Genomic heterogeneity and clinical implications in gastrointestinal neuroendocrine carcinoma: MYC and KRAS as predictive biomarkers

Abstract

Background

Gastrointestinal neuroendocrine carcinoma (GI-NEC) is a highly lethal malignancy with significant clinical and molecular heterogeneities. Given its rarity, large-scale studies are lacking, and research on its genomic landscape remains limited. Consequently, to date, no reliable biomarkers for treatment selection and prognosis have been identified. To address this gap in knowledge, we investigated the clinical impact of genomic features on GI-NEC.

Methods

We retrospectively analyzed 261 patients with advanced or recurrent GI-NEC using a nationwide comprehensive genomic profiling database. We analyzed the correlation between platinum-based chemotherapy and the clinical outcomes in 152 patients, focusing on time to treatment failure and overall survival. We integrated the sequencing data with clinical information to identify potential biomarkers predictive of chemotherapy efficacy and survival.

Results

In the GI-NECs analyzed, TP53 (85.8%) and RB1 (38.7%) were the most frequently mutated genes. Genetic alterations varied according to the primary tumor site, exhibiting co-occurring and mutually exclusive mutations. Notably, RB1 deficiency and CCNE1 amplification were mutually exclusive, particularly in esophageal and gastric NEC. MYC amplification was associated with a shorter time to treatment failure (P = 0.050), while KRAS alterations were significantly associated with a shorter overall survival (P = 0.001) in recurrent or unresectable GI-NECs.

Conclusion

This study underscored the clinical and genomic heterogeneity of GI-NEC and highlighted the need to integrate genomic and clinical data to achieve personalized medicine. MYC amplification and KRAS alterations may serve as valuable predictors of treatment response and prognosis in patients with GI-NEC.