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Ambient Ultraviolet Radiation and Sebaceous Carcinoma Incidence in the United States, 2000-2016

Ambient Ultraviolet Radiation and Sebaceous Carcinoma Incidence in the United States, 2000-2016 Downloaded from https://academic.oup.com/jncics/advance-article-abstract/doi/10.1093/jncics/pkaa020/5762618 by guest on 03 March 2020 Manuscript--FINAL Article Type: Brief Communications Title: Ambient Ultraviolet Radiation and Sebaceous Carcinoma Incidence in the United States, 2000-2016 1 2 3 Michael R. Sargen, MD , Zhi-Ming Mai, MD, PhD , Eric A. Engels, MD, MPH , Alisa M. 1 4 5 2 Goldstein, PhD , Margaret A. Tucker, MD , Ruth M. Pfeiffer, PhD , Elizabeth K. Cahoon, PhD Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD Human Genetics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD Corresponding Author: Michael R. Sargen, MD Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Rm. 6E-542, Rockville, MD 20850 Published by Oxford University Press 2020. This work is written by ( a) US Government employee(s) and is in the public domain in the US. Downloaded from https://academic.oup.com/jncics/advance-article-abstract/doi/10.1093/jncics/pkaa020/5762618 by guest on 03 March 2020 Office: (240) – 276 – 7354 Email: michael.sargen@nih.gov Abbreviations: sebaceous carcinoma, SC; ultraviolet radiation, UVR; Muir-Torre syndrome, MTS; Surveillance, Epidemiology, and End Results, SEER Downloaded from https://academic.oup.com/jncics/advance-article-abstract/doi/10.1093/jncics/pkaa020/5762618 by guest on 03 March 2020 Abstract Sebaceous carcinoma (SC) is an aggressive skin tumor. While ultraviolet radiation (UVR) is an important risk factor for some skin cancer types, no population-level study has evaluated for an association between UVR and SC risk. Herein, we examined satellite-based ambient UVR in relation to SC incidence using Surveillance, Epidemiology, and End Results 18 cancer registry data (2000-2016). There were 3,503 microscopically confirmed cases of SC diagnosed during the study period. For non-Hispanic whites, there was an association between increasing ambient UVR and SC risk (incidence rate ratio, IRR[per UVR quartile]=1.15; 95% CI, 1.11 to 1.19; two- sided P<0.001) including among individuals with and without putative Muir-Torre syndrome (MTS). In contrast, there was no association between ambient UVR and SC risk for other race/ethnicities. Our findings support a role for UVR in SC tumorigenesis, which suggests that photoprotection may reduce SC risk, particularly for high-risk populations (eg. MTS). Downloaded from https://academic.oup.com/jncics/advance-article-abstract/doi/10.1093/jncics/pkaa020/5762618 by guest on 03 March 2020 Sebaceous carcinoma (SC) is an aggressive skin cancer with a 5-year mortality rate of 20%. SC risk factors include male sex, older age, Muir-Torre syndrome (MTS; OMIM 158320), and immune suppression.[1-3] In contrast to many other cancer types, SC incidence in the United States has been increasing since 1973 when the Surveillance, Epidemiology, and End Results (SEER) database first began tracking cancer statistics.[4, 5] Therefore, it is important to identify exposures underlying these trends, which could assist with preventive efforts, screening and early diagnosis of SC. SC most commonly occurs on chronically sun-exposed skin of the head and neck in older, non-Hispanic white (NHW) patients suggesting that ultraviolet radiation (UVR) may contribute to SC development.[2, 5] However, population-based epidemiological data examining the association of UVR with SC are lacking. In this study, we examined the association between ambient UVR and SC risk in the United States by linking satellite-based ambient UVR with SEER 18 cancer registry data (27.8% of U.S. population) for the years 2000-2016 by county.[6] UVR data were cloud-adjusted daily ambient irradiance (wavelength=305nm) on a 1 degree latitude × 1 degree longitude grid, which were derived from the National Aeronautics Space Administration’s (NASA) Total Ozone Mapping Spectrometer database.[7] Because satellite-based estimates of UVR in the U.S. have varied little aside from relatively small fluctuations due to the 11-year solar cycle[8], in the present analysis, daily noon-time estimates over years 1982-1992 were averaged to represent a full solar cycle. SEER counties were assigned to UVR quartiles, low (Q1) to high (Q4), with cutoffs constructed to have similar person years at risk across quartiles. We report age-adjusted cancer rates and incidence rate ratios (IRRs) for microscopically confirmed cases of SC (ICD-O- 3 code 8410/3) using the Tiwari method in SEER*stat 8.3.6[9, 10]. Individuals were designated Downloaded from https://academic.oup.com/jncics/advance-article-abstract/doi/10.1093/jncics/pkaa020/5762618 by guest on 03 March 2020 as having putative MTS, a phenotypic variant of Lynch syndrome (OMIM: 120435), if they had SC plus another Lynch syndrome cancer.