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Research Paper
Allele-specific expression in the germline of patients with familial pancreatic cancer: An unbiased approach to cancer gene discovery
Aik Choon Tan, 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 and Aravinda Chakravarti
volume 7 | issue 1
January 2008Pages: 135 - 144
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Physiologic allele-specific expression (ASE) in germline tissues occurs during random X-chromosome inactivation1 and in genomic imprinting2, 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 genes3-14; 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.
Authors
Aik Choon Tan
Johns Hopkins University, Baltimore, MD, USA
Jian-Bing Fan
Illumina Inc., San Diego, CA, USA
Collins Karikari
The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Marina Bibikova
Illumina Inc., San Diego, CA, USA
Eliza Wickham Garcia
Illumina Inc., San Diego, CA, USA
Lixin Zhou
Illumina Inc., San Diego, CA, USA
David Barker
Illumina Inc., San Diego, CA, USA
David Serre
McGill University and Genome Quebec Innovation Center, Montreal, Quebec, CANADA
Georg Feldmann
The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Ralph H. Hruban
The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Alison P. Klein
Johns Hopkins University, Baltimore, Maryland
Michael Goggins
The Sol Goldman Center for Pancreatic Cancer Research
Fergus J. Couch
Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA
Thomas J. Hudson
Ontario Institute for Cancer Research, Toronto, Ontario, CANADA
Raimond L. Winslow
The Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD, USA
Anirban Maitra
Johns Hopkins University, Baltimore, Maryland
Aravinda Chakravarti
The Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD, USA