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Evaluation of the 4q32-34 Locus in European Familial Pancreatic Cancer

¹ Division of Surgery and Oncology, ² School of Dental Sciences, and ³ School of Biological Sciences, University of Liverpool, Liverpool, United Kingdom; ⁴ Medical Biometry and Epidemiology and ⁵ Department of Clinical Genetics, Philipps-University, Marburg, Germany; ⁶ Department of Internal Medicine, University of Bochum, Bochum, Germany; ⁷ Department of Clinical Genetics, University of Düsseldorf, Düsseldorf, Germany; and ⁸ Department of Visceral Surgery, Städtische Kliniken Bielefeld-Mitte, Bielefeld, Germany

Requests for reprints: William Greenhalf, Division of Surgery and Oncology, Royal Liverpool University Hospital, 5th Floor UCD Building, Liverpool, United Kingdom. Phone: 44-151-706-4184; Fax: 44-151-706-5826. E-mail: greenhaf{at}liverpool.ac.uk

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 nine microsatellite markers, and haplotyping was possible in 191 individuals from 41 families. Families were selected based on at least two affected first-degree relatives with no other cancer syndromes.

Results: Linkage to most of the locus was excluded based on LOD scores less than –2.0. Eight families were excluded from linkage to 4q32-34 based on haplotypes not segregating with the disease compared with a predicted six to seven families. Two groups of families were identified, which seem 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 tumor suppressor roles within the locus in regions that could not be excluded based on the LOD score. These were HMGB2, PPID, MORF4, and SPOCK3. 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 harbor a FPC gene in the majority of our European families. (Cancer Epidemiol Biomarkers Prev 2006;15(10):1948–55)

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