Germline variants in oculocutaneous albinism genes and predisposition to familial cutaneous melanoma

Abstract

Approximately 1%–2% of cutaneous melanoma (CM) is classified as strongly familial. We sought to investigate unexplained CM predisposition in families negative for the known susceptibility genes using next‐generation sequencing of affected individuals. Segregation of germline variants of interest within families was assessed by Sanger sequencing. Several heterozygous variants in oculocutaneous albinism (OCA) genes: TYR, OCA2, TYRP1 and SLC45A2, were present in our CM cohort. OCA is a group of autosomal recessive genetic disorders, resulting in pigmentation defects of the eyes, hair and skin. Missense variants classified as pathogenic for OCA were present in multiple families and some fully segregated with CM. The functionally compromised TYR p.T373K variant was present in three unrelated families. In OCA2, known pathogenic variants: p.V443I and p.N489D, were present in three families and one family, respectively. We identified a likely pathogenic SLC45A2 frameshift variant that fully segregated with CM in a family of four cases. Another four‐case family harboured cosegregating variants (p.A24T and p.R153C) of uncertain functional significance in TYRP1. We conclude that rare, heterozygous variants in OCA genes confer moderate risk for CM.

Whole-genome sequencing of acral melanoma reveals genomic complexity and diversity

“…This variant is present at a low frequency in the Gnomad database 27 (allele frequency of 8.2 × 10 −5 ) and has been reported as pathogenic in Clinvar (rs387906562) for oculocutaneous albinism type 3 (OCA3), an autosomal recessive disorder of melanin biosynthesis that reduces pigmentation of the hair, skin and eyes 28 . Mutations in OCA genes including TYRP1 have been proposed to confer a moderate risk for CM 29 . The p.N353Vfs*31 variant was not found in a previous analysis of 38 exome-sequenced AM specimens 7 , and p.N353Vfs*31 was found rarely (17/46651 tumors) in other cancer types queried in cBioportal 30 , 31 .…”

“…21q 20q 20p 19q 19p 18q 18p 17q 17p 16q 16p 15q 14q 13q 12q 12p 11q 11p 10q 10p 9q 9p 8q 8p 7q 7p 6q 6p 5q 5p 4q 4p 3q 3p 2q 2p 1q 1p CNS1 CNS6 WGD Specimen type Primary site MELA_0297 MELA_0281 MELA_0870 MELA_0187 MELA_0011 MELA_0279 MELA_0225 MELA_0064 MELA_0267 MELA_0314 MELA_0278 MELA_0290 MELA_0271 MELA_0014 MELA_0310 MELA_0295 MELA_0300 MELA_0872 MELA_0009 MELA_0081 MELA_0307 MELA_0333 MELA_0289 MELA_0315 MELA_0008 MELA_0061 MELA_0308 MELA_0276 MELA_0306 MELA_0349 MELA_0069 MELA_0026 MELA_0002 MELA_0060 MELA_0284 MELA_0004 MELA_0007 MELA_0292 MELA_0066 MELA_0336 MELA_0274 MELA_0015 MELA_0070 MELA_0305 MELA_0311 MELA_0057 MELA_0012 MELA_0072 MELA_0265 MELA_0294 MELA_0001 MELA_0164 MELA_0301 MELA_0282 MELA_0269 MELA_0304 MELA_0048 MELA_0283 MELA_0335 MELA_0873 MELA_0273 MELA_0288 MELA_0291 MELA_0275 MELA_0055 MELA_0334 MELA_0270 MELA_0266 MELA_0268 MELA_0293 MELA_0206 MELA_0005 MELA_0337 MELA_0272 MELA_0067 MELA_0296 MELA_0010 MELA_0286 MELA_0332 MELA_0309 MELA_0298 MELA_0285 MELA_0003 MELA_0068 MELA_0277 MELA_0871 MELA_0314 MELA_0270 MELA_0072 MELA_0334 MELA_0070 MELA_0057 MELA_0304 MELA_0068 MELA_0288 MELA_0289 MELA_0001 MELA_0290 MELA_0305 MELA_0005 MELA_0002 MELA_0297 MELA_0300 MELA_0269 MELA_0349 MELA_0282 MELA_0009 MELA_0014 MELA_0187 MELA_0069 MELA_0206 MELA_0067 MELA_0012 MELA_0301 MELA_0284 MELA_0283 MELA_0273 MELA_0265 MELA_0294 MELA_0164 MELA_0291 MELA_0275 MELA_0872 MELA_0278 MELA_0286 MELA_0292 MELA_0225 MELA_0332 MELA_0277 MELA_0081 MELA_0003 MELA_0010 MELA_0296 MELA_0048 MELA_0272 MELA_0267 MELA_0315 MELA_0870 MELA_0274 MELA_0268 MELA_0871 MELA_0306 MELA_0266 MELA_0007 MELA_0293 MELA_0281 MELA_0333 MELA_0026 MELA_0280 MELA_0337 MELA_0309 MELA_0271 MELA_0336 MELA_0004 MELA_0015 MELA_0308 MELA_0066 MELA_0011 MELA_0279 MELA_0310 MELA_0295 MELA_0307 MELA_0008 MELA_0061 MELA_0060 MELA_0311 MELA_0335 MELA_0873 MELA_0055 MELA_0298 autosomal recessive disorder of melanin biosynthesis that reduces pigmentation of the hair, skin and eyes 28 . Mutations in OCA genes including TYRP1 have been proposed to confer a moderate risk for CM 29 . The p.N353Vfs*31 variant was not found in a previous analysis of 38 exome-sequenced AM specimens 7 , and p. N353Vfs*31 was found rarely (17/46651 tumors) in other cancer types queried in cBioportal 30,31 .…”

Pathogenic germline variants are associated with poor survival in stage III/IV melanoma patients

“…Four patients had mutations at hotspots in MITF p.E318K (MelR06, MelR191) and TYR p.T373K (MelR014, MelR219) (Table 2 ). These variants are pathogenic in ClinVar and confer a more modest-risk of developing melanoma 4 , 35 , 36 .…”

Genetic ancestry, skin pigmentation, and the risk of cutaneous squamous cell carcinoma in Hispanic/Latino and non-Hispanic white populations

“…It is noteworthy that rs683 at TYRP1, known to influence skin color pigment but not previously associated with cSCC risk, showed suggestive association with cSCC risk in our GERA non-Hispanic white sample (P = 0.0064) (Supplementary Data 1). TYRP1 encodes the melanosomal enzyme tyrosinase-related protein 1, and mutations in this gene can cause albinism and confer increased risk for familial cutaneous melanoma [27][28][29] .…”