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Intronic sequence variants of the CDKN2A gene in melanoma pedigrees

Mark Harland1, Claire F Taylor, Sylvia Bass

  • 1Genetic Epidemiology Division, Cancer Research UK Clinical Centre, St. James's University Hospital, Leeds, England.

Genes, Chromosomes & Cancer
|March 12, 2005
PubMed

Insights

This study screened melanoma families for mutations in the CDKN2A gene. Two intronic variants were found to predispose to melanoma, suggesting a role for non-coding regions in cancer predisposition.

Area of Science:

  • Genetics
  • Oncology
  • Molecular Biology

Background:

  • Germ-line mutations in the CDKN2A tumor-suppressor gene are linked to hereditary melanoma.
  • A significant proportion of affected individuals lack detectable coding mutations in CDKN2A.
  • Intronic mutations in CDKN2A have been identified as a common cause of melanoma in some populations.

Purpose of the Study:

  • To comprehensively screen English and Australian melanoma pedigrees for intronic mutations in the CDKN2A gene.
  • To identify novel CDKN2A intronic variants associated with melanoma predisposition.
  • To investigate the functional impact of identified intronic variants on gene expression.

Main Methods:

  • Screening of 109 English and 26 Australian melanoma pedigrees for intronic mutations in CDKN2A.
  • DNA sequencing to identify sequence variants within the two introns of CDKN2A.
  • Analysis of identified variants for association with melanoma predisposition and impact on mRNA splicing.

Main Results:

  • A total of 24 sequence variants were identified across the two introns of CDKN2A.
  • Two intronic variants, IVS1 + 1104 C > A and IVS1 - 1104 C > G, were shown to predispose to melanoma.
  • The IVS1 + 1104 variant resulted in aberrant splicing of p16(INK4a) and p14(ARF) mRNA.

Conclusions:

  • Intronic mutations within the CDKN2A gene can predispose individuals to melanoma.
  • The identified intronic variants contribute to melanoma risk, particularly through effects on mRNA splicing.
  • While these variants are significant, they account for a small proportion of English melanoma families.

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