Report of a novel OCA2 gene mutation and an investigation of OCA2 variants on melanoma risk in a familial melanoma pedigree

Jason E. Hawkes, Pamela Cassidy, Prashiela Manga, Raymond E. Boissy, David Goldgar, Lisa Cannon-Albright, Scott R. Florell, Sancy Leachman

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Background: Oculocutaneous albinism type 2 (OCA2) is caused by mutations of the OCA2 gene. Individuals affected by OCA2 as well as other types of albinism are at a significantly increased risk for sun-induced skin-cancers, including malignant melanoma (MM). Objective: To identify the molecular etiology of oculocutaneous albinism in a previously uncharacterized melanoma pedigree and to investigate the relationship between two OCA2 variants and melanoma predisposition in this pedigree. Methods: DNA and RNA were isolated from the peripheral blood of seven patients in a familial melanoma pedigree. Electron microscopy was performed on the individual with clinical oculocutaneous albinism. OCA2, TYRP1, MC1R, CDKN2A/. p16, CDKN2A/. p19ARF, and CDK4 genes were sequenced in affected individuals. The relationship between OCA2 variants and melanoma was assessed using a pedigree likelihood-based method. Results: The proband was determined to be an OCA2 compound heterozygous mutation carrier with a previously reported conservative missense mutation (V443I) and a novel non-conservative missense mutation (L734R). The pedigree contained individuals diagnosed with both cutaneous and iris melanoma. Based on co-segregation analysis, the odds of these OCA2 variants being high penetrance loci for melanoma was: 1.3-to-1 if we include the iris melanoma as affected and 6.5-to-1 if we only consider cutaneous melanoma as affected. Conclusion: The discovery of this novel OCA2 variant adds to the body of evidence on the detrimental effects of OCA2 gene mutations on pigmentation, supports existing GWAS data on the relevance of the OCA2 gene in melanoma predisposition, and may ultimately assist in the development of targeted molecular therapies in the treatment of OCA and melanoma.

Original languageEnglish (US)
Pages (from-to)30-37
Number of pages8
JournalJournal of Dermatological Science
Volume69
Issue number1
DOIs
StatePublished - Jan 2013
Externally publishedYes

Fingerprint

Pedigree
Melanoma
Genes
Mutation
Oculocutaneous Albinism
Sun
Electron microscopy
Skin
Blood
Iris
Missense Mutation
RNA
Oculocutaneous albinism type 2
Cutaneous Malignant Melanoma
DNA
Albinism
Molecular Targeted Therapy
Penetrance
Genome-Wide Association Study
Pigmentation

Keywords

  • Familial melanoma
  • Melanoma
  • OCA
  • OCA2
  • Oculocutaneous albinism
  • Oculocutaneous albinism type 2

ASJC Scopus subject areas

  • Dermatology
  • Biochemistry
  • Molecular Biology

Cite this

Report of a novel OCA2 gene mutation and an investigation of OCA2 variants on melanoma risk in a familial melanoma pedigree. / Hawkes, Jason E.; Cassidy, Pamela; Manga, Prashiela; Boissy, Raymond E.; Goldgar, David; Cannon-Albright, Lisa; Florell, Scott R.; Leachman, Sancy.

In: Journal of Dermatological Science, Vol. 69, No. 1, 01.2013, p. 30-37.

Research output: Contribution to journalArticle

Hawkes, Jason E. ; Cassidy, Pamela ; Manga, Prashiela ; Boissy, Raymond E. ; Goldgar, David ; Cannon-Albright, Lisa ; Florell, Scott R. ; Leachman, Sancy. / Report of a novel OCA2 gene mutation and an investigation of OCA2 variants on melanoma risk in a familial melanoma pedigree. In: Journal of Dermatological Science. 2013 ; Vol. 69, No. 1. pp. 30-37.
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abstract = "Background: Oculocutaneous albinism type 2 (OCA2) is caused by mutations of the OCA2 gene. Individuals affected by OCA2 as well as other types of albinism are at a significantly increased risk for sun-induced skin-cancers, including malignant melanoma (MM). Objective: To identify the molecular etiology of oculocutaneous albinism in a previously uncharacterized melanoma pedigree and to investigate the relationship between two OCA2 variants and melanoma predisposition in this pedigree. Methods: DNA and RNA were isolated from the peripheral blood of seven patients in a familial melanoma pedigree. Electron microscopy was performed on the individual with clinical oculocutaneous albinism. OCA2, TYRP1, MC1R, CDKN2A/. p16, CDKN2A/. p19ARF, and CDK4 genes were sequenced in affected individuals. The relationship between OCA2 variants and melanoma was assessed using a pedigree likelihood-based method. Results: The proband was determined to be an OCA2 compound heterozygous mutation carrier with a previously reported conservative missense mutation (V443I) and a novel non-conservative missense mutation (L734R). The pedigree contained individuals diagnosed with both cutaneous and iris melanoma. Based on co-segregation analysis, the odds of these OCA2 variants being high penetrance loci for melanoma was: 1.3-to-1 if we include the iris melanoma as affected and 6.5-to-1 if we only consider cutaneous melanoma as affected. Conclusion: The discovery of this novel OCA2 variant adds to the body of evidence on the detrimental effects of OCA2 gene mutations on pigmentation, supports existing GWAS data on the relevance of the OCA2 gene in melanoma predisposition, and may ultimately assist in the development of targeted molecular therapies in the treatment of OCA and melanoma.",
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AU - Hawkes, Jason E.

AU - Cassidy, Pamela

AU - Manga, Prashiela

AU - Boissy, Raymond E.

AU - Goldgar, David

AU - Cannon-Albright, Lisa

AU - Florell, Scott R.

AU - Leachman, Sancy

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AB - Background: Oculocutaneous albinism type 2 (OCA2) is caused by mutations of the OCA2 gene. Individuals affected by OCA2 as well as other types of albinism are at a significantly increased risk for sun-induced skin-cancers, including malignant melanoma (MM). Objective: To identify the molecular etiology of oculocutaneous albinism in a previously uncharacterized melanoma pedigree and to investigate the relationship between two OCA2 variants and melanoma predisposition in this pedigree. Methods: DNA and RNA were isolated from the peripheral blood of seven patients in a familial melanoma pedigree. Electron microscopy was performed on the individual with clinical oculocutaneous albinism. OCA2, TYRP1, MC1R, CDKN2A/. p16, CDKN2A/. p19ARF, and CDK4 genes were sequenced in affected individuals. The relationship between OCA2 variants and melanoma was assessed using a pedigree likelihood-based method. Results: The proband was determined to be an OCA2 compound heterozygous mutation carrier with a previously reported conservative missense mutation (V443I) and a novel non-conservative missense mutation (L734R). The pedigree contained individuals diagnosed with both cutaneous and iris melanoma. Based on co-segregation analysis, the odds of these OCA2 variants being high penetrance loci for melanoma was: 1.3-to-1 if we include the iris melanoma as affected and 6.5-to-1 if we only consider cutaneous melanoma as affected. Conclusion: The discovery of this novel OCA2 variant adds to the body of evidence on the detrimental effects of OCA2 gene mutations on pigmentation, supports existing GWAS data on the relevance of the OCA2 gene in melanoma predisposition, and may ultimately assist in the development of targeted molecular therapies in the treatment of OCA and melanoma.

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