[3] Poisson models comparing SC incidence with UVR were adjusted for sex, age, diagnosis period, and registry volume to calculate IRRs. We report 95% confidence intervals and two-sided p-values for each IRR and statistical significance was defined as a p-value <0.05. Registry volume was categorized into tertiles using census-based population size to create 3 roughly equal categories. There was no evidence of over-dispersion in any of the Poisson models and these analyses were performed using STATA 15.0 (College Station, TX). There were 3,503 SCs diagnosed in the study population with 287 tumors (8.2%) occurring in individuals with putative MTS. Individuals with SC were predominantly non- Hispanic white (NHW, 77.7%) and male (61.1%) (Table 1). The overall incidence was 2.43 cases (95% CI, 2.35 to 2.52) per million persons per year and the incidence increased by 3.3% (95% CI, 2.2 to 4.5) per year between 2000-2016 (Table 1). Among NHWs (N=2,667 cases), there was an association between ambient UVR quartile and SC risk (IRR[per UVR quartile]=1.15; 95% CI, 1.11 to 1.19; P<0.001) (Figure 1). This association was also observed for NHWs with (N=222 cases; IRR[per UVR quartile]=1.22; 95% CI, 1.08 to 1.39; P=0.002) and without (N=2,445 cases; IRR[per UVR quartile]=1.14; 95% CI, 1.09 to 1.19; P<0.001) putative MTS (Figure 1) and for multiple age groups (50-64, 65-79, ≥80; P<0.05, all analyses) and diagnosis periods (2000-2005, 2006-2010, 2011-2016; P<0.05, all analyses) (Supplementary Table 1). In contrast to NHWs, there was no association between ambient UVR and SC risk among other race/ethnicities with increased skin pigmentation suggesting that melanin pigment, which absorbs UVR, is protective against SC tumorigenesis similar to other cutaneous Downloaded from https://academic.oup.com/jncics/advance-article-abstract/doi/10.1093/jncics/pkaa020/5762618 by guest on 03 March 2020 malignancies.[11] There were also differences in the effect size between NHW males (N=1,655 cases; IRR[per UVR quartile]=1.20; 95% CI, 1.15 to 1.26; P<0.001) and NHW females (N=1,012 cases; IRR[per UVR quartile]=1.06; 95% CI, 1.00 to 1.13; P=0.05), which may be partially explained by gender differences in sun protective behavior and an increased likelihood for outdoor occupations among males[12-14] (Figure 1). Since HIV infection is a risk factor for SC[1], we separately examined associations between ambient UVR and SC risk by county-level HIV prevalence (“low” prevalence counties: <308.5 cases per 100,000 persons [2016 national average][15]). Among NHWs, there was a statistically significant association between ambient UVR quartile and SC risk for areas with “low” (N=2,158 cases; IRR[per UVR quartile]=1.05; 95% CI, 1.01 to 1.09; P=0.02) and “high” (N=509 cases; IRR[per UVR quartile]=1.73; 95% CI, 1.38 to 2.18; P<0.001) HIV prevalence. The association was much stronger within “high” HIV prevalence counties suggesting that NHW patients with HIV in areas with high ambient UVR may be at particularly high risk for SC. Additional studies are necessary to confirm this finding given the limited number of cases and the absence of laboratory confirmation of patient HIV status. (Supplementary Table 1). The association between ambient UVR and SC risk may be partially explained by UVR- induced mutagenesis. In support of this hypothesis, one prior study identified UVR-mutational signatures in one third of SC tumors.[16] UVR-induced immunosuppression in the skin may also be contributing to SC tumorigenesis.[17-19] Immunosuppression is an important risk factor for several skin cancer types. Rates of melanoma and keratinocyte carcinomas are elevated for solid organ transplant recipients receiving immunosuppressant medications and individuals with HIV infection.[1, 20-23] Additionally, higher ambient UVR is associated with an increased risk for Kaposi sarcoma (KS) among HIV-infected patients, suggesting that UVR could be contributing Downloaded from https://academic.oup.com/jncics/advance-article-abstract/doi/10.1093/jncics/pkaa020/5762618 by guest on 03 March 2020 to KS-associated herpesvirus infection and subsequent tumor development through UVR- induced immunosuppression.