Variants at theOCA2/HERC2locus affect time to first cutaneous squamous cell carcinoma in solid organ transplant recipients collected using two different study designs

Abstract

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.

Genome‐wide association studies and polygenic risk scores for skin cancer: clinically useful yet?

“…One area where PRS may show particular value is in improving risk stratification for OTRs. Fitzpatrick skin phototype and polymorphisms in the OCA2 / HERC2 and IRF4 pigmentation genes have been associated with development of post‐transplant cSCC . Additional research is needed to determine whether PRS can improve risk prediction above established risk factors.…”

Whole genome sequencing and 6-year follow-up of a mother and daughter with frontometaphyseal dysplasia associated with keratitis, xerosis, poikiloderma, and acro-osteolysis

“…Mutations of HERC2 , affecting stabilization and chromatin retention of XP complementation group A (XPA), might also be involved in cutaneous SCC. [ 13 , 14 ] XPA is controlled by circadian clock-mediated transcriptional regulation, while the ubiquitination mediated by homologous to the E6-AP carboxyl terminus domain and RCC1-like domain-containing protein 2 (HERC2), which leads to XPA's degradation, could also contributes to the circadian oscillation. [ 14 ] A recent study, in addition, reported variants at the OCA2/HERC2 locus have strong association between time to first cutaneous SCC post-transplant.…”

Towards the use of precision medicine in predicting cutaneous squamous cell carcinoma risk among solid organ transplant recipients

“…Although this is a preliminary study, Wei et al . demonstrate that risk prediction models can be extended to incorporate a transplant patient's genetic susceptibility to cSCC to better identify individuals at higher risk of early cSCC development post‐transplant and tailor screening intensity.…”

“…Wei and colleagues report findings combining data from two observational cohorts of solid organ transplant recipients (OTRs) at different medical centres showing that OCA2/HERC2 locus variants impact the time to first cutaneous squamous cell carcinoma (cSCC) post‐transplant . OTRs with two blue‐eye‐associated alleles for OCA2/HERC2 , variants rs916977 and rs12913832, each had an estimated median time to first cSCC of 14·2 years post‐transplant, which was 12·3 and 7·4 years earlier, respectively, compared with OTRs with two corresponding brown‐eye‐associated alleles.…”