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Dissection of the Mouse Pancreas for Histological Analysis and Metabolic Profiling
Published on: August 19, 2017
Genomic FHIT analysis in RER+ and RER- adenocarcinomas of the pancreas
W Hilgers1, B Groot Koerkamp, J Geradts
1Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.
Abstract:
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.
Insights
Investigating the fragile histidine triad (FHIT) gene in pancreatic cancer revealed frequent homozygous deletions in RER(+) tumors, suggesting a unique genomic instability mechanism. This contrasts with RER(-) tumors, where FHIT alterations are less common.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- The candidate tumor suppressor gene, FHIT (fragile histidine triad), is frequently altered in various cancers, including pancreatic carcinoma.
- FHIT inactivation typically occurs via homozygous deletion, with missense mutations being rare, leading to altered transcripts and reduced protein expression.
- The genetic basis for FHIT alterations and their role in pancreatic tumorigenesis, particularly in tumors with different microsatellite instability profiles, requires further investigation.
Purpose of the Study:
- To investigate the specific mechanisms and frequency of FHIT genomic alterations in pancreatic carcinomas.
- To compare FHIT alterations between pancreatic tumors with and without microsatellite instability (RER(-) and RER(+) respectively).
- To assess the significance of homozygous deletions and missense mutations in FHIT inactivation within pancreatic cancer.
Main Methods:
- Analysis of FHIT genomic alterations, including loss of heterozygosity (LOH) and homozygous deletions, in 93 pancreatic carcinomas.
- Genomic sequencing to detect mutations in FHIT.
- Screening of FHIT alterations in a subset of RER(+) pancreatic carcinomas.
Main Results:
- Loss of heterozygosity (LOH) was observed in 41% of RER(-) pancreatic carcinomas, with no mutations detected by sequencing.
- Homozygous deletions within the FRA3B fragile site were found in four RER(-) tumors, but only two affected the FHIT coding region.
- In RER(+) pancreatic carcinomas, FHIT alterations were more frequent, including two cases with homozygous deletions affecting exon 5 and one with a heterozygous missense mutation (H76N). The excess of homozygous deletions in RER(+) tumors was statistically significant (P < 0.01).
Conclusions:
- The study highlights an unusually high rate of site-specific homozygous deletions within the FRA3B-related FHIT gene in RER(+) pancreatic cancers, a phenomenon not previously reported in RER(+) carcinomas.
- The findings suggest a distinct mechanism of FHIT inactivation in RER(+) pancreatic tumors compared to RER(-) tumors.
- The rarity of inactivating point mutations in RER(-) tumors indicates that their absence does not preclude FHIT-related selective pressures during tumorigenesis, while the heterozygous mutation in an RER(+) tumor raises questions about the selective advantage of FHIT inactivation in this context.
