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Driver mutations occur frequently in metastases of well‐differentiated small intestine neuroendocrine tumours
Author(s) -
Samsom Kris G,
Levy Sonja,
Veenendaal Linde M,
Roepman Paul,
Kodach Liudmila L,
Steeghs Neeltje,
Valk Gerlof D,
Wouter Dercksen M,
Kuhlmann Koert F D,
Verbeek Wieke H M,
Meijer Gerrit A,
Tesselaar Margot E T,
Berg José G
Publication year - 2021
Publication title -
histopathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.626
H-Index - 124
eISSN - 1365-2559
pISSN - 0309-0167
DOI - 10.1111/his.14252
Subject(s) - cdkn2a , kras , neuroblastoma ras viral oncogene homolog , stk11 , cancer research , bap1 , pdgfra , biology , mutation , medicine , gene , cancer , colorectal cancer , oncology , genetics , stromal cell , gist
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.