Genetic Risk Factors of Melanoma
Cleveland Clinic Dermatologist Dr. Josh Arbesman discusses a new skin cancer study with Variant Bio
Two hundred years ago, the first report of familial melanoma was placed into medical literature by Dr. W. Norris.¹ Melanoma is a type of skin cancer that starts specifically in pigment-producing cells or melanocytes; familial melanoma refers to cases where multiple people in the same family develop this disease. In his 1820 paper entitled “Case of Fungoid Disease,” Dr. Norris described a man with metastatic melanoma whose father also died of the same disease and whose children and brothers had many moles. Even with this very early indication of a clear genetic basis for familial melanoma, it would take another 170 years before the first genetic risk factor, CDKN2A, was discovered.² Since then, significant work has uncovered other genes that predispose individuals and families. However, many genetic risk factors remain undiscovered. Even in high-risk families or individuals who have developed multiple melanomas, a known genetic risk factor is identified in less than 50% of patients, with the most commonly identified gene being CDKN2A.³ Not only do these discoveries allow families and individuals to understand their own risks for cancer, a greater genetic understanding of familial cancers has often been valuable for sporadic (or non-familial) cancers as well. For example, CDKN2A, the first gene identified in familial melanoma, is also altered in many sporadic melanoma cases.⁴
Over the past few decades, melanoma rates have rapidly increased, with the US lifetime risk increasing from 1/600 in 1960 to 1/75 in 2000 and continuing to rise.⁵ Is this steady rise because we have steadily gotten more sun over the years? In short, yes and no. While sun exposure definitely plays a large role in melanoma development, twin studies identify melanoma as highly heritable, significantly higher than other cancers that are classically thought to be genetic, such as breast and ovarian cancers.⁶ This finding means that, while environmental risk factors may increase certain individuals’ risk for melanoma, some people inherit particular genetic changes that put them at significantly higher risk for melanoma compared to the general population.
In 2017 at Cleveland Clinic, we established the Gross Familial Melanoma Registry (led by medical oncologist Dr. Pauline Funchain and myself, Dr. Josh Arbesman) to better understand the genetic risks that characterize families and individuals who are at higher risk for melanoma in addition to other cancers. We are uncovering genes that may predispose individuals to melanoma and hope to add to the body of literature of genetic risk factors for this cancer. As such, we focus specifically on patients with multiple melanomas and other cancers in an individual or family to help pinpoint novel genetic risk factors. We are seeking out melanoma outliers, those who develop significantly more melanomas, to help us understand what genetics factors are critical for cancer formation.
Many high-risk patients know that they can help reduce their risk for future melanomas by managing their sun exposure, but we know that this is only part of the story. For many, genetics also plays a large role in cancer development. Also, much of the cancer risk related to sun exposure is already set from childhood and adolescence.⁷ So what can we do to help high-risk individuals be proactive about their health going forward?
In 2020, Cleveland Clinic has begun a skin cancer study with Variant Bio in a joint effort to better understand phenotypic outliers and genetic risk for melanoma. Using the registry we established, we can identify patients with a high disease burden who have no known genetic risk factor yet clearly display a heritable genetic component to the development of their cancer. Variant Bio will provide genomic analysis in connection with the study. We hope to fill the biological gap between disease manifestation and underlying genetic cause. Armed with deeper genetic knowledge, we can better help our patients understand their cancer risks, and hope to fully mitigate that risk in the future for high-risk individuals and their families.
- Norris, William. 1820. “Case of Fungoid Disease.” Edinburgh Medical and Surgical Journal 16 (65): 562–65.
- Hussussian, C. J., J. P. Struewing, A. M. Goldstein, P. A. Higgins, D. S. Ally, M. D. Sheahan, W. H. Clark Jr, M. A. Tucker, and N. C. Dracopoli. 1994. “Germline p16 Mutations in Familial Melanoma.” Nature Genetics 8 (1): 15–21.
- Rossi, Mariarita, Cristina Pellegrini, Ludovica Cardelli, Valeria Ciciarelli, Lucia Di Nardo, and Maria Concetta Fargnoli. 2019. “Familial Melanoma: Diagnostic and Management Implications.” Dermatology Practical & Conceptual 9 (1): 10–16.
- Shain, A. Hunter, Iwei Yeh, Ivanka Kovalyshyn, Aravindhan Sriharan, Eric Talevich, Alexander Gagnon, Reinhard Dummer, et al. 2015. “The Genetic Evolution of Melanoma from Precursor Lesions.” The New England Journal of Medicine 373 (20): 1926–36.
- Volkovova, Katarina, Dagmar Bilanicova, Alena Bartonova, Silvia Letašiová, and Maria Dusinska. 2012. “Associations between Environmental Factors and Incidence of Cutaneous Melanoma. Review.” Environmental Health: A Global Access Science Source 11 Suppl 1 (June): S12.
- Mucci, Lorelei A., Jacob B. Hjelmborg, Jennifer R. Harris, Kamila Czene, David J. Havelick, Thomas Scheike, Rebecca E. Graff, et al. 2016. “Familial Risk and Heritability of Cancer Among Twins in Nordic Countries.” JAMA: The Journal of the American Medical Association 315 (1): 68–76.
- Wu, Shaowei, Jiali Han, Francine Laden, and Abrar A. Qureshi. 2014. “Long-Term Ultraviolet Flux, Other Potential Risk Factors, and Skin Cancer Risk: A Cohort Study.” Cancer Epidemiology, Biomarkers & Prevention: A Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology 23 (6): 1080–89.
