BACKGROUND Exome and targeted sequencing studies have identified potential driver mutations for a variety of tumor types. Cutaneous squamous cell carcinoma (cSCC) is one of the most highly mutated cancers but is typically associated with low rates of metastasis and high survival rates. Nevertheless, metastatic cSCC is a significant health threat; up to 8800 individuals die yearly from this disease. METHODS As it is difficult to predict which cSCCs are more likely to metastasize, and because there are no targeted therapies specifically designated for metastatic cSCC, we performed exome and/or targeted sequencing of 18 metastatic and 10 primary cSCCs to identify mutations that were more frequent in metastatic tumors and might be targeted for therapeutic benefit. We compared our results to published sequencing results of an additional 223 primary tumors and 68 metastatic cSCCs. RESULTS We identified genes showing higher mutation frequencies in metastatic cSCC relative to primary tumors including the chromatin remodeling gene KMT2D and the classic skin tumor suppressor TP53 which was mutated in 54% of primary tumors relative to 85% of metastatic tumors (p <0.0001). CONCLUSIONS These studies uncover potential pathways important in metastatic cSCC that broaden our understanding of the biology contributing to aggressive tumor behavior and may lead to new therapeutic strategies.

Background Variants at the Oculocutaneous albinism 2 (OCA2)/HECT and RLD Domain Containing E3 Ubiquitin Protein Ligase 2 (HERC2) locus have been associated with pigmentation phenotypes as well as risk of developing multiple types of skin cancer. Objectives The goal of this study was to evaluate OCA2/HERC2 locus variants for impact on time to develop cutaneous squamous cell carcinoma (cSCC) in organ transplant recipients (OTRs) who are at elevated risk of developing cSCC. Methods Participants were solid organ transplant recipients ascertained from two centers (n=125 and 261) with an average of 13.1 years follow-up post-transplant. DNA was available for genotyping for all participants in addition to medical records and questionnaire data. The Ohio State University (OSU) study design was a case-control with prospective follow-up, and the University of California San Francisco (UCSF) study design was a national cross-sectional survey with retrospective chart review. Results OCA2 variants rs12913832 and rs916977 were significantly associated with time to first cSCC post-transplant. OTRs homozygous for the brown eye alleles of rs916977 (GG) and rs12913832 (AA) had significant delays of time to first cSCC post-transplant compared to individuals homozygous for the blue eye alleles [HR=0.34, p<0.001and HR=0.54, p=0.012, respectively]. Both variants were highly associated with eye color in combined studies (p<0.001). Conclusions This study is the first to show an association between OCA2/HERC2 variants and time to first cSCC post-transplant which may impact dermatologic screening recommendations for high-risk populations.