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 non-parametric 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 non-parametric linkage analyses using SIMWALK2 as well as non-parametric 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.

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Linkage analysis of chromosome 4 in families with familial pancreatic cancer