Mutations in the RAS/RAF/MAP kinase pathway commonly occur in gallbladder adenomas but are uncommon in gallbladder adenocarcinomas

Reetesh K. Pai, Rish Pai, Kaveh Mojtahed

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

The role of gallbladder adenomas in the pathogenesis of gallbladder carcinoma is still controversial. Comparison of the genetic abnormalities seen in adenomas may provide insight into the potential role of gallbladder adenomas as precursor lesions to gallbladder carcinoma. The purpose of this study was to evaluate gallbladder carcinomas, gallbladder adenomas, and high-grade dysplastic lesions for the BRAF and the KRAS mutations and the mismatch repair protein abnormalities. We analyzed 29 gallbladder carcinomas (9 papillary and 20 nonpapillary adenocarcinomas), 16 adenomas (6 pyloric, 3 intestinal, 3 biliary, 3 mixed pyloric-biliary, and 1 mixed pyloric-intestinal), and 5 cases of high-grade dysplasia for activating missense mutations in KRAS codons 12 and 13 and BRAF V600E mutations. Mismatch repair protein immunohistochemistry for MLH1, MSH2, MSH6, and PMS2 was also carried out. KRAS mutations were infrequently identified in gallbladder carcinoma (2/29, 7%) and high-grade dysplastic lesions (0/5, 0%). Compared with gallbladder carcinoma and high-grade dysplastic lesions, gallbladder adenomas frequently showed KRAS codon 12 mutations (5/16, 31%) (P=0.02). Adenomas with pyloric-type histology harbored KRAS mutations more often (4/10, 40%) than other histologic subtypes (1/6, 17%). Adenomas rarely showed BRAF mutations (1/16, 6%), and no cases of gallbladder carcinoma or high-grade dysplasia were positive for BRAF mutations. Both the adenomas and the carcinomas displayed intact expression of mismatch repair proteins by immunohistochemistry. The presence of frequent mutations in the RAS/RAF/MAPK pathway in the gallbladder adenomas compared with the gallbladder carcinomas suggest that the adenomas and the gallbladder carcinomas arise through distinctly different molecular pathways.

Original languageEnglish (US)
Pages (from-to)133-140
Number of pages8
JournalApplied Immunohistochemistry and Molecular Morphology
Volume19
Issue number2
DOIs
StatePublished - Mar 1 2011
Externally publishedYes

Fingerprint

Gallbladder
Adenoma
Adenocarcinoma
Phosphotransferases
Mutation
Carcinoma
DNA Mismatch Repair
Codon
Immunohistochemistry
Papillary Carcinoma
Missense Mutation
Histology
Proteins

Keywords

  • BRAF
  • gallbladder adenocarcinoma
  • Gallbladder adenoma
  • KRAS
  • pyloric gland adenoma

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Histology
  • Medical Laboratory Technology

Cite this

Mutations in the RAS/RAF/MAP kinase pathway commonly occur in gallbladder adenomas but are uncommon in gallbladder adenocarcinomas. / Pai, Reetesh K.; Pai, Rish; Mojtahed, Kaveh.

In: Applied Immunohistochemistry and Molecular Morphology, Vol. 19, No. 2, 01.03.2011, p. 133-140.

Research output: Contribution to journalArticle

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abstract = "The role of gallbladder adenomas in the pathogenesis of gallbladder carcinoma is still controversial. Comparison of the genetic abnormalities seen in adenomas may provide insight into the potential role of gallbladder adenomas as precursor lesions to gallbladder carcinoma. The purpose of this study was to evaluate gallbladder carcinomas, gallbladder adenomas, and high-grade dysplastic lesions for the BRAF and the KRAS mutations and the mismatch repair protein abnormalities. We analyzed 29 gallbladder carcinomas (9 papillary and 20 nonpapillary adenocarcinomas), 16 adenomas (6 pyloric, 3 intestinal, 3 biliary, 3 mixed pyloric-biliary, and 1 mixed pyloric-intestinal), and 5 cases of high-grade dysplasia for activating missense mutations in KRAS codons 12 and 13 and BRAF V600E mutations. Mismatch repair protein immunohistochemistry for MLH1, MSH2, MSH6, and PMS2 was also carried out. KRAS mutations were infrequently identified in gallbladder carcinoma (2/29, 7{\%}) and high-grade dysplastic lesions (0/5, 0{\%}). Compared with gallbladder carcinoma and high-grade dysplastic lesions, gallbladder adenomas frequently showed KRAS codon 12 mutations (5/16, 31{\%}) (P=0.02). Adenomas with pyloric-type histology harbored KRAS mutations more often (4/10, 40{\%}) than other histologic subtypes (1/6, 17{\%}). Adenomas rarely showed BRAF mutations (1/16, 6{\%}), and no cases of gallbladder carcinoma or high-grade dysplasia were positive for BRAF mutations. Both the adenomas and the carcinomas displayed intact expression of mismatch repair proteins by immunohistochemistry. The presence of frequent mutations in the RAS/RAF/MAPK pathway in the gallbladder adenomas compared with the gallbladder carcinomas suggest that the adenomas and the gallbladder carcinomas arise through distinctly different molecular pathways.",
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