Journal Article

High-Throughput Genotyping in Metastatic Esophageal Squamous Cell Carcinoma Identifies Phosphoinositide-3-Kinase and BRAF Mutations

van Hummelen, Paul, Shim, Young-Mog, Palescandolo, Emanuele, Park, Ha Young, MacConaill, Laura, Kim, Kyoung-Mee, Lee, Jeeyun, Kang, So Young, Jang, Jiryeon, Maeng, Chi Hoon, Park, Se Hoon

2012

Overview

Given the high incidence of metastatic esophageal squamous cell carcinoma, especially in Asia, we screened for the presence of somatic mutations using OncoMap platform with the aim of defining subsets of patients who may be potential candidate for targeted therapy. We analyzed 87 tissue specimens obtained from 80 patients who were pathologically confirmed with esophageal squamous cell carcinoma and received 5-fluoropyrimidine/platinum-based chemotherapy. OncoMap 4.0, a mass-spectrometry based assay, was used to interrogate 471 oncogenic mutations in 41 commonly mutated genes. Tumor specimens were prepared from primary cancer sites in 70 patients and from metastatic sites in 17 patients. In order to test the concordance between primary and metastatic sites from the patient for mutations, we analyzed 7 paired (primary-metastatic) specimens. All specimens were formalin-fixed paraffin embedded tissues and tumor content was >70%. In total, we have detected 20 hotspot mutations out of 80 patients screened. The most frequent mutation was PIK3CA mutation (four E545K, five H1047R and one H1047L) (N = 10, 11.5%) followed by MLH1 V384D (N = 7, 8.0%), TP53 (R306, R175H and R273C) (N = 3, 3.5%), BRAF V600E (N = 1, 1.2%), CTNNB1 D32N (N = 1, 1.2%), and EGFR P733L (N = 1, 1.2%). Distributions of somatic mutations were not different according to anatomic sites of esophageal cancer (cervical/upper, mid, lower). In addition, there was no difference in frequency of mutations between primary-metastasis paired samples. Our study led to the detection of potentially druggable mutations in esophageal SCC which may guide novel therapies in small subsets of esophageal cancer patients.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adaptor Proteins, Signal Transducing - genetics / Adaptor Proteins, Signal Transducing - metabolism / Adult / Aged / Amino Acid Substitution / Analysis / Biology / Brain cancer / Cancer / Cancer metastasis / Cancer therapies / Carcinoma, Squamous Cell - drug therapy / Carcinoma, Squamous Cell - genetics / Carcinoma, Squamous Cell - metabolism / Carcinoma, Squamous Cell - mortality / Cervix / Chemotherapy / Class I Phosphatidylinositol 3-Kinases / Disease-Free Survival / Epidermal growth factor receptors / Esophageal cancer / Esophageal Neoplasms - drug therapy / Esophageal Neoplasms - genetics / Esophageal Neoplasms - metabolism / Esophageal Neoplasms - mortality / Esophageal Neoplasms - pathology / Esophagus / Female / Formaldehyde / Gene mutation / Genes / Genetic aspects / Genomes / Genotyping / Hematology / Humans / Kinases / Male / Medical prognosis / Medicine / Melanoma / Metastases / Metastasis / Middle Aged / MLH1 protein / Mutation / Mutation hot spots / Mutation, Missense / MutL Protein Homolog 1 / Neoplasm Metastasis / Nuclear Proteins - genetics / Nuclear Proteins - metabolism / Oncology / p53 Protein / Paraffin / Pathology / Patients / Phosphatidylinositol 3-Kinases - genetics / Phosphatidylinositol 3-Kinases - metabolism / Platinum / Proto-Oncogene Proteins B-raf - genetics / Proto-Oncogene Proteins B-raf - metabolism / Pyrimidines - administration & dosage / Spectrometry / Squamous cell carcinoma / Survival Rate / Systematic review / Thoracic surgery / Tissues / Tumor proteins / Tumor Suppressor Protein p53 - genetics / Tumor Suppressor Protein p53 - metabolism / Tumors