Genome-wide allelotypes of familial pancreatic adenocarcinomas and familial and sporadic intraductal papillary mucinous neoplasms.
OBJECTIVE
Most familial cancer susceptibility genes are tumor suppressor genes that are biallelically inactivated in familial neoplasms through somatic deletion of the wild-type allele. Identifying the genomic losses that occur in pancreatic neoplasms, particularly those that occur in familial and precursor neoplasms, may help localize the genes responsible for pancreatic cancer susceptibility.


METHODS
Normal and neoplastic tissue DNA was isolated from fresh-frozen surgically resected tissues from 20 patients with primary familial pancreatic adenocarcinoma (defined as having at least one first-degree relative with pancreatic cancer), 31 with sporadic intraductal papillary mucinous neoplasms (IPMN), and 7 with familial IPMNs using laser capture microdissection. Microdissected DNA was whole genome amplified using multiple strand displacement. Genome-wide allelotypes were determined using 391 microsatellite markers. The accuracy of microdissection and fidelity of the whole genome amplification were determined by comparing the genotypes of microdissected primary pancreatic cancers to the genotypes of xenografts derived from these cancers and by comparing the results of amplified to nonamplified specimens.


RESULTS
The concordance of genotypes between LCM whole genome amplified primary pancreatic cancers and their corresponding pancreatic cancer xenograft DNAs was 98%. Among the 20 primary familial pancreatic adenocarcinomas, we found a high prevalence of loss of heterozygosity (LOH) with an average fractional allelic loss (FAL) of 49.9% of an aggregate of 2,378 informative markers. The level of FAL in the IPMNs (10%) was significantly lower than in the pancreatic adenocarcinomas. The most common locus of LOH in the IPMNs was at 19p (LOH at 24% of markers). The regions of frequent allelic loss observed in the familial pancreatic cancers were similar to those found in sporadic pancreatic cancers.


CONCLUSIONS
The allelic loss patterns of familial and sporadic pancreatic cancers and IPMNs provide clues as to the genomic locations of tumor suppressor genes inactivated in these neoplasms.
Abe
Tadayoshi
T
Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA.
Fukushima
Noriyoshi
N
Brune
Kieran
K
Boehm
Corinne
C
Sato
Norihiro
N
Matsubayashi
Hiroyuki
H
Canto
Marcia
M
Petersen
Gloria M
GM
Hruban
Ralph H
RH
Goggins
Michael
M
D000230:Adenocarcinoma / Q000235:genetics*; D002288:Adenocarcinoma, Mucinous / Q000235:genetics*; D000231:Adenocarcinoma, Papillary / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D002874:Chromosome Mapping; D005192:Family Health; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016678:Genome; D006579:Heterozygote; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000235:genetics*