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

Abstract

Summary Background Genome‐wide association studies (GWAS) have identified thousands of susceptibility variants, although most have been associated with small individual risk estimates that offer little predictive value. However, combining multiple variants into polygenic risk scores (PRS) may be more informative. Multiple studies have developed PRS composed of GWAS‐identified variants for cutaneous cancers. This review highlights data from these studies. Objectives To review published GWAS and PRS studies for melanoma, cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC), and discuss their potential clinical utility. Methods We searched PubMed and the National Human Genome Research Institute–European Bioinformatics Institute GWAS catalogue to identify relevant studies. Results Results from 21 GWAS (11 melanoma, 3 cSCC, 7 BCC) and 11 PRS studies are summarized. Six loci in pigmentation genes overlap between these three cancers (ASIP/RALY, IRF4, MC1R, OCA2, SLC45A2 and TYR). Additional loci overlap for cSCC/BCC and BCC/melanoma, but no other loci are shared between cSCC and melanoma. PRS for melanoma show roughly two‐to‐threefold increases in risk and modest improvements in risk prediction (2–7% increases). PRS are associated with twofold and threefold increases in risk of cSCC and BCC, respectively, with small improvements (2% increase) in predictive ability. Conclusions Existing data indicate that PRS may offer small, but potentially meaningful, improvements to risk prediction. Additional research is needed to clarify the potential utility of PRS in cutaneous carcinomas. Clinical translation will require well‐powered validation studies incorporating known risk factors to evaluate PRS as tools for screening. What's already known about this topic? Over 50 susceptibility loci for melanoma, basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) have been identified in genome‐wide association studies (GWAS). Polygenic risk scores (PRS) using variants identified from GWAS have also been developed for melanoma, BCC and cSCC, and investigated with respect to clinical risk prediction. What does this study add? This review provides an overview of GWAS findings and the potential clinical utility of PRS for melanoma, BCC and cSCC.

Polygenic Risk Scores Allow Risk Stratification for Keratinocyte Cancer in Organ-Transplant Recipients

“…Despite the individual magnitude of association for each SNP being small, they can be used in aggregate to characterize the genetic liability toward disease outcomes through a polygenic risk score (PRS). These scores have substantial clinical utility for disease (in this case, KC) prediction (Roberts et al, 2019). Previous studies have shown that PRSs, in combination with conventional risk factors, can provide useful information for risk stratification for common complex diseases such as cancers (Dai et al, 2019;Mavaddat et al, 2019;Seibert et al, 2018) and cardiovascular disease (Abraham et al, 2019;Inouye et al, 2018;Khera et al, 2018).…”

Identification of Germline Mutations in Melanoma Patients with Early Onset, Double Primary Tumors, or Family Cancer History by NGS Analysis of 217 Genes

“…An increased melanoma risk has been documented in carriers of germline mutations causing other cancer syndromes, including hereditary breast and ovarian cancer ( BRCA1/BRCA2 ), retinoblastoma ( RB1 ), or xeroderma pigmentosum ( XPs ) [ 16 ]. The low-risk group includes variants in genes coding for proteins involved in melanogenesis (MC1R, MITF, OCA2, SLC45A2, TYR, TYRP1) and other processes (ASIP, CASP8, MTAP, OBFC1), revealed dominantly by genome-wide association studies (GWAS) [ 17 , 18 , 19 ]. The identification of individuals carrying germline mutations in melanoma-predisposition genes enables their tailored surveillance with an early detection of melanoma and other associated tumors, and with genetic counselling for their relatives.…”

Implementing polygenic risk scores in skin cancer: a step towards personalized risk prediction

“…Their thorough review maps the literature of genetic/PRSs including assessment of the populations and other clinical and phenotypic characteristics used. In one included study, for example, a 204‐single‐nucleotide polymorphism PRS model using data from a large GWAS meta‐analysis in melanoma and validated in a Southern European population showed a c‐statistic of 64·4%, with an up to 7% increase in the risk predictive ability for melanoma compared with when using only traditional phenotypic risk factors . The PRS‐based c‐statistic in this model was larger than those observed in other cancers, for example lung cancer (56·4%) and breast cancer (61·5%) and is equivalent to PRS models for prostate cancer (65·4%), suggesting that for cancers with a strong heritable component such as melanoma and prostate cancer, PRS can improve risk prediction and help identify individuals at risk who may benefit from increased surveillance …”

“…The paper by Roberts et al . in this issue of the BJD reports a systematic approach and comprehensive evaluation of all currently available data from 21 GWAS and 11 PRS studies in melanoma and epithelial skin cancers (basal cell carcinoma and squamous cell carcinoma) .…”