Driver mutations occur frequently in metastases of well-differentiated small intestine neuroendocrine tumours

Histopathology. 2021 Mar;78(4):556-566. doi: 10.1111/his.14252. Epub 2020 Nov 3.


Aims: To investigate the clinicopathological significance of driver mutations in metastatic well-differentiated small intestine neuroendocrine tumours (SI-NETs).

Methods and results: Whole genome sequencing (WGS) of 35 metastatic SI-NETs and next-generation sequencing (NGS) of eight metastatic SI-NETs were performed. Biopsies were obtained between 2015 and 2019. Tumours were classified according to the 2019 World Health Organization classification. WGS included assessment of somatic mutations in all cancer-related driver genes, the tumour mutational burden (TMB), and microsatellite status. NGS entailed a cancer hotspot panel of 58 genes. Our cohort consisted of 21% grade 1, 60% grade 2 and 19% grade 3 SI-NETs. Driver mutations were identified in ~50% of SI-NETs. In total, 27 driver mutations were identified, of which 74% were in tumour suppressor genes (e.g. TP53, RB1, and CDKN1B) and 22% were in proto-oncogenes (e.g. KRAS, NRAS, and MET). Allelic loss of chromosome 18 (63%), complete loss of CDKN2A and CDKN1B (both 6%) and CDKN1B mutations (9%) were most common. Potential targetable genetic alterations were detected in 21% of metastasised SI-NETs. All tumours were microsatellite-stable and showed low TMBs (median 1.10; interquartile range 0.87-1.35). The Ki67 proliferation index was significantly associated with the presence of driver mutations (P = 0.015).

Conclusion: Driver mutations occur in 50% of metastasised SI-NETs, and their presence is associated with a high Ki67 proliferation index. The identification of targetable mutations make these patients potentially eligible for targeted therapy.

Keywords: genetics; neuroendocrine tumour; small intestine; whole genome sequencing.

MeSH terms

  • Biomarkers, Tumor / genetics*
  • Cohort Studies
  • Female
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Intestinal Neoplasms / genetics*
  • Intestinal Neoplasms / pathology
  • Intestine, Small / pathology
  • Male
  • Mutation
  • Neuroendocrine Tumors / genetics*
  • Neuroendocrine Tumors / pathology
  • Sequence Analysis, DNA


  • Biomarkers, Tumor