Linkage analysis of chromosome 4 in families with familial pancreatic cancer.
BACKGROUND
Approximately 10% of pancreatic ductal adenocarcinomas have a familial basis. While a small portion of this familial clustering can be explained by inherited mutations in known genes (BRCA2, p16/CDKN2A, PRSS1, and STK11), the genetic basis for the majority of this familial clustering remains unknown. In addition, a pancreatic cancer susceptibility locus has been reported to be linked to chromosome 4q32-34 in a single family having a high penetrance of early-onset pancreatic ductal adenocarcinoma and pancreatic insufficiency. The goal of this study is to determine if linkage to chromosome 4q exists in our series of well-characterized families with idiopathic familial pancreatic cancer enrolled in the Pancreatic Cancer Genetic Epidemiology Consortium (PACGENE).


METHODS
Parametric and nonparametric linkage analyses were performed using 21 microsatellite markers on chromosome 4 on affected individuals with pancreatic cancer from 42 familial pancreatic cancer kindreds.


RESULTS
Markov Chain Monte Carlo parametric and nonparametric linkage analyses using SIMWALK2 as well as nonparametric linkage analysis using MERLIN did not provide strong evidence of linkage in this region (LOD < 1.0). Only one family provided a multipoint LOD score of >0.5 adjacent to the reported region.


CONCLUSIONS
Our results do not support linkage to the 4q32-34 region in the majority of our familial pancreatic cancer kindreds. However, because multiple pancreatic cancer susceptibility genes are likely to exist, it is possible that a subset of the families in this study may be linked to this region.
Klein
Alison P
AP
The Sol Goldman Pancreatic Research Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland 21231, USA. aklein1@jhmi.edu
de Andrade
Mariza
M
Hruban
Ralph H
RH
Bondy
Melissa
M
Schwartz
Ann G
AG
Gallinger
Steven
S
Lynch
Henry T
HT
Syngal
Sapna
S
Rabe
Kari G
KG
Goggins
Michael G
MG
Petersen
Gloria M
GM
D000328:Adult; D000368:Aged; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics*; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D008126:Lod Score; D008297:Male; D008390:Markov Chains; D008875:Middle Aged; D009010:Monte Carlo Method; D010190:Pancreatic Neoplasms / Q000235:genetics*; D010375:Pedigree