Genomic profiling of esophageal squamous cell carcinoma (ESCC)-Basis for precision medicine.

PURPOSE: Preparing for precision medicine, we surveyed genomic alterations in esophageal squamous cell carcinoma (ESCC) and identified candidate therapeutic targets by genomic profiling using next-generation sequencing (NGS).

MATERIALS AND METHODS: Single-nucleotide variations, indels, and copy number variations in 80 genes were evaluated by targeted deep sequencing in 24 surgically resected ESCC specimens. Immunohistochemistry analyses and silver in situ hybridization for ERBB2 (HER2) were conducted to verify the NGS results. Associations between clinicopathological factors and detected genomic alterations were estimated.

RESULTS: The mean coverage of sequencing of the tumor tissues from 24 patients was 464.8X with 85.1% over 100X. We detected a total of 115 genetic alterations and more than one genetic alteration was detected in most patients (23/24, 95.8%). Genes with genetic alterations detected in more than 20% of cases included TP53 (20/24, 83%), NOTCH1 (7/24, 29%), and MTOR (6/24, 25%). Amplification of 7 genes was detected in 8 cases. Genes showing amplification included AKT2 (1/24, 4.2%), EGFR (2/24, 8.3%), ERBB2 (HER2; 1/24, 4.2%), FGFR1 (1/24, 4.2%), KRAS (1/24, 4.2%), MDM2 (1/24, 4.2%), and PIK3CA (1/24, 4.2%). The ERBB2 alteration was confirmed by immunohistochemistry and silver in situ hybridization. Patients with NF1 and ARID1A mutations were younger than the patients without the mutations. (p=0.024 and 0.014, respectively). NOTCH1 mutation and EGFR genetic alteration were associated with a larger tumor size (p=0.019) and lesser invasion depth (p=0.005), respectively.

CONCLUSION: This study revealed the genetic profiles of ESCC, which may provide a foundation for the development of novel targeted therapy and precision medicine.