Abstract A83: Host phenotype characteristics and MC1R in relation to early-onset basal cell carcinoma

Background: Basal cell carcinoma (BCC), which accounts for 80% of non-melanoma skin cancers, is the most common cancer in the United States, with more than two million BCCs diagnosed annually. In recent decades, BCC incidence has been increasing, particularly among adults under age 40. While pigment-related characteristics have been associated with BCC in older populations, epidemiologic studies of these exposures in relation to BCC in younger individuals are lacking. In addition, investigations of potential interactions between pigment phenotype and pigment-related genotype for this malignancy are limited. Methods: We examined self-reported phenotypes and melanocortin 1 receptor gene (MC1R) variants in relation to early-onset BCC in the Yale Study of Skin Health in Young People. BCC cases (n=377) and controls with benign skin conditions (n=390) under age 40 were identified through Yale Dermatopathology between 2006 and 2010. Approximately two-thirds of dermatologists in Connecticut send their biopsied tissue to Yale dermatopathologists for diagnosis. Controls were frequency matched to cases on age, gender, and body site of biopsy. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariate logistic regression. Cross-product terms in the multivariate models were used to evaluate potential effect modification of the association between MC1R and BCC by host phenotypes. Results: Skin reaction to first summer sun of the season (severe sunburn vs. tan OR=12.27, 95% CI=4.08–36.94) and skin color (very fair vs. olive OR=11.06, 95% CI=5.90–20.74) were most strongly associated with early-onset BCC. Individuals with two or more MC1R non-synonymous variants were 3.59 times (95% CI=2.37–5.43) more likely to have BCC than those without variants. All exposures were much more strongly associated with multiple BCC (two or more BCCs; 37% of cases). For example, the OR for two or more MC1R non-synonymous variants compared to no variants was 2.93 (95% CI=1.82–4.71) for single BCC, while the OR for multiple BCC was 5.15 (95% CI=2.84–9.32). With mutual adjustment, MC1R, moles, skin reaction to sun exposure, and hair and skin color remained independently associated with BCC. Even after accounting for other pigment related factors, very fair skin was associated with a 4.48 fold increased risk of BCC compared to olive skin (95% CI=2.21–9.09) and individuals with two or more MC1R non-synonymous variants had a 91% independent increased risk of BCC compared to those with no non-synonymous variants (95% CI=1.20–3.03). While there were no statistically significant phenotype-genotype interactions, BCC risk conferred by MC1R tended to be stronger among those with darker pigment phenotypes, such as darker eye color and skin color, fewer moles and freckles, as well as tanning rather than burning with sun exposure. Conclusions: Several pigment-related phenotypes and MC1R were strongly and independently associated with early-onset BCC. Even persons with darker phenotypes, traditionally considered to be at low risk of skin cancer, were at substantial risk of early-onset BCC if they had MC1R variants. Our observation of a pronounced effect of MC1R within low risk phenotype strata parallels existing research for melanoma and supports growing evidence that BCC may share etiologic similarities with melanoma. Despite an increasing prevalence of skin cancers in young people, this is the first epidemiologic investigation of BCC in this population. One-third of cases already had multiple BCCs, suggesting an urgent need for preventive interventions in at-risk persons. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A83.