UC Irvine

Cutaneous melanoma disproportionally affects the fair-skinned populations in the US and worldwide. UV radiation has long been recognized as the primary environmental cause of cutaneous melanoma. However, counterfactual evidence has indicated a non-straightforward relationship between UV radiation and melanoma transformation. For instance, melanoma tumors that grow on the body surface can be found in the non-UV-exposed regions such as the trunk, hip, and lower extremities. Melanoma incidence rates tend to be higher in adolescent and young adult females without a direct connection to excessive UV exposure. Nevertheless, few studies have investigated the impact of additional secondary drivers which contribute to the heterogeneity of melanoma tumors.

The overarching goal of the current dissertation was to make a contribution to the research of secondary drivers in addition to UV radiation that play a role in the development of melanoma heterogeneity in diverse ethnic backgrounds. The specific aims include 1) determine the association between reactive oxygen species ‒ a leading secondary driver and risk factor for melanoma; 2) examine the age-dependent gender differences in the incidence rates of melanoma in multiple ethnic groups; 3) investigate the relationship between estrogen receptors’ signaling network and risk of melanoma.

Utilizing the International Gene, Environment, and Melanoma Study dataset, a case-control design was performed to study the first aim. It turned out that the activator of NADPH oxidase complex 1 enzyme ‒ the RAC 1-GTPase, contributed to an oxidative stress-associated predisposed risk of melanoma in the fair-skinned population. The second aim was explored by using the US Surveillance, Epidemiology, and End Results Program (SEER) dataset. The results demonstrated a shared phenomenon of early disease onset in adolescent and young adult females in multiple ethnic groups regardless of skin color variations that have different sensitivities to the sun. In addition, the darker-skinned populations presented an even younger age of disease diagnosis than the fair-skinned population and the tumors that grow on the non-UV-exposed regions exhibited the fastest increase in incidence rates over the years. These findings suggested that female-sex is a pivotal secondary driver in addition to UV radiation in melanoma transformation. Therefore, the third aim carried out a genetic analysis of estrogen receptors’ signaling network in the fair-skinned population, in our preliminary attempts to explain the early melanoma-onset tendency introduced by female-sex. Using the NCBI High Density SNP Association Analysis of Melanoma: Case-Control and Outcomes Investigation dataset, findings showed that estrogen’s downstream IGF1 and its receptor IGF1R may play a critical role in the predisposed gender disparity of melanoma in the fair-skinned population.

This current dissertation should lead to an improved melanoma UV-protection message that is currently conveyed to the public. Additionally, a female-sex-oriented message should be incorporated into educational campaigns to help improve melanoma primary prevention strategy.