[24] Further studies are needed to determine whether UVR-induced immunosuppression contributes to SC development. A limitation of this study is that ambient UVR data may not be representative of individual UVR exposure, which can be influenced by sun-seeking (leisure time outdoors, outdoor occupation) and sun-protective behavior (sunscreen, hats, etc.). Misclassification of exposure may also occur if individuals frequently migrate between areas with disparate ambient UVR. However, we identified associations between ambient UVR and SC risk for multiple subgroups which strongly implicates UVR in SC tumorigenesis. This is the first population-based epidemiological study to identify UVR as a risk factor for SC. Photoprotective measures should be advocated in high-risk populations to prevent this aggressive skin cancer. The biologic mechanisms underlying this association require further investigation. Funding: This work was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. Notes Role of the funder: The funder had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; and the decision to submit the manuscript for publication. Downloaded from https://academic.oup.com/jncics/advance-article-abstract/doi/10.1093/jncics/pkaa020/5762618 by guest on 03 March 2020 Disclosures: The authors have no disclosures. Acknowledgments: We would like to thank Sara Schonfeld (National Cancer Institute) for her assistance with the SEER*stat analyses. References: 1. Lanoy E, Dores GM, Madeleine MM, et al. Epidemiology of nonkeratinocytic skin cancers among persons with AIDS in the United States. AIDS 2009;23(3):385-93. 2. Tripathi R, Chen Z, Li L, et al. Incidence and survival of sebaceous carcinoma in the United States. J Am Acad Dermatol 2016;75(6):1210-1215. 3. Baglietto L, Lindor NM, Dowty JG, et al. Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst 2010;102(3):193-201. 4. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018;68(1):7- 5. Dasgupta T, Wilson LD, Yu JB. A retrospective review of 1349 cases of sebaceous carcinoma. Cancer 2009;115(1):158-65. 6. Surveillance, Epidemiology, and End Results (SEER). Number of Persons by Race and Hispanic Ethnicity for SEER Participants (2010 Census Data). https://seer.cancer.gov/registries/data.html#a1. Accessed September 15, 2019. 7. National Aeronautics Space Administration. Total Ozone Mapping Spectrometer data product: erythemal UV exposure. In. Greenbelt, MD: Goddard Space Flight Center; 2004. 8. Lean JL. Estimating Solar Irradiance Since 850 CE. Earth and Space Science 2018;5:133- Downloaded from https://academic.oup.com/jncics/advance-article-abstract/doi/10.1093/jncics/pkaa020/5762618 by guest on 03 March 2020 9. Surveillance, Epidemiology, and End Results (SEER). SEER*Stat Software. https://seer.cancer.gov/seerstat/. Accessed August 30, 2019. 10. Tiwari RC, Clegg LX, Zou Z. Efficient interval estimation for age-adjusted cancer rates. Stat Methods Med Res 2006;15(6):547-69. 11. Lin JY, Fisher DE. Melanocyte biology and skin pigmentation. Nature 2007;445(7130):843-50. 12. Branstrom R, Kasparian NA, Chang YM, et al. Predictors of sun protection behaviors and severe sunburn in an international online study. Cancer Epidemiol Biomarkers Prev 2010;19(9):2199-210. 13. Glanz K, Buller DB, Saraiya M. Reducing ultraviolet radiation exposure among outdoor workers: state of the evidence and recommendations. Environ Health 2007;6:22. 14. Gabriel P, Schmitz S (Bureau of Labor Statistics). Gender differences in occupational distributions among workers. https://www.bls.gov/opub/mlr/2007/06/art2full.pdf. Accessed January 20, 2020. 15. Centers for Disease Control (CDC). HIV Surveillance Report, 2017. https://www.cdc.gov/hiv/pdf/library/reports/surveillance/cdc-hiv-surveillance-report-2017-vol- 29.pdf. Accessed September 15, 2019. 16. North JP, Golovato J, Vaske CJ, et al. Cell of origin and mutation pattern define three clinically distinct classes of sebaceous carcinoma. Nat Commun 2018;9(1):1894. 17. Racz E, Prens EP, Kurek D, et al. Effective treatment of psoriasis with narrow-band UVB phototherapy is linked to suppression of the IFN and Th17 pathways. J Invest Dermatol 2011;131(7):1547-58. Downloaded from https://academic.oup.com/jncics/advance-article-abstract/doi/10.1093/jncics/pkaa020/5762618 by guest on 03 March 2020 18. Johnson-Huang LM, Suarez-Farinas M, Sullivan-Whalen M, et al. Effective narrow-band UVB radiation therapy suppresses the IL-23/IL-17 axis in normalized psoriasis plaques. J Invest Dermatol 2010;130(11):2654-63. 19. Ozawa M, Ferenczi K, Kikuchi T, et al. 312-nanometer ultraviolet B light (narrow-band UVB) induces apoptosis of T cells within psoriatic lesions. J Exp Med 1999;189(4):711-8. 20. Jensen P, Hansen S, Moller B, et al. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol 1999;40(2 Pt 1):177-86. 21. Silverberg MJ, Leyden W, Warton EM, et al. HIV infection status, immunodeficiency, and the incidence of non-melanoma skin cancer. J Natl Cancer Inst 2013;105(5):350-60. 22. Robbins HA, Clarke CA, Arron ST, et al. Melanoma Risk and Survival among Organ Transplant Recipients. J Invest Dermatol 2015;135(11):2657-2665. 23. Lindelof B, Sigurgeirsson B, Gabel H, et al. Incidence of skin cancer in 5356 patients following organ transplantation. Br J Dermatol 2000;143(3):513-9. 