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

Abstract

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.

Clinicopathological and genetic characteristics of gastric neuroendocrine tumour (NET) G3 and comparisons with neuroendocrine carcinoma and NET G2

“…6 However, mutation in another DNA damage repair gene, POLE, was detected in one gNET G3. In siNET, recurrently mutated genes are rare, 7,18 which was similar to our gNET G3 cases. The mutational landscape of gNET is obviously different from that of pan-NET and siNET, 6 supporting the site specificity of NET and the necessity of molecular research for each organ.…”

“…Recently, NET G3 was proposed to originate from NET G1/2 owing to similar genetic alterations, but is clearly different NEC, in which TP53 and RB1 mutations are more frequent 4,5 . However, the majority of previous studies investigated gastroenteropancreatic neuroendocrine neoplasms (GEP‐NENs) collectively or focused upon pancreatic or small intestinal NENs independently 6,7 . Overall, there is a lack of systematic investigation of the molecular characteristics of gastric NET G3 (gNET G3) and comparative studies among gastric NEN (gNEN) samples based on high‐throughput technologies.…”

CD3+, CD8+, CD4+ and FOXP3+ T Cells in the Immune Microenvironment of Small Bowel Neuroendocrine Tumors

“…High mutational burden is often associated with a stronger host immune response since they are "altered self" and immune tolerance has not developed [11,19,23,24,27]. A recent study found driver mutations (27 mutations in total, including TP53, RB1, CDKN1B, KRAS and NRAS mutations) occurring in 50% of metastasized SB-NETs but no difference in survival was seen in patients with or without these mutations [28].…”

Biology-guided precision medicine in rare cancers: Lessons from sarcomas and neuroendocrine tumours

“…These discoveries may help predict the clinical behaviour of sporadic pNET and hopefully develop new biomarkers predicting response to everolimus or other targeted agents, including peptide receptor radionuclide therapy. Although it was previously thought that driver mutations were exclusively found in high-grade neuroendocrine carcinoma, a recent study identified driver mutations in about 50 % of SI-NET, of which the majority affected tumour suppressor genes such as TP53, RB1, and CDKN1B; however, potentially targetable alterations were detected in 21 % of patients with metastatic SI-NET [100]. In general, NET have a low mutational burden, which may render these tumours less sensitive to immune checkpoint inhibition.…”