Genomic FHIT analysis in RER+ and RER- adenocarcinomas of the pancreas

W Hilgers, BG Koerkamp, J Geradts, DJ Tang, CJ Yeo, RH Hruban, SE Kern

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22 Citations (Scopus)


Alterations of the candidate tumor suppressor gene FHIT have been reported in multiple tumor types, including pancreatic carcinoma. The mechanism of FHIT genomic inactivation is unusual, most frequently occurring by homozygous deletion, whereas only rare cases have missense mutations. Altered (shortened) transcripts and reduced protein expression are reported, but a genetic basis for these is often inapparent. We studied FHIT genomic alterations of pancreatic carcinomas. Loss of heterozygosity (LOH) was found in 41% of 93 carcinomas without microsatellite instability (RER-), but no mutations were found by genomic sequencing. Homozygous deletions inside the FRA3B fragile site were found in four RER- tumors, but only two affected the FHIT coding region, In contrast, FHIT alterations were found in the three RER+ pancreatic carcinomas screened; two had FHIT homozygous deletions affecting exon 5 and the third had a heteroroygous missense mutation (H76N). The excess occurrence of homozygous deletions at this site in RER+ pancreatic cancers is statistically significant (P < 0.01). Since homozygous deletions have not previously been reported in RER+ carcinomas at any genomic site, an extremely high rate of site-specific deletion must exist within the FRA3 B-related FHIT gene. Consequently, the paucity of documented inactivating point mutations cannot be used to judge the presence or absence of putative FHIT-related selective pressures that act during tumorigenesis of RER- neoplasia. Nonetheless, the identification of a heterozygous mutation as the sole sequence abnormality might raise doubt as to whether strong selective pressures are afforded by FHIT genomic inactivation in this tumor type. (C) 2000 Wiley-Liss, Inc.
Original languageEnglish
Pages (from-to)239-243
Number of pages5
JournalGenes Chromosomes & Cancer
Issue number3
Publication statusPublished - Mar 2000
Externally publishedYes


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