24. Cahoon EK, Engels EA, Freedman DM, et al. Ultraviolet Radiation and Kaposi Sarcoma Incidence in a Nationwide US Cohort of HIV-Infected Men. J Natl Cancer Inst 2017;109(5). Downloaded from https://academic.oup.com/jncics/advance-article-abstract/doi/10.1093/jncics/pkaa020/5762618 by guest on 03 March 2020 Table 1. Incidence rates of sebaceous carcinoma by clinical characteristics Rate per million Characteristic No. of cases (%)* IRR (95% CI)‡ P§ persons (95% CI)† -- Total 3,503 (100.0) 2.43 (2.35 to 2.52) -- Tumor Location -- -- Non-Head and Neck 909 (25.9) 0.62 (0.58 to 0.66) -- -- Head and Neck 2,566 (73.3) 1.80 (1.73 to 1.87) Unknown 28 (0.8) -- Gender -- Female 1,363 (38.9) 1.67 (1.58 to 1.76) 1.00 (Reference) <0.0001 Male 2,140 (61.1) 3.46 (3.31 to 3.61) 2.07 (1.94 to 2.22) Age -- <50 254 (7.3) 0.26 (0.23 to 0.30) 1.00 (Reference) <0.0001 50-64 837 (23.9) 3.27 (3.05 to 3.50) 12.5 (10.9 to 14.5) <0.0001 65-79 1,330 (38.0) 10.8 (10.2 to 11.4) 41.2 (36.0 to 47.3) <0.0001 ≥80 1,082 (30.9) 22.7 (21.4 to 24.1) 86.8 (75.6 to 99.9) Race/Ethnicity -- Black 100 (2.9) 0.71 (0.57 to 0.87) 1.00 (Reference) <0.0001 Asian or Pacific Islander 187 (5.3) 1.51 (1.30 to 1.75) 2.14 (1.66 to 2.77) 0.009 American Indian or Alaskan Native 21 (0.6) 1.50 (0.90 to 2.33) 2.12 (1.22 to 3.47) <0.0001 Hispanic White 255 (7.3) 1.71 (1.50 to 1.95) 2.42 (1.90 to 3.10) <0.0001 Non-Hispanic White 2,722 (77.7) 2.65 (2.55 to 2.75) 3.73 (3.05 to 4.64) Unknown 218 (6.2) -- -- Diagnosis Period -- 2000-2005 871 (24.9) 1.92 (1.80 to 2.06) 1.00 (Reference) <0.0001 2006-2010 1,030 (29.4) 2.48 (2.33 to 2.64) 1.29 (1.18 to 1.41) <0.0001 2011-2016 1,602 (45.7) 2.82 (2.68 to 2.96) 1.46 (1.35 to 1.59) * Clinical characteristics of microscopically confirmed cases of sebaceous carcinoma (ICD-O-3 code 8410/3) diagnosed in Surveillance, Epidemiology, and End Results (SEER) 18 database. Analysis includes cases from: San Francisco-Oakland, Connecticut, Detroit (Metropolitan), Hawaii, Iowa, New Mexico, Seattle (Puget Sound), Utah, Atlanta (Metropolitan), San Jose-Monterey, Los Angeles, Alaska, Rural Georgia, California excluding SF/SJM/LA, Kentucky, Louisiana, New Jersey, and Greater Georgia. There were 3,503 sebaceous carcinomas diagnosed in 3,352 persons between 2000-2016. † Rates with 95% confidence intervals (CI, Tiwari method) are age-adjusted to the 2000 U.S standard population (19 age groups - Census P25-1130). ‡ Incidence rate ratios (IRR) with 95% confidence intervals (CI) comparing incidence rate to reference group were calculated in SEER*stat 8.3.6 using the Tiwari method. Downloaded from https://academic.oup.com/jncics/advance-article-abstract/doi/10.1093/jncics/pkaa020/5762618 by guest on 03 March 2020 § Two-sided p-values for incidence rate ratios. Downloaded from https://academic.oup.com/jncics/advance-article-abstract/doi/10.1093/jncics/pkaa020/5762618 by guest on 03 March 2020 Figure 1 title. Ambient ultraviolet radiation and incidence rate ratios for sebaceous carcinoma in select subgroups Incidence rate ratios (IRR) with 95% confidence intervals (CIs) for microscopically confirmed cases of sebaceous carcinoma (ICD-O-3 code 8410/3) diagnosed in Surveillance, Epidemiology, and End Results cancer registries (2000-2016) with increasing ultraviolet radiation (UVR). UVR data were cloud-adjusted daily ambient irradiance (wavelength=305nm). Analysis includes cases of sebaceous carcinoma from: San Francisco-Oakland, Connecticut, Detroit (Metropolitan), Iowa, New Mexico, Seattle (Puget Sound), Utah, Atlanta (Metropolitan), San Jose-Monterey, Los Angeles, Rural Georgia, California excluding SF/SJM/LA, Kentucky, Louisiana, New Jersey, and Greater Georgia. Cases from Hawaii and Alaska were excluded from the analysis because they were outliers for ambient UVR. Incidence for each UVR quartile was compared to UVR quartile 1 to calculate the IRR. Models are adjusted for sex, age (<50 years old, 50-64 years old, 65-79 years old, ≥80 years old), diagnosis period (2000-2005, 2006-2010, 2011-2016), and registry volume. Individuals were designated as having putative Muir-Torre syndrome (MTS), a phenotypic variant of Lynch syndrome (OMIM: 120435), if they had SC plus one of the following Lynch syndrome cancers: colon, rectum, stomach, liver, biliary tract, urinary bladder, renal pelvis, ureter, small intestine, pancreas, ovary, endometrial. Downloaded from https://academic.oup.com/jncics/advance-article-abstract/doi/10.1093/jncics/pkaa020/5762618 by guest on 03 March 2020 Figure 1--FINAL http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JNCI Cancer Spectrum Oxford University Press

Ambient Ultraviolet Radiation and Sebaceous Carcinoma Incidence in the United States, 2000-2016

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Published by Oxford University Press 2020.
