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.
Tan
Aik Choon
AC
The Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Fan
Jian-Bing
JB
Karikari
Collins
C
Bibikova
Marina
M
Garcia
Eliza Wickham
EW
Zhou
Lixin
L
Barker
David
D
Serre
David
D
Feldmann
Georg
G
Hruban
Ralph H
RH
Klein
Alison P
AP
Goggins
Michael
M
Couch
Fergus J
FJ
Hudson
Thomas J
TJ
Winslow
Raimond L
RL
Maitra
Anirban
A
Chakravarti
Aravinda
A
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