Low incidence of KRAS, BRAF, and PIK3CA mutations in adenocarcinomas of the ampulla of Vater and their prognostic value

Hum Pathol. 2016 Apr:50:90-100. doi: 10.1016/j.humpath.2015.11.009. Epub 2015 Nov 30.

Abstract

Ampullary adenocarcinomas (A-ACs) are rare malignancies with considerable importance because of their high curable resection rate and improved survival rate among periampullary cancers. The RAS-RAF-MAPK pathway is involved in the development of A-ACs and is a potential therapeutic target. However, molecular profiles of A-ACs and their prognostic impact are poorly understood. Peptide nucleic acid-mediated polymerase chain reaction clamping and Mutyper were used to detect KRAS, BRAF, and PIK3CA mutations in 62 paraffinized samples of A-ACs. Of 62 A-ACs, 30.6% had KRAS mutations, but no BRAF mutations and low frequency (1.6%) of PIK3CA mutation were detected. KRAS mutation was correlated with poor tumor differentiation and was a predictor of shorter recurrence-free survival period in overall A-ACs, whereas the prognosis according to the histologic subtypes was not affected by KRAS mutation. Lymph node metastasis was an independent prognostic factor of poor overall survival. Intestinal- and pancreatobiliary-type A-ACs had similar prognosis. Intestinal- and pancreatobiliary-type A-ACs had different prognostic factors; tumor differentiation and lymph node metastasis strongly predicted overall survival and recurrence-free survival in pancreatobiliary-type tumors, respectively, whereas no independent prognostic factors were demonstrated for intestinal-type tumors. Low incidence of KRAS mutations and their strong prognostic value in A-ACs may suggest the potential of survival benefit depending on the epidermal growth factor receptor-targeted therapy. Much lower frequencies of BRAF and PIK3CA mutations may suggest that they do not play a major role in the tumorigenesis of A-ACs. Different therapeutic protocols should be considered for treating pancreatobiliary- and intestinal-type A-ACs.

Keywords: Adenocarcinoma; Ampulla of Vater; BRAF; KRAS; Mutation; PIK3CA; Prognosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics*
  • Adenocarcinoma / mortality
  • Adenocarcinoma / pathology
  • Adenocarcinoma / therapy
  • Adult
  • Aged
  • Aged, 80 and over
  • Ampulla of Vater* / pathology
  • Biomarkers, Tumor / genetics*
  • Cell Differentiation
  • Class I Phosphatidylinositol 3-Kinases
  • Common Bile Duct Neoplasms / genetics*
  • Common Bile Duct Neoplasms / mortality
  • Common Bile Duct Neoplasms / pathology
  • Common Bile Duct Neoplasms / therapy
  • DNA Mutational Analysis / methods
  • Disease-Free Survival
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Mutation*
  • Phenotype
  • Phosphatidylinositol 3-Kinases / genetics*
  • Polymerase Chain Reaction
  • Predictive Value of Tests
  • Proportional Hazards Models
  • Proto-Oncogene Proteins B-raf / genetics*
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Republic of Korea
  • Risk Factors
  • Time Factors
  • Treatment Outcome

Substances

  • Biomarkers, Tumor
  • KRAS protein, human
  • Phosphatidylinositol 3-Kinases
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins p21(ras)