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Abstract

Downloaded from https://academic.oup.com/jncics/advance-article-abstract/doi/10.1093/jncics/pkaa020/5762618 by guest on 03 March 2020 Manuscript--FINAL Article Type: Brief Communications Title: Ambient Ultraviolet Radiation and Sebaceous Carcinoma Incidence in the United States, 2000-2016 1 2 3 Michael R. Sargen, MD , Zhi-Ming Mai, MD, PhD , Eric A. Engels, MD, MPH , Alisa M. 1 4 5 2 Goldstein, PhD , Margaret A. Tucker, MD , Ruth M. Pfeiffer, PhD , Elizabeth K. Cahoon, PhD Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD Human Genetics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD Corresponding Author: Michael R. Sargen, MD Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Rm. 6E-542, Rockville, MD 20850 Published by Oxford University Press 2020. This work is written by ( a) US Government employee(s) and is in the public domain in the US. Downloaded from https://academic.oup.com/jncics/advance-article-abstract/doi/10.1093/jncics/pkaa020/5762618 by guest on 03 March 2020 Office: (240) – 276 – 7354 Email: michael.sargen@nih.gov Abbreviations: sebaceous carcinoma, SC; ultraviolet radiation, UVR; Muir-Torre syndrome, MTS; Surveillance, Epidemiology, and End Results, SEER Downloaded from https://academic.oup.com/jncics/advance-article-abstract/doi/10.1093/jncics/pkaa020/5762618 by guest on 03 March 2020 Abstract Sebaceous carcinoma (SC) is an aggressive skin tumor. While ultraviolet radiation (UVR) is an important risk factor for some skin cancer types, no population-level study has evaluated for an association between UVR and SC risk. Herein, we examined satellite-based ambient UVR in relation to SC incidence using Surveillance, Epidemiology, and End Results 18 cancer registry data (2000-2016). There were 3,503 microscopically confirmed cases of SC diagnosed during the study period. For non-Hispanic whites, there was an association between increasing ambient UVR and SC risk (incidence rate ratio, IRR[per UVR quartile]=1.15; 95% CI, 1.11 to 1.19; two- sided P<0.001) including among individuals with and without putative Muir-Torre syndrome (MTS). In contrast, there was no association between ambient UVR and SC risk for other race/ethnicities. Our findings support a role for UVR in SC tumorigenesis, which suggests that photoprotection may reduce SC risk, particularly for high-risk populations (eg. MTS). Downloaded from https://academic.oup.com/jncics/advance-article-abstract/doi/10.1093/jncics/pkaa020/5762618 by guest on 03 March 2020 Sebaceous carcinoma (SC) is an aggressive skin cancer with a 5-year mortality rate of 20%. SC risk factors include male sex, older age, Muir-Torre syndrome (MTS; OMIM 158320), and immune suppression.[1-3] In contrast to many other cancer types, SC incidence in the United States has been increasing since 1973 when the Surveillance, Epidemiology, and End Results (SEER) database first began tracking cancer statistics.[4, 5] Therefore, it is important to identify exposures underlying these trends, which could assist with preventive efforts, screening and early diagnosis of SC. SC most commonly occurs on chronically sun-exposed skin of the head and neck in older, non-Hispanic white (NHW) patients suggesting that ultraviolet radiation (UVR) may contribute to SC development.[2, 5] However, population-based epidemiological data examining the association of UVR with SC are lacking. In this study, we examined the association between ambient UVR and SC risk in the United States by linking satellite-based ambient UVR with SEER 18 cancer registry data (27.8% of U.S. population) for the years 2000-2016 by county.[6] UVR data were cloud-adjusted daily ambient irradiance (wavelength=305nm) on a 1 degree latitude × 1 degree longitude grid, which were derived from the National Aeronautics Space Administration’s (NASA) Total Ozone Mapping Spectrometer database.[7] Because satellite-based estimates of UVR in the U.S. have varied little aside from relatively small fluctuations due to the 11-year solar cycle[8], in the present analysis, daily noon-time estimates over years 1982-1992 were averaged to represent a full solar cycle. SEER counties were assigned to UVR quartiles, low (Q1) to high (Q4), with cutoffs constructed to have similar person years at risk across quartiles. We report age-adjusted cancer rates and incidence rate ratios (IRRs) for microscopically confirmed cases of SC (ICD-O- 3 code 8410/3) using the Tiwari method in SEER*stat 8.3.6[9, 10]. Individuals were designated Downloaded from https://academic.oup.com/jncics/advance-article-abstract/doi/10.1093/jncics/pkaa020/5762618 by guest on 03 March 2020 as having putative MTS, a phenotypic variant of Lynch syndrome (OMIM: 120435), if they had SC plus another Lynch syndrome cancer.