Interaction of Arsenic Exposure and Transcriptomic Profile in Basal Cell Carcinoma

SIMPLE SUMMARY: Over 100 million individuals worldwide are exposed to arsenic through drinking water. Arsenic is a cancer-causing chemical. While ultraviolet light exposure and skin sensitivity are known risk factors for skin cancers, especially in Caucasians, arsenic exposure may be a major risk factor for other populations. This is the first study to address the genome-wide gene expression in basal cell carcinoma (BCC) of skin in the context of arsenic exposure. Our study confirms many of the gene pathways involved in BCC; in addition, we found that high arsenic exposure was associated with impaired (a) DNA replication, (b) cellular response to DNA damage repair and (c) immune response that leads to BCC. This study suggests a lower chance of platinum drug resistance in BCC patients with high arsenic exposure compared to the higher chance of platinum drug resistance in patients with low arsenic exposure. These findings may have biological and clinical significance. ABSTRACT: Exposure to inorganic arsenic (As) is recognized as risk factor for basal cell carcinoma (BCC). We have followed-up 7000 adults for 6 years who were exposed to As and had manifest As skin toxicity. Of them, 1.7% developed BCC (males = 2.2%, females = 1.3%). In this study, we compared transcriptome-wide RNA sequencing data from the very first 26 BCC cases and healthy skin tissue from independent 16 individuals. Genes in “ cell carcinoma pathway”, “Hedgehog signaling pathway”, and “Notch signaling pathway” were overexpressed in BCC, confirming the findings from earlier studies in BCC in other populations known to be exposed to As. However, we found that the overexpression of these known pathways was less pronounced in patients with high As exposure (urinary As creatinine ratio (UACR) > 192 µg/gm creatinine) than patients with low UACR. We also found that high UACR was associated with impaired DNA replication pathway, cellular response to different DNA damage repair mechanisms, and immune response. Transcriptomic data were not strongly suggestive of great potential for immune checkpoint inhibitors; however, it suggested lower chance of platinum drug resistance in BCC patients with high UACR compared high platinum drug resistance potential in patients with lower UACR.