Allele-specific expression in the germline of patients with familial pancreatic cancer: An unbiased approach to cancer gene discovery

Choon Tan Aik, Jian Bing Fan, Collins Karikari, Marina Bibikova, Eliza Wickham Garcia, Lixin Zhou, David Barker, David Serre, Georg Feldmann, Ralph H. Hruban, Alison P. Klein, Michael Goggins, Fergus J. Couch, Thomas J. Hudson, Raimond L. Winslow, Anirban Maitra, Aravinda Chakravarti

Research output: Contribution to journalArticlepeer-review

Abstract

Physiologic allele-specific expression (ASE) in germline tissues occurs during random X-chromosome inactivation1 and in genomic imprinting,2 wherein the two alleles of a gene in a heterozygous individual are not expressed equally. Recent studies have confirmed the existence of ASE in apparently non-imprinted autosomal genes;3-14 however, the extent of ASE in the human genome is unknown. We explored ASE in lymphoblastoid cell lines of 145 individuals using an oligonucleotide array based assay. ASE of autosomal genes was found to be a very common phenomenon in ∼20% of heterozygotes at 78% of SNPs at 84% of the genes examined. Comparison of 100 affected individuals from familial pancreatic cancer kindreds and 45 controls revealed three types of changes in the germline: (a) loss of ASE, (b) gain of ASE, and, (c) rare instances of "extreme" (near monoallelic) ASE. The latter changes identified heterozygous deleterious mutations in a subset of these genes. Consequently, an ASE assay efficiently identifies candidate disease genes with altered germline expression properties as compared to controls, and provides insights into mechanisms that confer an inherited disease risk for pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)137-146
Number of pages10
JournalCancer Biology and Therapy
Volume7
Issue number1
StatePublished - Jan 1 2008

Keywords

  • Allele-specific
  • Cancer
  • Familial
  • Microarray
  • Mutation
  • Pancreatic
  • Regulation

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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