Gastric Poorly Cohesive Carcinoma: A correlative study of mutational signatures and prognostic significance based on histopathologic subtypes

Abstract

Aims

Genome-wide next-generation sequencing has revealed several driver mutations and allows establishing a molecular taxonomy of gastric cancer. However, correlation between the broad mutational spectrum of gastric cancer and its various clinicopathological characteristics has yet to be fully elucidated.

Methods and Results

Herein, we analyzed the mutational pattern of 77 genes in a cohort of 91 patients with poorly cohesive carcinoma using targeted sequencing and evaluated the clinicopathological significance of the various mutations based its histologic pattern, either signet ring cell (SRC) or other types of poorly cohesive carcinoma (not otherwise specified) (PCC-NOS). A panel of seven (PIK3CA, CDH1, PTEN, RHOA, HDCA9, KRAS, and ATM), three (PIK3CA, CTNNB1, and KRAS), and two (HDCA9 and IGF1R) genes were associated with a diffuse infiltrative growth pattern, lymphovascular invasion, and perineural invasion, respectively. Furthermore, PDGFRB mutations were associated with a favorable prognosis, whereas MET mutations were associated with a poor prognosis. PCC-NOS predominant types was associated with a greater depth of invasion, lymph node metastasis, and poorer prognosis than SRC predominant type. Mutations in TP53, BRAF, PI3CA, SMAD4, and RHOA were associated with PCC-NOS. Interestingly, RHOA-mutated gastric cancer exhibited a distinct morphology as they were characterized by a superficial signet ring cells or tubular component and deep invasive PCC-NOS component with desmoplasia.

Conclusions

Taken together, our findings show that gastric poorly cohesive carcinomas demonstrate several mutational patterns which are associated with specific clinicopathologic characteristics and particularly exhibit distinct morphologic findings when associated with RHOA mutation.

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