Molecular prognostic factors in small-intestinal neuroendocrine tumours

Abstract

Background Small-intestinal neuroendocrine tumours (SI-NETs) represent a heterogeneous group of rare tumours. In recent years, basic research in SI-NETs has attempted to unravel the molecular events underlying SI-NET tumorigenesis. Aim We aim to provide an overview of the current literature regarding prognostic and predictive molecular factors in patients with SI-NETs. Method A PubMed search was conducted on (epi)genetic prognostic factors in SI-NETs from 2000 until 2019. Results The search yielded 1522 articles of which 20 reviews and 35 original studies were selected for further evaluation. SI-NETs are mutationally quiet tumours with a different genetic make-up compared to pancreatic NETs. Loss of heterozygosity at chromosome 18 is the most frequent genomic aberration (44–100%) followed by mutations of CDKN1B in 8%. Prognostic analyses were performed in 16 studies, of which 8 found a significant (epi)genetic association for survival or progression. Loss of heterozygosity at chromosome 18, gains of chromosome 4, 5, 7, 14 and 20p, copy gain of the SRC gene and low expression of RASSF1A and P16 were associated with poorer survival. In comparison with genetic mutations, epigenetic alterations are significantly more common in SI-NETs and may represent more promising targets in the treatment of SI-NETs. Conclusion SI-NETs are mutationally silent tumours. No biomarkers have been identified yet that can easily be adopted into current clinical decision making. SI-NETs may represent a heterogeneous disease and larger international studies are warranted to translate molecular findings into precision oncology.

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

“…In this study, we aimed to investigate the presence of driver mutations in metastatic SI‐NETs and to explore their clinicopathological significance. We show that well‐differentiated SI‐NETs are mutationally quiet tumours with few genomic disruptions, which is in agreement with earlier studies (as reviewed in Samsom et al 15 . for SI‐NETs).…”

Clinical Features, Management, and Molecular Characteristics of Familial Small Bowel Neuroendocrine Tumors

“…Aside from genetic mutations, chromosomal analysis has also shown broad recurrent chromosomal aberrations. Loss of heterozygosity in chromosome 18 has been identified in up to 50% of SBNET ( 12 , 13 , 19 , 20 ). This frequent alteration has led to further investigation of tumor suppressor genes contained within chromosome 18 with conflicting conclusions.…”

“…TCEB3C is unique in that it is the only known imprinted gene on chromosome 18 and, as a potential tumor suppressor gene, could be more vulnerable to a single gene mutation than a non-imprinted gene ( 23 ). Survival analysis with these various loss of function mutations has also yielded conflicting results ( 12 ). Looking at the above studies, one can see that the only common finding is that there is frequently a loss of heterozygosity in chromosome 18 in SBNET, but the specific gene alteration is not consistent across studies.…”

“…Furthering this point, a recent study investigating multifocal disease in sporadic SBNET patients showed that primary tumors from the same patient could present with different distinct patterns of chromosome 18 allelic loss ( 24 ). Additional chromosomal alterations identified in SBNET have included copy number gains in chromosomes 4, 5, 14, and 20 ( 12 , 13 ). These chromosomal gains have also had unclear clinical significance with some studies finding an association with worse prognosis, while other studies have not seen any difference.…”

“…Epigenetic modifications have also commonly been identified in SBNET. Alterations in DNA methylation were identified in 65–82% of SBNET ( 12 ). SBNET epigenetic studies have most commonly shown hypermethylation in chromosome 18 gene sets and also in the promoter region of the gastric inhibitory polypeptide receptor.…”