The Role of UV Radiation and Exposure in Melanoma Ashley Wysong MD, MS Founding Chairman William W. Bruce MD Distinguished Chair of Dermatology UNMC College of Medicine, Department of Dermatology Department of Otolaryngology Head and Neck Surgery (Courtesy) Department of Pathology/Microbiology (Courtesy) UNMC College of Public Health, Department of Epidemiology University of Nebraska Graduate Faculty, Cancer Biology Disclosures Nature of Relevant Financial Commercial Interest Relationship What was received For what role • Research Grant • Castle Biosciences • Investigator (pending) SEER Melanoma New Cases & Deaths 1992 - 2018 SEER Incidence (rate per 100,000) 2013 - 2017 30 25 20 15 10 5 0 White Black Asian/PI American Indian/Alaska Hispanic Native U.S. Cancer Statistics Data Visualizations Tool; UNMC Department of Dermatology CDC/NCI www.cdc.gov/cancer/dataviz, June 2019 Trends in Melanoma • Epidemiologic studies show an increase in melanoma incidence primarily among white populations – Believed 2/2 sun exposure and changing recreational behaviors + tanning bed exposures – Increased surveillance • The lifetime risk of melanoma = 1 in 28 • Annual increases in melanoma incidence vary from 3-7% per year = a doubling of rates every 10-20 years • Annually melanoma costs approx $3.3 billion Nikolaou 2014; Garbe 2009, Glazer 2017 Known Risk Factors for Melanoma Genetics Environment Skin Type I, II Ultraviolet Radiation – Light hair, light eyes, – Lifetime freckling – Intermittent intense UV Family Hx 2x increased risk exposure – 30-40% from inherited – Tanning Beds mutations in CDKN2A, CDK4 – Sunburns during Childhood – BAP1 Latitudes – MCR1 High socieoeconomic status (SES) Number and Size of Nevi Immunosuppression Atypical Nevus Syndrome Environmental exposures (heavy DNA repair defects metals, insecticides, hormones) Large Congenital Nevi Personal History of Melanoma UV & Melanoma • An estimated 70% of melanomas are believed to be UV related Koh Arch Derm 1996, Mechanisms of UV Induction of Melanoma Ultraviolet at the Earth’s Surface • UVB (290-320nm) • UVC (200-290nm) – 5% of total UV at – <1% of total UV at surface surface – Blocked by glass – Blocked by ozone – Effects on skin • Burning • Tanning • SCC • Aging • UVA (320-400) – 95% of total UV at surface – Penetrates glass – Effects on skin • Tanning • Photoaging Photomutagenesis UVB Sunburns / Delayed Tanning direct DNA damage through the formation of DIMERS: – Cyclobutane pyrimidine dimer formation (T-T) – 6-4 photoproducts (T-C) Response – Inhibits cell replication & transcription – Oncogene transformation • Mutagenesis • Carcinogenesis – Immunosuppression Photomutagenesis UVA Immediate Tanning / Photoaging indirect damage of DNA – Generation of reactive oxygen species • Free radicals: Singlet oxygen, H2O2, super oxide, hydroxyl – Conversion of guanine residues to 8- hydroxydeoxyguanosine ssDNA breaks – Substantial immunosuppression Response – Carcinogenesis DNA Repair and UV Damage DNA repair is critical for suppressing the development of melanoma – Xeroderma pigmentosum (XP), a disease caused by defective nucleotide excision repair (NER) – 2000x risk of melanoma UVB exposure inhibition of NER accelerated melanomagenesis in mouse models melanoma. Immunosuppressive Effects of UV Light UV light has been associated with: – Depletion of Langerhans cells from epidermis, leading to decreased ability for antigen presentation • Reduced immune surveillance – Release of immunosuppressive cytokines • IL-10 – Possible decrease in tumor surveillance leading to unopposed tumor growth Melanoma is 1.6 to 2.5 times more common among organ transplant recipients Genetics and Melanoma Genetics and Melanoma INHERITED/FAMILIAL • 3–15% of melanomas arise due to familial genetic predisposition, in which UV-independent mutations play a significant role • Germline mutations and polymorphisms in CDKN2A/p16/p14 in 20-40% of melanoma families Genetics and Melanoma WHEN TO SEND FOR GENETIC TESTING: Low melanoma incidence area/population – Two primary melanomas in an individual, or – Two cases of melanoma among first- or second-degree relatives, or – One case of melanoma and one case of pancreatic cancer in first- or second-degree relatives. Moderate to high melanoma incidence area/population – Three primary melanomas in an individual, or – Three cases of melanoma in first- or second-degree relatives, or – Two cases of melanoma and one pancreatic cancer in first- or second-degree relatives, or – One case of melanoma and two of pancreatic cancer in first- or second-degree relatives. • GWAS performed in 281 with multiple primary melanomas (MPM), 304 with single primary melanoma (SPM) and 659 controls • CDKN2A, MC1R and MTAP variants were more frequent in patients who developed melanomas