title: Claudin-1 Expression Is Elevated in Colorectal Cancer Precursor Lesions Harboring the BRAF V600E Mutation.
abstract: BACKGROUND
  Sessile serrated adenomas/polyps (SSA/P) are now recognised precursors of colorectal cancer (CRC) including cancers harbouring somatic BRAF (V600E) mutations. While the morphological diagnostic criteria of SSA/P have been established, distinguishing between small/early SSA/P and microvesicular hyperplastic polyps (MVHP) is challenging and may not be possible in routine practice.
  
  
  METHODS
  Gene expression profiling of MVHP (n=5, all BRAF V600E wild-type) and SSA/P (n=5, all BRAF V600E mutant) samples was performed. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemical analysis was performed to verify the expression of claudin 1 (CLDN1) in MVHP and SSA/P.
  
  
  RESULTS
  Gene expression profiling studies conducted between MVHP and SSA/P identified CLDN1 as the most statistically significant differentially expressed gene (p<0.05). Validation with qRT-PCR confirmed an up-regulation of CLDN1 in BRAF V600E mutant polyps regardless of polyp type (p<0.0005). Immunohistochemical analysis of CLDN1 expression in BRAF V600E mutant SSA/Ps (n=53) and MVHPs (n=111) and BRAF wild-type MVHPs (n=58), demonstrated a strong correlation between CLDN1 expression and the BRAF V600E mutation in both SSA/P and MVHP samples when compared to wild-type polyps (p<0.0001).
  
  
  CONCLUSIONS
  This study demonstrates an up regulation of CLDN1 protein in serrated colorectal polyps including MVHP harbouring the BRAF V600E mutation. Our results demonstrated an apparent heterogeneity on the molecular level within the MVHP group and suggest that MVHP with somatic BRAF V600E mutation and up-regulated expression of CLDN1 are closely related to SSA/P and may in fact represent a continuous spectrum of the same neoplastic process within the serrated pathway of colorectal carcinogenesis.
authors: Centre for Cancer Biology, Gastroenterology Research Laboratory, University of South Australia, Adelaide, Australia.
authors: Maria
authors: M
authors: Caruso
authors: CSIRO Preventative Health National Research Flagship, Adelaide, Australia.
authors: Kim Y C
authors: KY
authors: Fung
authors: Royal Adelaide Hospital, Adelaide, Australia; University of Adelaide, Adelaide, Australia.
authors: James
authors: J
authors: Moore
authors: CSIRO Preventative Health National Research Flagship, Adelaide, Australia.
authors: Gemma V
authors: GV
authors: Brierley
authors: CSIRO Preventative Health National Research Flagship, Adelaide, Australia.
authors: Leah J
authors: LJ
authors: Cosgrove
authors: Royal Adelaide Hospital, Adelaide, Australia; University of Adelaide, Adelaide, Australia.
authors: Michelle
authors: M
authors: Thomas
authors: Molecular Pathology, SA Pathology, Adelaide, Australia.
authors: Glenice
authors: G
authors: Cheetham
authors: University of Adelaide, Adelaide, Australia.
authors: Emma
authors: E
authors: Brook
authors: University of Adelaide, Adelaide, Australia.
authors: Louise M
authors: LM
authors: Fraser
authors: Centre for Cancer Biology, Gastroenterology Research Laboratory, University of South Australia, Adelaide, Australia.
authors: Teresa
authors: T
authors: Tin
authors: Centre for Cancer Biology, Gastroenterology Research Laboratory, University of South Australia, Adelaide, Australia.
authors: Ha
authors: H
authors: Tran
authors: Centre for Cancer Biology, Gastroenterology Research Laboratory, University of South Australia, Adelaide, Australia; University of Adelaide, Adelaide, Australia; Genetic Pathology, SA Pathology, Adelaide, Australia. Electronic address: Andrew.Ruszkiewicz@health.sa.gov.au.
authors: Andrew
authors: A
authors: Ruszkiewicz