Evaluation of the 4q32-34 locus in European familial pancreatic cancer

Abstract

Background: Familial pancreatic cancer (FPC) describes a group of families where the inheritance of pancreatic cancer is consistent with an autosomal dominant mode of inheritance. The 4q32-34 region has been previously identified as a potential locus for FPC in a large American family. Methods: The region was allelotyped in 231 individuals from 77 European families using 9 microsatellite markers and haplotyping was possible in 191 individuals from 41 families. Families were selected on the basis of at least two affected first degree relatives with no other cancer syndromes. Results: Linkage to most of the locus was excluded on the basis of LOD scores < -2.0. Eight families were excluded from linkage to 4q32-34 on the basis of haplotypes not segregating with the disease, compared to a predicted six to seven families. Two groups of families were identified which appear to share common alleles within the minimal disease associated region of 4q32-34, one group with an apparently earlier age of cancer death than the other pancreatic cancer families. Four genes were identified with potential tumour suppressor roles within the locus in regions that could not be excluded on the basis of LOD score: These were HMGB2, PPID, MORF4 and SPOCK 3. DNA sequence analysis of exons of these genes in affected individuals and in pancreatic cancer cell lines did not reveal any mutations. Conclusion: This locus is unlikely to harbour a familial pancreatic cancer gene in the majority of our European families.