[3] Poisson models comparing SC incidence with UVR were adjusted for sex, age, diagnosis period, and registry volume to calculate IRRs. We report 95% confidence intervals and two-sided p-values for each IRR and statistical significance was defined as a p-value <0.05. Registry volume was categorized into tertiles using census-based population size to create 3 roughly equal categories. There was no evidence of over-dispersion in any of the Poisson models and these analyses were performed using STATA 15.0 (College Station, TX). There were 3,503 SCs diagnosed in the study population with 287 tumors (8.2%) occurring in individuals with putative MTS. Individuals with SC were predominantly non- Hispanic white (NHW, 77.7%) and male (61.1%) (Table 1). The overall incidence was 2.43 cases (95% CI, 2.35 to 2.52) per million persons per year and the incidence increased by 3.3% (95% CI, 2.2 to 4.5) per year between 2000-2016 (Table 1). Among NHWs (N=2,667 cases), there was an association between ambient UVR quartile and SC risk (IRR[per UVR quartile]=1.15; 95% CI, 1.11 to 1.19; P<0.001) (Figure 1). This association was also observed for NHWs with (N=222 cases; IRR[per UVR quartile]=1.22; 95% CI, 1.08 to 1.39; P=0.002) and without (N=2,445 cases; IRR[per UVR quartile]=1.14; 95% CI, 1.09 to 1.19; P<0.001) putative MTS (Figure 1) and for multiple age groups (50-64, 65-79, ≥80; P<0.05, all analyses) and diagnosis periods (2000-2005, 2006-2010, 2011-2016; P<0.05, all analyses) (Supplementary Table 1). In contrast to NHWs, there was no association between ambient UVR and SC risk among other race/ethnicities with increased skin pigmentation suggesting that melanin pigment, which absorbs UVR, is protective against SC tumorigenesis similar to other cutaneous Downloaded from https://academic.oup.com/jncics/advance-article-abstract/doi/10.1093/jncics/pkaa020/5762618 by guest on 03 March 2020 malignancies.[11] There were also differences in the effect size between NHW males (N=1,655 cases; IRR[per UVR quartile]=1.20; 95% CI, 1.15 to 1.26; P<0.001) and NHW females (N=1,012 cases; IRR[per UVR quartile]=1.06; 95% CI, 1.00 to 1.13; P=0.05), which may be partially explained by gender differences in sun protective behavior and an increased likelihood for outdoor occupations among males[12-14] (Figure 1). Since HIV infection is a risk factor for SC[1], we separately examined associations between ambient UVR and SC risk by county-level HIV prevalence (“low” prevalence counties: <308.5 cases per 100,000 persons [2016 national average][15]). Among NHWs, there was a statistically significant association between ambient UVR quartile and SC risk for areas with “low” (N=2,158 cases; IRR[per UVR quartile]=1.05; 95% CI, 1.01 to 1.09; P=0.02) and “high” (N=509 cases; IRR[per UVR quartile]=1.73; 95% CI, 1.38 to 2.18; P<0.001) HIV prevalence. The association was much stronger within “high” HIV prevalence counties suggesting that NHW patients with HIV in areas with high ambient UVR may be at particularly high risk for SC. Additional studies are necessary to confirm this finding given the limited number of cases and the absence of laboratory confirmation of patient HIV status. (Supplementary Table 1). The association between ambient UVR and SC risk may be partially explained by UVR- induced mutagenesis. In support of this hypothesis, one prior study identified UVR-mutational signatures in one third of SC tumors.[16] UVR-induced immunosuppression in the skin may also be contributing to SC tumorigenesis.[17-19] Immunosuppression is an important risk factor for several skin cancer types. Rates of melanoma and keratinocyte carcinomas are elevated for solid organ transplant recipients receiving immunosuppressant medications and individuals with HIV infection.[1, 20-23] Additionally, higher ambient UVR is associated with an increased risk for Kaposi sarcoma (KS) among HIV-infected patients, suggesting that UVR could be contributing Downloaded from https://academic.oup.com/jncics/advance-article-abstract/doi/10.1093/jncics/pkaa020/5762618 by guest on 03 March 2020 to KS-associated herpesvirus infection and subsequent tumor development through UVR- induced immunosuppression.