Cutaneous squamous cell cancer (cSCC) risk and the human leukocyte antigen (HLA) system

Abstract

Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer among Caucasians in the United States, with rising incidence over the past decade. Treatment for non-melanoma skin cancer, including cSCC, in the United States was estimated to cost $4.8 billion in 2014. Thus, an understanding of cSCC pathogenesis could have important public health implications. Immune function impacts cSCC risk, given that cSCC incidence rates are substantially higher in patients with compromised immune systems. We report a systematic review of published associations between cSCC risk and the human leukocyte antigen (HLA) system. This review includes studies that analyze germline class I and class II HLA allelic variation as well as HLA cell-surface protein expression levels associated with cSCC risk. We propose biological mechanisms for these HLA-cSCC associations based on known mechanisms of HLA involvement in other diseases. The review suggests that immunity regulates the development of cSCC and that HLA-cSCC associations differ between immunocompetent and immunosuppressed patients. This difference may reflect the presence of viral co-factors that affect tumorigenesis in immunosuppressed patients. Finally, we highlight limitations in the literature on HLA-cSCC associations, and suggest directions for future research aimed at understanding, preventing and treating cSCC.

Gene expression imputation identifies candidate genes and susceptibility loci associated with cutaneous squamous cell carcinoma

“…We conducted a two-phase discovery and validation study to test for gene expression level associations with cSCC case/control status, using the Kaiser GERA cohort for discovery and the 23andMe research participant dataset for validation, and using prediXcan tissue-specific gene expression imputation models trained on GTEx expression data. Because of previous evidence that TWAS associations in non-disease-relevant tissues are often non-causal 16 , we limited our analysis to four disease-relevant tissue types: the two types of skin tissue available in GTEx (sun-exposed lower leg skin and non-sun-exposed suprapubic skin), as well as whole blood and lymphocyte cell lines (LCLs) based on evidence of immune involvement in cSCC risk 17 , 18 . Note that the skin tissue expression training data come from bulk skin tissue and are not broken down into specific cell types, such as keratinocytes.…”

Keratinocyte Carcinomas: Current Concepts and Future Research Priorities

“…HLA-DRB1 Ã 01 also correlated with increased BCC risk and early tumor development in renal transplant recipients (84). Among immunosuppressed patients, class-I antigens HLA-A03, HLA-A11, and HLA-B27 and class-II antigens, HLA-DRB1 Ã 07 and HLA-DQA1 Ã 01 correlated with increased risk cSCC (80). GWAS analyses revealed higher cSCC risk in association with DRB1 Ã 01, DQA1 Ã 05:01, and DQA1 Ã 05:05 (85), in addition to variants in HLA-DQB1 (72), HLA-DQA1 (71), HLA-DRB1 (85), and HLA-DQA1 (85).…”

“…Associations between aberrant human leukocyte antigen (HLA) expression (75,76), or germline class-I and II allelic variations and keratinocyte carcinoma have been controversial (77)(78)(79)(80) and are affected by high UV exposure (81), immunosuppression (82), and HPV infection (83). Multiple variants in HLA-DRB1 ( Ã 01, Ã 07) have shown increased risk for BCC while HLA-DRB1 Ã 04 was protective (82).…”

European interdisciplinary guideline on invasive squamous cell carcinoma of the skin: Part 1. epidemiology, diagnostics and prevention

“…Genome-wide association studies have highlighted single nucleotide polymorphisms associated with cSCC risk, including MC1R, ASIP, TYR, SLC45A2, OCA2, IRF4, BNC2, the metastasis suppressor gene CADM1, AHR, a transcription factor that regulates cell proliferation, and SEC16A involved in secretion and cellular proliferation [78e81]. Microenvironment is implicated in cSCC, with a role for human leukocyte antigen (HLA) variants [82] and the programmed cell death protein 1/programmed cell death ligand-1 (PD-1/PD-L1) axis. PD-L1 expression was detected in around 26% of primary cSCC [83e85] and up to 50% of metastatic lesions [84,85] Hereditary syndromes that increase cSCC risk include xeroderma pigmentosum, epidermolysis bullosa, oculocutaneous albinism and Fanconi anaemia and Lynch syndrome/Muir Torre syndrome [7].…”