Assessment of copy number in protooncogenes are predictive of poor survival in advanced gastric cancer

Meihui Li,Woo Ho Kim,Tae-Shin Kim,Gyeong Hoon Kang,Nam-Yun Cho,Jeong Mo Bae,Younghoon Kim

doi:10.1038/s41598-021-91652-y

Meihui Li, Woo Ho Kim + Show 5 more

Open Access

https://doi.org/10.1038/s41598-021-91652-y

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Abstract

The copy number (CN) gain of protooncogenes is a frequent finding in gastric carcinoma (GC), but its prognostic implication remains elusive. The study aimed to characterize the clinicopathological features, including prognosis, of GCs with copy number gains in multiple protooncogenes. Three hundred thirty-three patients with advanced GC were analyzed for their gene ratios in EGFR, GATA6, IGF2, and SETDB1 using droplet dPCR (ddPCR) for an accurate assessment of CN changes in target genes. The number of GC patients with 3 or more genes with CN gain was 16 (4.8%). Compared with the GCs with 2 or less genes with CN gain, the GCs with 3 or more CN gains displayed more frequent venous invasion, a lower density of tumor-infiltrating lymphocytes, and lower methylation levels of L1 or SAT-alpha. Microsatellite instability-high tumors or Epstein–Barr virus-positive tumors were not found in the GCs with 3 or more genes with CN gain. Patients of this groups also showed the worst clinical outcomes for both overall survival and recurrence-free survival, which was persistent in the multivariate survival analyses. Our findings suggest that the ddPCR-based detection of multiple CN gain of protooncogenes might help to identify a subset of patients with poor prognosis.

Highlights

The copy number (CN) gain of protooncogenes is a frequent finding in gastric carcinoma (GC), but its prognostic implication remains elusive
A total of 333 advanced GC patients were analyzed for their gene ratios using droplet Digital polymerase chain reaction (dPCR) (ddPCR)
To determine the cut-off value of the gene ratios with prognostic utility, we partitioned the GC patients into 10 subsets according to the gene ratios and performed survival analysis, which revealed that subset 10 with the highest gene ratios for EGFR, FGFR1, GATA6, IGF2, and SETDB1 was associated with worse clinical outcomes in patients with GC

Summary

Introduction

The copy number (CN) gain of protooncogenes is a frequent finding in gastric carcinoma (GC), but its prognostic implication remains elusive. The study aimed to characterize the clinicopathological features, including prognosis, of GCs with copy number gains in multiple protooncogenes. Microsatellite instability-high tumors or Epstein–Barr virus-positive tumors were not found in the GCs with 3 or more genes with CN gain Patients of this groups showed the worst clinical outcomes for both overall survival and recurrence-free survival, which was persistent in the multivariate survival analyses. Through the TCGA project, many genes have been found to be amplified or undergo copy number gain, including EGFR, FGFR1, GATA6, HER2 (ERBB2), IGF2, MYC, and SETDB1 in GCs2. We aimed to elucidate whether copy number changes in seven genes (EGFR, FGFR1, GATA6, HER2, IGF2, MYC, and SETDB1) are related to the survival of patients with advanced GC and might serve to detect a subset of GC cases with poor prognosis. We used droplet dPCR (ddPCR) to evaluate the copy number changes of the seven genes in formalin-fixed, paraffin embedded tissue samples of advanced GC

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