Sex-Specific Associations of MDM2 and MDM4 Variants with Risk of Multiple Primary Melanomas and Melanoma Survival in Non-Hispanic Whites

Sarah V Ward; Isidora Autuori; Li Luo; Emily LaPilla; Sarah Yoo; Ajay Sharma; Klaus J Busam; David W Olilla; Terence Dwyer; Hoda Anton-Culver; Roberto Zanetti; Lidia Sacchetto; Anne E Cust; Richard P Gallagher; Peter A Kanetsky; Stefano Rosso; Colin B Begg; Marianne Berwick; Nancy E Thomas; Irene Orlow; GEM Study Group

doi:10.3390/cancers15102707

Sex-Specific Associations of MDM2 and MDM4 Variants with Risk of Multiple Primary Melanomas and Melanoma Survival in Non-Hispanic Whites

Cancers (Basel). 2023 May 11;15(10):2707. doi: 10.3390/cancers15102707.

Authors

Sarah V Ward^{1

2}, Isidora Autuori¹, Li Luo³, Emily LaPilla¹, Sarah Yoo¹, Ajay Sharma¹, Klaus J Busam¹, David W Olilla⁴, Terence Dwyer^{5

6

7

8

9}, Hoda Anton-Culver¹⁰, Roberto Zanetti¹¹, Lidia Sacchetto¹¹, Anne E Cust^{12

13}, Richard P Gallagher^{14

15}, Peter A Kanetsky¹⁶, Stefano Rosso¹¹, Colin B Begg¹, Marianne Berwick³, Nancy E Thomas^{4

17}, Irene Orlow¹; GEM Study Group

Affiliations

¹ Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
² School of Population and Global Health, The University of Western Australia, Perth, WA 6009, Australia.
³ Department of Internal Medicine, The University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87106, USA.
⁴ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27514, USA.
⁵ Clinical Sciences Theme, Heart Group, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia.
⁶ Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford OX3 9DU, UK.
⁷ Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Carlton, VIC 3010, Australia.
⁸ Oxford Martin School, University of Oxford, Oxford OX1 3BD, UK.
⁹ Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7000, Australia.
¹⁰ Department of Medicine, University of California, Irvine, CA 92617, USA.
¹¹ Piedmont Cancer Registry, Centre for Epidemiology and Prevention in Oncology in Piedmont, 10126 Turin, Italy.
¹² The Daffodil Centre, The University of Sydney, A Joint Venture with Cancer Council NSW, Sydney, NSW 2006, Australia.
¹³ Melanoma Institute Australia, The University of Sydney, Wollstonecraft, NSW 2065, Australia.
¹⁴ BC Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada.
¹⁵ Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC V5Z 4E8, Canada.
¹⁶ Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
¹⁷ Department of Dermatology, University of North Carolina, Chapel Hill, NC 27514, USA.

Abstract

MDM2-SNP309 (rs2279744), a common genetic modifier of cancer incidence in Li-Fraumeni syndrome, modifies risk, age of onset, or prognosis in a variety of cancers. Melanoma incidence and outcomes vary by sex, and although SNP309 exerts an effect on the estrogen receptor, no consensus exists on its effect on melanoma. MDM2 and MDM4 restrain p53-mediated tumor suppression, independently or together. We investigated SNP309, an a priori MDM4-rs4245739, and two coinherited variants, in a population-based cohort of 3663 primary incident melanomas. Per-allele and per-haplotype (MDM2_SNP309-SNP285; MDM4_rs4245739-rs1563828) odds ratios (OR) for multiple-melanoma were estimated with logistic regression models. Hazard ratios (HR) for melanoma death were estimated with Cox proportional hazards models. In analyses adjusted for covariates, females carrying MDM4-rs4245739*C were more likely to develop multiple melanomas (OR_per-allele = 1.25, 95% CI 1.03-1.51, and P_trend = 0.03), while MDM2-rs2279744*G was inversely associated with melanoma-death (HR_per-allele = 0.63, 95% CI 0.42-0.95, and P_trend = 0.03). We identified 16 coinherited expression quantitative loci that control the expression of MDM2, MDM4, and other genes in the skin, brain, and lungs. Our results suggest that MDM4/MDM2 variants are associated with the development of subsequent primaries and with the death of melanoma in a sex-dependent manner. Further investigations of the complex MDM2/MDM4 motif, and its contribution to the tumor microenvironment and observed associations, are warranted.

Keywords: MDM2; MDM4; estrogen-receptor; functional; gene; melanoma; polymorphism; risk; sex; survival.

Abstract

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