Cancer Res Treat.  2025 Apr;57(2):492-506. 10.4143/crt.2024.667.

Presence of RB1 or Absence of LRP1B Mutation Predicts Poor Overall Survival in Patients with Gastric Neuroendocrine Carcinoma and Mixed Adenoneuroendocrine Carcinoma

• Song IH
• Ahn B
• Park YS
• Kim DH
• Hong SM

• KMID: 2566866
• DOI: http://doi.org/10.4143/crt.2024.667

Abstract

Purpose
Neuroendocrine carcinomas (NECs) of the stomach are extremely rare, but fatal. However, our understanding of the genetic alterations in gastric NECs is limited. We aimed to evaluate genomic and clinicopathological characteristics of gastric NECs and mixed adenoneuroendocrine carcinomas (MANECs).
Materials and Methods
Fourteen gastric NECs, three gastric MANECs, and 1,381 gastric adenocarcinomas were retrieved from the departmental next-generation sequencing database between 2017 and 2022. Clinicopathological parameters and next-generation sequencing test results were retrospectively collected and reviewed.
Results
Gastric NECs and MANECs frequently harbored alterations of TP53, RB1, SMARCA4, RICTOR, APC, TOP1, SLX4, EGFR, BRCA2, and TERT. In contrast, gastric adenocarcinomas exhibited alterations of TP53, CDH1, LRP1B, ARID1A, ERBB2, GNAS, CCNE1, NOTCH, and MYC. Mutations of AKT3, RB1, and SLX4; amplification of BRCA2 and RICTOR; and deletion of ADAMTS18, DDX11, KLRC3, KRAS, MAX, NFKBIA, NUDT7, and RB1 were significantly more frequent in gastric NECs and MANECs than in gastric adenocarcinomas. The presence of LRP1B mutation was significantly associated with longer overall survival (OS), whereas RB1 mutation and advanced TNM stage were associated with shorter OS.
Conclusion
We identified frequently mutated genes and potential predictors of survival in patients with gastric NECs and MANECs.

Keyword

Stomach neoplasms; Carcinoma; Neuroendocrine tumors; RB1; Survival

Figure

• 

  Fig. 1. Representative microscopic images of gastric neuroendocrine carcinomas (NECs) and mixed adenoneuroendocrine carcinomas (MANECs). (A) Small cell gastric NEC exhibits compactly arranged tumor cells with hyperchromatic nuclei, little cytoplasm, and nuclear molding (H&E, ×600). The tumor cells are weakly positive for synaptophysin by immunohistochemistry and show Ki-67 labeling index of > 90%. (B) Large cell gastric NEC consists of tumor cells showing abundant cytoplasm and prominent nucleoli. Mitotic figures are frequently seen (arrows) (H&E, ×600). The tumor cells are diffusely positive for chromogranin A by immunohistochemistry and show Ki-67 labeling index of approximately 50%. (C) Gastric MANEC composed of two different components, poorly differentiated adenocarcinoma and small cell NEC. Poorly differentiated adenocarcinoma component exhibits poorly formed glandular structures and intracytoplasmic and extracellular mucin production. In contrast, small cell NEC component shows no glandular differentiation but solid arrangement of tumor cells with hyperchromatic nuclei, little cytoplasm, nuclear molding, and frequent mitotic figures (H&E, ×600). The NEC component shows diffuse insulinoma-associated protein 1 (INSM-1) immunolabelling, which supports neuroendocrine differentiation.

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  Fig. 2. OncoPrint plot for gastric neuroendocrine carcinomas (NECs) and mixed adenoneuroendocrine carcinomas (MANECs). TP53, RB1, and SMARCA4 are the three most frequently altered genes. CNA, copy number alteration; OS, overall survival.

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  Fig. 3. Comparison of genetic alterations detected by next-generation sequencing between gastric neuroendocrine carcinoma (NEC) or mixed adenoneuroendocrine carcinoma (MANEC) and gastric adenocarcinoma. (A) Total number of small-scale mutations in each case. (B) Total number of copy number alterations in each case, including amplification and loss. (C) Frequency of small-scale mutations. (D) Frequency of gene amplifications. (E) Frequency of homozygous deletions. *p < 0.05, **q < 0.05.

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  Fig. 4. Comparison of genetic alterations detected by next-generation sequencing of gastric neuroendocrine carcinoma or mixed adenoneuroendocrine carcinoma between survival groups. (A) Total number of small-scale mutations per case. (B) Total number of copy number alterations per case, including amplification and loss. (C) Frequency of small-scale mutations. (D) Frequency of gene amplifications. (E) The longer overall survival group seemed to harbor more frequent homozygous deletions of multiple genes than the shorter overall survival group, but these were not statistically significant. *p < 0.10, **p < 0.05.

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  Fig. 5. Kaplan-Meier curve of overall survival in patients with gastric neuroendocrine carcinoma (NEC) and mixed adenoneuroendocrine carcinoma (MANEC). Each is in relation to TNM stage and genetic alterations (A), including copy number alteration (CNA) (B), LRP1B mutation (C), RB1 mutation (D), BRCA2 amplification (E), AURKA amplification (F), and LRP1B or RB1 mutation (G).

Reference

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