Analysis of perioperative chemotherapy-mediated genomic changes in gastric cancer

TL;DR

This study examines how perioperative chemotherapy affects genomic changes in gastric cancer, finding that most oncogenic mutations persist through treatment and recurrence.

Contribution

The study identifies genomic stability of oncogenic mutations during perioperative chemotherapy and their persistence in recurrent tumors.

Findings

Most oncogenic mutations (TP53, CDH1, KRAS, etc.) remained after neoadjuvant chemotherapy.

Some low-frequency mutations were lost or gained, and new mutations emerged post-surgery.

MAPK signaling pathway genes were overexpressed in non-recurrent cases.

Abstract

Surgery remains the mainstay of treatment for advanced gastric cancer, but in recent years perioperative chemotherapy has been administered in an attempt to improve treatment results. The Cancer Genome Atlas (TCGA) has illuminated the molecular landscape of gastric cancer. However, genomic changes before and after perioperative chemotherapy and the associated effects on treatment resistance remain unclear. This study aimed to clarify genomic change in gastric cancers treated with perioperative chemotherapy.

Of the 532 patients who underwent gastrectomy for gastric cancer between January 2015 and December 2020, this study included eight patients who received neoadjuvant chemotherapy (NAC). We collected biopsy samples before NAC and surgical samples after NAC. Recurrent tumor biopsy samples after adjuvant chemotherapy were also collected in two cases. DNA and RNA were extracted from these samples and analyzed by next-generation sequencing.

Most of the oncogenic mutations found before NAC (TP53, CDH1, KRAS, PIK3CA, RNF43, and SMAD4) were also found in the post-NAC surgical sample. Several gene mutations with low allele frequency were lost or gained. In the recurrent biopsy samples, gene mutations shared before NAC and after NAC were also detected. In addition, some gene mutations were acquired as new mutations following surgery. Gene expression analysis showed genes related to the MAPK signaling pathway were overexpressed in the group without recurrence.

Most of the oncogenic mutations were maintained throughout perioperative chemotherapy and remained in recurrent tumors. The development of drugs that affect oncogenic mutations during perioperative chemotherapy is required.

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