title: Heterogeneous distribution of EGFR mutations is extremely rare in lung adenocarcinoma.
abstract: OBJECTIVE
  Some studies have shown that epidermal growth factor receptor (EGFR) mutations can be heterogeneously distributed in individual tumors. In this study, we re-evaluated the distribution of EGFR mutations within tumors.
  
  
  METHODS
  We used multiple approaches, including an analysis of simultaneous dual hot spot mutations, a trans-sectional analysis of individual lung adenocarcinomas, and comparisons of the mutation patterns between primary and metastatic sites and between primary and recurrent tumors.
  
  
  RESULTS
  None of the 862 tumors harboring an EGFR mutation showed simultaneous dual hot spot mutations, although identical EGFR mutations were found throughout individual tumors in a trans-sectional analysis involving 50 tumors divided into three parts and five lung adenocarcinomas divided into 100 parts. In addition, no discordant mutation patterns were detected among 77 paired primary and metastatic site samples or among 54 primary and recurrent tumor pairs.
  
  
  CONCLUSIONS
  All of these results suggest that the heterogeneous distribution of EGFR mutations is extremely rare. However, it is possible that pseudoheterogeneity occurs because of a combination of mutant allele-specific imbalance and heterogeneously distributed EGFR amplification, especially when a less sensitive method is used for detection. Specifically, when EGFR amplification occurs, the mutant allele is amplified, and this amplification is involved in invasive growth. Accordingly, invasive growth area significantly over-represents the mutation signal. In contrast, weak EGFR mutation signals in the area without EGFR amplification may not reach the threshold of detection because of the mixture with normal cells. Such unbalanced mutation signals might lead to pseudoheterogeneity.
authors: Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan. yyatabe@aichi-cc.jp
authors: Yasushi
authors: Y
authors: Yatabe
authors: Keitaro
authors: K
authors: Matsuo
authors: Tetsuya
authors: T
authors: Mitsudomi
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000556:secondary; D000328:Adult; D000368:Aged; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics
chemical_list: D066246:ErbB Receptors