[24] Further studies are needed to determine whether UVR-induced immunosuppression contributes to SC development. A limitation of this study is that ambient UVR data may not be representative of individual UVR exposure, which can be influenced by sun-seeking (leisure time outdoors, outdoor occupation) and sun-protective behavior (sunscreen, hats, etc.). Misclassification of exposure may also occur if individuals frequently migrate between areas with disparate ambient UVR. However, we identified associations between ambient UVR and SC risk for multiple subgroups which strongly implicates UVR in SC tumorigenesis. This is the first population-based epidemiological study to identify UVR as a risk factor for SC. Photoprotective measures should be advocated in high-risk populations to prevent this aggressive skin cancer. The biologic mechanisms underlying this association require further investigation. Funding: This work was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. Notes Role of the funder: The funder had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; and the decision to submit the manuscript for publication. Downloaded from https://academic.oup.com/jncics/advance-article-abstract/doi/10.1093/jncics/pkaa020/5762618 by guest on 03 March 2020 Disclosures: The authors have no disclosures. Acknowledgments: We would like to thank Sara Schonfeld (National Cancer Institute) for her assistance with the SEER*stat analyses. References: 1. Lanoy E, Dores GM, Madeleine MM, et al. Epidemiology of nonkeratinocytic skin cancers among persons with AIDS in the United States. AIDS 2009;23(3):385-93. 2. Tripathi R, Chen Z, Li L, et al. Incidence and survival of sebaceous carcinoma in the United States. J Am Acad Dermatol 2016;75(6):1210-1215. 3. Baglietto L, Lindor NM, Dowty JG, et al. Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst 2010;102(3):193-201. 4. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018;68(1):7- 5. Dasgupta T, Wilson LD, Yu JB. A retrospective review of 1349 cases of sebaceous carcinoma. Cancer 2009;115(1):158-65. 6. Surveillance, Epidemiology, and End Results (SEER). Number of Persons by Race and Hispanic Ethnicity for SEER Participants (2010 Census Data). https://seer.cancer.gov/registries/data.html#a1. Accessed September 15, 2019. 7. National Aeronautics Space Administration. Total Ozone Mapping Spectrometer data product: erythemal UV exposure. In. Greenbelt, MD: Goddard Space Flight Center; 2004. 8. Lean JL. Estimating Solar Irradiance Since 850 CE. Earth and Space Science 2018;5:133- Downloaded from https://academic.oup.com/jncics/advance-article-abstract/doi/10.1093/jncics/pkaa020/5762618 by guest on 03 March 2020 9. Surveillance, Epidemiology, and End Results (SEER). SEER*Stat Software. https://seer.cancer.gov/seerstat/. Accessed August 30, 2019. 10. Tiwari RC, Clegg LX, Zou Z. Efficient interval estimation for age-adjusted cancer rates. Stat Methods Med Res 2006;15(6):547-69. 11. Lin JY, Fisher DE. Melanocyte biology and skin pigmentation. Nature 2007;445(7130):843-50. 12. Branstrom R, Kasparian NA, Chang YM, et al. Predictors of sun protection behaviors and severe sunburn in an international online study. Cancer Epidemiol Biomarkers Prev 2010;19(9):2199-210. 13. Glanz K, Buller DB, Saraiya M. Reducing ultraviolet radiation exposure among outdoor workers: state of the evidence and recommendations. Environ Health 2007;6:22. 14. Gabriel P, Schmitz S (Bureau of Labor Statistics). Gender differences in occupational distributions among workers. https://www.bls.gov/opub/mlr/2007/06/art2full.pdf. Accessed January 20, 2020. 15. Centers for Disease Control (CDC). HIV Surveillance Report, 2017. https://www.cdc.gov/hiv/pdf/library/reports/surveillance/cdc-hiv-surveillance-report-2017-vol- 29.pdf. Accessed September 15, 2019. 16. North JP, Golovato J, Vaske CJ, et al. Cell of origin and mutation pattern define three clinically distinct classes of sebaceous carcinoma. Nat Commun 2018;9(1):1894. 17. Racz E, Prens EP, Kurek D, et al. Effective treatment of psoriasis with narrow-band UVB phototherapy is linked to suppression of the IFN and Th17 pathways. J Invest Dermatol 2011;131(7):1547-58. Downloaded from https://academic.oup.com/jncics/advance-article-abstract/doi/10.1093/jncics/pkaa020/5762618 by guest on 03 March 2020 18. Johnson-Huang LM, Suarez-Farinas M, Sullivan-Whalen M, et al. Effective narrow-band UVB radiation therapy suppresses the IL-23/IL-17 axis in normalized psoriasis plaques. J Invest Dermatol 2010;130(11):2654-63. 19. Ozawa M, Ferenczi K, Kikuchi T, et al. 312-nanometer ultraviolet B light (narrow-band UVB) induces apoptosis of T cells within psoriatic lesions. J Exp Med 1999;189(4):711-8. 20. Jensen P, Hansen S, Moller B, et al. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol 1999;40(2 Pt 1):177-86. 21. Silverberg MJ, Leyden W, Warton EM, et al. HIV infection status, immunodeficiency, and the incidence of non-melanoma skin cancer. J Natl Cancer Inst 2013;105(5):350-60. 22. Robbins HA, Clarke CA, Arron ST, et al. Melanoma Risk and Survival among Organ Transplant Recipients. J Invest Dermatol 2015;135(11):2657-2665. 23. Lindelof B, Sigurgeirsson B, Gabel H, et al. Incidence of skin cancer in 5356 patients following organ transplantation. Br J Dermatol 2000;143(3):513-9. 