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Genomic FHIT analysis in RER + and RER − adenocarcinomas of the pancreas
Author(s) -
Hilgers Werner,
Koerkamp Bas Groot,
Geradts Joseph,
Tang David J.,
Yeo Charles J.,
Hruban Ralph H.,
Kern Scott E.
Publication year - 2000
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/(sici)1098-2264(200003)27:3<239::aid-gcc3>3.0.co;2-x
Subject(s) - fhit , loss of heterozygosity , missense mutation , biology , carcinogenesis , chromosomal fragile site , cancer research , tumor suppressor gene , exon , point mutation , genome instability , genetics , microsatellite instability , microbiology and biotechnology , gene , mutation , microsatellite , chromosome , allele , dna damage , dna
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 heterozygous 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 FRA3B‐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. Genes Chromosomes Cancer 27:239–243, 2000. © 2000 Wiley‐Liss, Inc.