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

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42 Citations (Scopus)


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
Pages (from-to)137-146
Number of pages10
JournalCancer Biology and Therapy
Issue number1
Publication statusPublished - 2008 Jan

Bibliographical note

Funding Information:
The research was funded by grants from the National Institutes of Health [P50CA062924 (A.M.), RO1HD28088 (A.C.), R01MH060007 (A.C.)], the Mayo Clinic Pancreatic Cancer SPORE [P50102701 (F.J.C.)], The Sol Goldman Pancreatic Cancer Research Center (R.H.H.) and the Henry J. Knott professorship (A.C.). The study was designed by J.B.F., D.B., A.M. and A.C.; genes and SNPs was selected by J.B.F. and A.M.; the chip was designed by L.Z.; array experiment and data extraction was performed by M.B. and E.W.G.; the array experiments were supervised by D.B. and J.B.F.; cell culture and DNA and RNA extraction was performed by C.K.; NFPTR samples was acquired by R.H.H., A.P.K. and M.G.; the analysis algo‑ rithm was designed by A.C.T., D.S., T.J.H., R.L.W. and A.C.; data analysis and interpretation was conducted by A.C.T., A.M. and A.C.; experimental validation was performed by G.F. and F.J.C.; A.C.T., A.M. and A.C. wrote the paper.


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

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research


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