title: Intratumor Heterogeneity of KRAS Mutation Status in Pancreatic Ductal Adenocarcinoma Is Associated With Smaller Lesions.
abstract: Recent studies have demonstrated intratumor heterogeneity (ITH) for genetic mutations in various tumors and suggest that ITH might have significant clinical impact. Because KRAS is the most commonly mutated oncogene in pancreatic ductal adenocarcinoma and has an important role in pancreatic carcinogenesis, the purpose of this study was to evaluate ITH for KRAS gene mutation and its clinical significance.
  
  
  
  Deep sequencing of 47 pancreatic ductal adenocarcinoma cases was used to determine the fraction of KRAS mutant alleles. In addition, computerized morphometry was used to calculate the fraction of tumor cells. After analysis of both results, cases were classified as ITH or as having amplification of mutant KRAS. The presence of ITH was correlated with clinical and pathological factors.
  
  
  
  KRAS mutation was found in 38 (81%) cases, of which 12 (32%) showed ITH and 9 (23%) were found to have KRAS mutant allele amplification. The presence of ITH was associated with smaller tumors, whereas amplification was associated with higher tumor diameter.
  
  
  
  In pancreatic ductal adenocarcinoma, ITH for KRAS gene mutation was associated with smaller tumors. It is possible that, as the tumor progresses, more cells carry this mutation, which leads to more aggressive tumor features.
authors.affiliation: From the *B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology; and †Institute of Pathology, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Sima S
authors.initials: SS
authors.lastname: Nagawkar
authors.forename: Samah
authors.initials: S
authors.lastname: Abu-Funni
authors.forename: Einav
authors.initials: E
authors.lastname: Simon
authors.forename: Tova
authors.initials: T
authors.lastname: Bick
authors.forename: Elad
authors.initials: E
authors.lastname: Prinz
authors.forename: Edmond
authors.initials: E
authors.lastname: Sabo
authors.forename: Ofer
authors.initials: O
authors.lastname: Ben-Izhak
authors.forename: Dov
authors.initials: D
authors.lastname: Hershkovitz
mesh_terms: D000368:Aged; D000704:Analysis of Variance; D001483:Base Sequence; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D005787:Gene Frequency; D018740:Genetic Heterogeneity; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010179:Pancreas / Q000378:metabolism* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D016019:Survival Analysis
chemical_list: C117307:KRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)