Clonality analysis of synchronous gastroesophageal junction carcinoma and distal gastric cancer by whole-exome sequencing

ABSTRACT

Gastroesophageal junction (GEJ) carcinoma and distal gastric cancer (GC) have distinct epidemiology and clinical features and their relationship is uncertain. Synchronous multiple gastric cancers located mostly at proximal and distal sites provide rare specimens for investigating the comprehensive genomic relationships among these cancers in the context of identical genetic circumstances. Formalin-fixed, paraffin-embedded (FFPE) samples from 12 patients with synchronous GEJ carcinoma and distal GC were collected in this study. Whole-exome sequencing (WES) was performed using normal tissues as a control. Mutational profiling, clonality analysis, a detailed clinico-pathological review, determination of MSI status, EBER in situ hybridization (ISH), and PD1/PD-L1 immunohistochemical staining were performed. Twenty-three of the 24 samples were microsatellite stable (MSS). Subclonal analysis revealed that 9 pairs of GEJ and distal GC tumors in neoadjuvant chemotherapy naïve patients developed independently from different origins. Two patients who received neoadjuvant chemotherapy shared clonal origins with highly similar somatic alterations. The remaining 1 patient who shared a rare mutation died within 6.2 months at the N3 stage. However, the enriched pathway identified from the overall mutation spectra in distal GC and GEJ carcinoma showed the close relationship of these cancers. Thus, although these cancers may have similar characteristics, histopathologic and genetic profiling from single tumor specimens may still underestimate the mutational burden and somatic heterogeneity of multiple GCs. In addition, this series of cases also showed a PDL1 expression rate of 58.3% and 66.7% in distal GC and GEJ carcinoma, respectively, with all the cases expressing PD1. This result suggests the potential benefit of immuno-therapeutic treatments.

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