24. Cahoon EK, Engels EA, Freedman DM, et al. Ultraviolet Radiation and Kaposi Sarcoma Incidence in a Nationwide US Cohort of HIV-Infected Men. J Natl Cancer Inst 2017;109(5). Downloaded from https://academic.oup.com/jncics/advance-article-abstract/doi/10.1093/jncics/pkaa020/5762618 by guest on 03 March 2020 Table 1. Incidence rates of sebaceous carcinoma by clinical characteristics Rate per million Characteristic No. of cases (%)* IRR (95% CI)‡ P§ persons (95% CI)† -- Total 3,503 (100.0) 2.43 (2.35 to 2.52) -- Tumor Location -- -- Non-Head and Neck 909 (25.9) 0.62 (0.58 to 0.66) -- -- Head and Neck 2,566 (73.3) 1.80 (1.73 to 1.87) Unknown 28 (0.8) -- Gender -- Female 1,363 (38.9) 1.67 (1.58 to 1.76) 1.00 (Reference) <0.0001 Male 2,140 (61.1) 3.46 (3.31 to 3.61) 2.07 (1.94 to 2.22) Age -- <50 254 (7.3) 0.26 (0.23 to 0.30) 1.00 (Reference) <0.0001 50-64 837 (23.9) 3.27 (3.05 to 3.50) 12.5 (10.9 to 14.5) <0.0001 65-79 1,330 (38.0) 10.8 (10.2 to 11.4) 41.2 (36.0 to 47.3) <0.0001 ≥80 1,082 (30.9) 22.7 (21.4 to 24.1) 86.8 (75.6 to 99.9) Race/Ethnicity -- Black 100 (2.9) 0.71 (0.57 to 0.87) 1.00 (Reference) <0.0001 Asian or Pacific Islander 187 (5.3) 1.51 (1.30 to 1.75) 2.14 (1.66 to 2.77) 0.009 American Indian or Alaskan Native 21 (0.6) 1.50 (0.90 to 2.33) 2.12 (1.22 to 3.47) <0.0001 Hispanic White 255 (7.3) 1.71 (1.50 to 1.95) 2.42 (1.90 to 3.10) <0.0001 Non-Hispanic White 2,722 (77.7) 2.65 (2.55 to 2.75) 3.73 (3.05 to 4.64) Unknown 218 (6.2) -- -- Diagnosis Period -- 2000-2005 871 (24.9) 1.92 (1.80 to 2.06) 1.00 (Reference) <0.0001 2006-2010 1,030 (29.4) 2.48 (2.33 to 2.64) 1.29 (1.18 to 1.41) <0.0001 2011-2016 1,602 (45.7) 2.82 (2.68 to 2.96) 1.46 (1.35 to 1.59) * Clinical characteristics of microscopically confirmed cases of sebaceous carcinoma (ICD-O-3 code 8410/3) diagnosed in Surveillance, Epidemiology, and End Results (SEER) 18 database. Analysis includes cases from: San Francisco-Oakland, Connecticut, Detroit (Metropolitan), Hawaii, Iowa, New Mexico, Seattle (Puget Sound), Utah, Atlanta (Metropolitan), San Jose-Monterey, Los Angeles, Alaska, Rural Georgia, California excluding SF/SJM/LA, Kentucky, Louisiana, New Jersey, and Greater Georgia. There were 3,503 sebaceous carcinomas diagnosed in 3,352 persons between 2000-2016. † Rates with 95% confidence intervals (CI, Tiwari method) are age-adjusted to the 2000 U.S standard population (19 age groups - Census P25-1130). ‡ Incidence rate ratios (IRR) with 95% confidence intervals (CI) comparing incidence rate to reference group were calculated in SEER*stat 8.3.6 using the Tiwari method. Downloaded from https://academic.oup.com/jncics/advance-article-abstract/doi/10.1093/jncics/pkaa020/5762618 by guest on 03 March 2020 § Two-sided p-values for incidence rate ratios. Downloaded from https://academic.oup.com/jncics/advance-article-abstract/doi/10.1093/jncics/pkaa020/5762618 by guest on 03 March 2020 Figure 1 title. Ambient ultraviolet radiation and incidence rate ratios for sebaceous carcinoma in select subgroups Incidence rate ratios (IRR) with 95% confidence intervals (CIs) for microscopically confirmed cases of sebaceous carcinoma (ICD-O-3 code 8410/3) diagnosed in Surveillance, Epidemiology, and End Results cancer registries (2000-2016) with increasing ultraviolet radiation (UVR). UVR data were cloud-adjusted daily ambient irradiance (wavelength=305nm). Analysis includes cases of sebaceous carcinoma from: San Francisco-Oakland, Connecticut, Detroit (Metropolitan), Iowa, New Mexico, Seattle (Puget Sound), Utah, Atlanta (Metropolitan), San Jose-Monterey, Los Angeles, Rural Georgia, California excluding SF/SJM/LA, Kentucky, Louisiana, New Jersey, and Greater Georgia. Cases from Hawaii and Alaska were excluded from the analysis because they were outliers for ambient UVR. Incidence for each UVR quartile was compared to UVR quartile 1 to calculate the IRR. Models are adjusted for sex, age (<50 years old, 50-64 years old, 65-79 years old, ≥80 years old), diagnosis period (2000-2005, 2006-2010, 2011-2016), and registry volume. Individuals were designated as having putative Muir-Torre syndrome (MTS), a phenotypic variant of Lynch syndrome (OMIM: 120435), if they had SC plus one of the following Lynch syndrome cancers: colon, rectum, stomach, liver, biliary tract, urinary bladder, renal pelvis, ureter, small intestine, pancreas, ovary, endometrial. Downloaded from https://academic.oup.com/jncics/advance-article-abstract/doi/10.1093/jncics/pkaa020/5762618 by guest on 03 March 2020 Figure 1--FINAL

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JNCI Cancer SpectrumOxford University Press

Published: Apr 1, 2020

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