Interaction of Arsenic Exposure and Transcriptomic Profile in Basal Cell Carcinoma

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.

Molecular Profiling and the Interaction of Somatic Mutations with Transcriptomic Profiles in Non-Melanoma Skin Cancer (NMSC) in a Population Exposed to Arsenic

“…For this study, we selected the first 32 subjects from the BEST study developing histopathologically confirmed NMSC and had the tumor tissue properly preserved in RNA later, an RNA stabilizing buffer (ThermoFisher Scientific, Waltham, MA, USA). The BEST study included 7000 men and women (m = 2840, f = 4160) who were known to be exposed to As through consuming well water containing As [ 32 , 39 ]. This study included all subjects with clinically visible non-malignant skin lesions (melanosis, leukomelanosis, or keratosis)—a known manifestation of As toxicity.…”

“…A skin biopsy was performed on a total of 727 participants (m = 417, f = 310). Among them, 37.7% of the biopsies showed BD, 2.9% had invasive SCC, 16.1% showed BCC, and the rest (43.3%) showed arsenical keratosis or other skin conditions [ 32 ]. Thus, among the As-exposed study population, 2.2% of the male and 1.3% of the female participants developed BCC, while 0.4% of the male and 0.2% of the female participants developed SCC over the six-year follow-up.…”

“…For RNA sequencing on the Illumina platform, we used Lexogen’s QuantSeq 3′ mRNA–Seq kit (Vienna, Austria) for library preparation as described previously [ 32 ]. The final library was measured by a fluorometer, and after pooling, qPCR was performed to quantify the input library for sequencing on the Illumina HiSeq platform (San Diego, CA, USA).…”

“…Concurrently, As inhibits DNA repair, modifies the epigenetic regulation of gene expression, and targets protein function due to its ability to replace zinc in select proteins [ 31 ]. In a recent study, we have shown that high As exposure was associated with impaired DNA replication pathways, cellular response to different DNA damage repair mechanisms, and immune response [ 32 ].…”

“…Seven thousand subjects were followed up for 6 years for the development of NMSC. Of them, 1.7% developed BCC (males = 2.2%, females = 1.3%) [ 32 ]. Our previous study showed interactions of As exposure and gene expression profiling in BCC in the study group who were exposed to inorganic As through drinking As-contaminated well water [ 32 ].…”