environment and Melanoma Study, we investigated the relationship of germline variants in newly identified low-penetrance melanoma risk loci to histologic markers of divergent causal pathways in melanoma. We present strong evidence that the IRF4 rs12203592*T genotype is positively associated with chronic sun exposure-related melanoma and inversely associated with nevus-related melanoma. We also found that the IRF4 rs12203592 genotype is linked to the bi-model age distribution known to occur in melanoma and which is related to the divergent pathways. IRF4 rs12203592 is a functional variant known to affect IRF4 expression in human skin and melanoma cell lines. We conclude that IRF4rs12203592 is likely, at least in part, to determine pathway-specific risk for melanoma development.

Medical Research: What should clinicians and patients take away from your report?

Dr. Thomas: This is the first study to our knowledge that provides evidence that inherited genetic variation likely underlies susceptibility to divergent pathways in melanoma development.  In other words, you could be more susceptible to one type of melanoma if you have one particular genotype of IRF4 and more susceptible to another type of melanoma if you have the other genotype of IRF4. One’s IRF4 genotype could also determine the likelihood that melanoma would arise earlier or later in life. Understanding risk factors for different types of melanoma could lead to distinct prevention opportunities.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Thomas: Our results characterize the association of inherited melanoma-associated SNPs with histopathological markers of the divergent pathways (solar elastosis and neval remnants).  Further work needs to be done to determine the associations of inherited SNPs with molecular markers of divergent pathways such as DNA driver mutations in the BRAF and NRAS oncogenes and alterations in tumor suppressor genes.

It is highly likely that the full spectrum of risk factors for melanoma has not yet been identified and some risk factors may only be identified through study of divergent pathways. Mounting evidence suggests that melanoma is a heterogeneous disease with distinct etiologic pathways, and this has likely been a barrier to the discovery of new risk loci. If associations are opposite for the different pathways as we found for IRF4rs12203592 then they may not be identified in studies that combine melanomas that formed along different pathways.  We speculate in the paper that this could be why IRF4 rs12203592 has been inconsistently associated with melanoma risk in different studies.

Future research should be conducted to clarify the etiologically distinctive melanoma subtypes and use the results to both refine our search of new risk factors and develop more accurate risk prediction tools for these distinctive subtypes.

Medical Research: Is there anything else you would like to add?

Dr. Thomas: We chose 47 single-nucleotide polymorphisms (SNPs) within 21 genetic loci previously reported to be in associated with melanoma in other studies. Since our work has been initiated, additional SPNs have been found to be associated with melanoma and fine mapping has been done of some of the loci to identify the most strongly associated SNPs.  These additional SNPs warrant examination in relationship to markers of divergent pathways in further similar analyses.


David C. Gibbs, Irene Orlow, Jennifer I. Bramson, Peter A. Kanetsky, Li Luo,Anne Kricker, Bruce K. Armstrong, Hoda Anton-Culver, Stephen B. Gruber,Loraine D. Marrett, Richard P. Gallagher, Roberto Zanetti, Stefano Rosso,Terence Dwyer, Ajay Sharma, Emily La Pilla, Lynn From, Klaus J. BusamAnne E. Cust, David W. Ollila, Colin B. Begg, Marianne Berwick, Nancy E. Thomas,and on behalf of the GEM Study Group

Association of Interferon Regulatory Factor-4 Polymorphism rs12203592 With Divergent Melanoma Pathways JNCI J Natl Cancer Inst (2016) 108 (7): djw004 doi:10.1093/jnci/djw004 First published online February 8, 2016 (9 pages)

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Nancy E. Thomas, MD PhD (2016). Genetics Study Points To Different Pathways For Melanoma Risk 

Last Updated on February 21, 2016 by Marie Benz MD FAAD