at a younger age, but also in those whose melanomas were all on visibly UV-damaged sites. • Polygenic risk score predicted increased risk of single and multiple melanomas The majority of melanomas are sporadic! Non-UV UV signature signature mutations: mutations, but • CDKN2A more common • TP53 in sun-exposed • NF1 areas: • RAC1 • BRAF (60%) • PTEN • NRAS (20%) UV & Driver Mutations in Melanoma • Whole exome sequencing of 121 melanomas • UV-induced DNA damage signatures seen in 46% of driver mutations • “Provided unequivocal genomic evidence for a direct mutagenic role of UV light in melanoma pathogenesis” Cell 150, 251–263, July 20, 2012. Heterogeneity of Melanoma by UV exposure Intermittent sun exposure – Superficial spreading melanoma or nodular subtype – Younger patients – BRAF mutations Chronic sun induced damage – Lentigo maligna • linked to cumulative (rather than intermittent) sun exposure – Older patients – NRAS, CCND1 mutations Sun protected sites: acral, mucosal, ocular – Different types of mutations – less likely UV dependent – KIT/MAPK, CDK4/CDKN4A, TERT mutations common in acral melanoma – GNAQ in uveal/ocular melanoma • Signature 7 = UV radiation mutational signature • Signature 7 patients had longer disease-free and better overall survival independent of disease stage at diagnosis than non-Signature 7 patients. • Signature 7 predicted favorable outcome in patients with melanoma undergoing immunotherapy. Nature Medicine 2019, 25;221–224. Acral Lentiginous Melanoma • Different cancer pathways are activated in acral melanoma • UV radiation signatures are identified in only a small proportion of ALMs • UV radiation signatures in subungual melanomas are reported, whereas it has been shown that the nail plate blocks the majority of UV radiation. JAAD International 2020 1135-147DOI: (10.1016/j.jdin.2020.07.004) Uveal Melanoma • Recent genetic mutations study suggests there are more genetic similarities between UM and CM than previously thought • A subset of UM tumors harbored mutations in several known cancer genes classically associated with CM and/or UV light exposure – BRAF, NRAS, CDKN2A, PTEN, TP53, TERT, ARID2, and KMT2C. Neoplasma 2020; 67(5): 958–971 UV in Melanoma: Epidemiologic Data Types of UV Exposure Intermittent = acute and periodic sun exposure on skin that has not adapted to the sun Chronic = continuous pattern of exposure Total = cumulative lifetime sun exposure Early Sunburns/Exposure Tanning Beds Relative risk & 95% confidence interval for melanoma risk INTERMITTENT SUN EXPOSURE RR=1.61 increased melanoma risk RR=2.35 for sun-sensitive phenotype Relative risk & 95% confidence interval for melanoma risk CHRONIC SUN EXPOSURE RR=0.95 Slight protective effect of chronic sun exposure on melanoma risk Relative risk & 95% confidence interval for melanoma risk TOTAL SUN EXPOSURE RR=1.34 Modest increased melanoma risk with total sun exposure Summary – Results of Meta-Analyses Relative risk & 95% confidence interval for melanoma risk SUNBURN HISTORY RR=2.03 Modest increased melanoma risk with sunburn Blistering sunburns in 15 to 20 year olds was associated with an increased risk of melanoma (RR = 2.2 (1.2-3.8) for 5+ vs. 0 burns). % of High School Students Reporting a Sunburn CDC. MMWR Surveill Summ 2018;6. Tanning Beds Emit UVR in amounts 10-15x higher than sun at its most direct exposure Meta-analysis including 31 studies & almost 15,000 adult melanoma cases • Ever use of tanning beds = OR 1.16 (1.05-1.28) • >10 tanning sessions = OR 1.34 (1.05- 1.71) BMJ. 2012 Jul 24; 345:e4757 Colantonio, JAAD, 2014 Tanning Beds Age Matters! – If first tanning bed use < 35 years of age 75% increased risk of melanoma – Australian case-control study, more than10 lifetime tanning sessions = RR of 2.01 • If melanoma dx at age 18-29yrs = 6.57 • If melanoma dx at age 30-39 = 1.67 – First tanning bed use < age 35 RR of 1.87 (1.41 – 2.48) In 2009, IARC/WHO classified UV radiation from tanning beds as carcinogenic to humans International Journal of Cancer, 120(5):1116-1122. BMJ. 2012 Jul 24; 345:e4757 Legislative efforts started in 2009 42 states now limit use of tanning beds for minors! Surgeon General Report Call to Action to Prevent Skin Cancer “The rates of skin cancer in our nation are increasing, creating a serious public health concern we cannot ignore. Now is the time for a comprehensive approach to prevent skin cancer, bringing together community partners, business leaders, government agencies, and individuals for a common cause.” -- Acting Surgeon General, Boris Lushniak (dermatologist!) The report calls for: -- Strategies to protect us from UV radiation (shade in recreational/play areas, businesses provide sun protection for outdoor workers, policies for shade planning in land development, all health