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beta-Catenin splice variants and downstream targets as markers for neoplastic progression of esophageal cancer.

Abstract
This study characterizes the frequency of exon 3 CTNNB1 mutations and compares the expression of CTNNB1 transcript variants and downstream targets MYC and WAF1 (p21) across the neoplastic progression of esophageal squamous cell carcinomas (ESCCs). Mutational analysis was performed on 56 tumors and corresponding germline DNA, using primers to exon 3 of CTNNB1 and SSCP DNA sequencing gels. Quantitative Real Time RT-PCR was performed on 45 foci representing the histological spectrum from normal to invasive cancer, using specific primer sets for alternative splice variants that differ by the presence (16A) or absence (16B) of a 159-bp noncoding segment of exon 16 of CTNNB1, in conjunction with downstream targets MYC and WAF1. Two unique mutations were identified, S37F in the SxxxS repeat region, and a germline polymorphism, T59A. Thus, mutation of CTNNB1 exon 3 is a rare event in this population. RT-PCR analysis successfully confirmed the presence of both beta-catenin splice variants in histologically normal and preneoplastic squamous epithelium, and invasive tumors of the esophagus, and identified a significant reduction in the 16A/16B ratio (P = 0.014) and an accompanying significant increase in the MYC/WAF1 expression ratio (P = 0.001) with progression from normal mucosa to dysplasia. This represents the first identification of two CTNNB1 transcripts in histologically "normal" esophageal squamous cells, squamous dysplasia, and invasive ESCC. These results show an increase in the minor mRNA (16B) isoform and changes in the expression of downstream markers consistent with increased transcription during the histological progression from normal to squamous dysplasia.
AuthorsMark J Roth, Nan Hu, Laura Lee Johnson, Wang Quon-Hang, Dennis J Ahnen, Michiko Iwamoto, Sanford M Dawsey, Philip R Taylor, Konrad Huppi
JournalGenes, chromosomes & cancer (Genes Chromosomes Cancer) Vol. 44 Issue 4 Pg. 423-8 (Dec 2005) ISSN: 1045-2257 [Print] United States
PMID16114033 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
CopyrightPublished 2005 Wiley-Liss, Inc.
Chemical References
  • Genetic Markers
  • RNA, Messenger
  • beta Catenin
Topics
  • Alternative Splicing
  • Base Pairing
  • Base Sequence
  • Carcinoma, Squamous Cell (pathology)
  • DNA Mutational Analysis
  • Disease Progression
  • Esophageal Neoplasms (genetics, pathology)
  • Exons
  • Gene Expression
  • Genetic Markers
  • Genetic Variation
  • Humans
  • Mutation
  • Polymorphism, Single-Stranded Conformational
  • Precancerous Conditions
  • RNA, Messenger (metabolism)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription, Genetic
  • beta Catenin (genetics, metabolism)

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