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Approved Research

A contemporary assessment of high-penetrance melanoma genes

Principal Investigator: Dr Peter Kanetsky
Approved Research ID: 52303
Approval date: August 7th 2020

Lay summary

Our current understanding of spectrum of disease outcomes associated with inherited genetic variation in major genes, including ACD, CDKN2A, CDK4, MITF, POT1, SLC45A2, TERF2IP, and TERT, that result in familial melanoma is limited.  We plan to use genotype and whole-exome sequencing data available in the UKBB resource to agnostically determine associations with other (non-melanoma) cancers and non-cancer phenotypes through linkage to cancer registry, hospital, and primary care files.  Results will be combined with those arising from parallel analyses in an independent large US data resource to identify top ranking genetically-associated cancers and non-cancer conditions.  Findings will be used to inform follow up of melanoma-prone families across the globe.

Scope extension: We propose a "modern" approach to identify associations of inherited genetic variation in known melanoma high- and moderate-penetrance genes (i.e. CDKN2A, CDK4, ACD, POT1, TERF2IP, TERT, MITF, and SLC45A2) with a spectrum of cancer and non-cancer outcomes. 

  1. We will query germline exome data on 450,000 individuals in UK Biobank for genetic variation in known high- and moderate-penetrance melanoma susceptibility genes.  After validation and prioritization , we will conduct a phenotype-wide association study (PheWAS) to determine associations with cancer and non-cancer phenotypic outcomes.  We will conduct a similar exercise in an independent set of 200,000 patients enrolled in a US-based health system.  Results will be meta-analyzed.
  2. Using existing array genotyping, we will calculate melanoma polygenic risk scores in 450,000 individuals in UK Biobank and 200,000 patients from a US-based health system and will meta-analyze PheWAS results to determine top associations with cancer and non-cancer phenotypic outcomes.  We will assess whether phenotypic profiles associated with the polygenic risk score differs among individuals with and without variants in the targeted set of high- and moderate-penetrance melanoma genes.

3.  Using array genotype data, we will infer family structure for individuals with melanoma and other top ranking associated cancers and determine the effect of a PRS for melanoma and related heritable traits on melanoma risk according to number of family members affected with melanoma and taking into consideration carriage of genetic variation in the targeted set of melanoma genes.