Allele-specific expression in the germline of patients with familial pancreatic cancer: an unbiased approach to cancer gene discovery.
Physiologic allele-specific expression (ASE) in germline tissues occurs during random X-chromosome inactivation and in genomic imprinting, 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; 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 approximately 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.
The Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Aik Choon
AC
Tan
Jian-Bing
JB
Fan
Collins
C
Karikari
Marina
M
Bibikova
Eliza Wickham
EW
Garcia
Lixin
L
Zhou
David
D
Barker
David
D
Serre
Georg
G
Feldmann
Ralph H
RH
Hruban
Alison P
AP
Klein
Michael
M
Goggins
Fergus J
FJ
Couch
Thomas J
TJ
Hudson
Raimond L
RL
Winslow
Anirban
A
Maitra
Aravinda
A
Chakravarti
D000483:Alleles; D002460:Cell Line; D041321:Chromosomes, Human, X; D052138:Genes, Neoplasm; D008040:Genetic Linkage; D015894:Genome, Human; D006801:Humans; D010190:Pancreatic Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012042:Registries; D049951:X Chromosome Inactivation