Genetic and epigenetic prognosticators of neuroendocrine tumours of the GI tract, liver, biliary tract and pancreas: A systematic review and meta‐analysis

Abstract

Multiple recurrent genetic and epigenetic aberrations have been associated with worse prognosis in multiple studies of neuroendocrine tumours (NETs), but these have been mainly small cohorts and univariate analysis. This review and meta‐analysis will focus upon the literature available on NETs of the gastrointestinal (GI) tract, liver, biliary tract and pancreas. PubMed and Embase were searched for publications that investigated the prognostic value of (epi)genetic changes of neuroendocrine tumours. A meta‐analysis was performed assessing the association of the (epi)genetic alterations with overall survival (OS), disease‐free survival (DFS) or locoregional control (LRC). In the pancreas DAXX/ATRX [hazard ratio (HR) = 3.29; 95% confidence interval (CI) = 2.28–4.74] and alternative lengthening telomeres (ALT) activation (HR = 8.20; 95% CI = 1.40–48.07) showed a pooled worse survival. In the small bowel NETs gains on chromosome 14 were associated with worse survival (HR 2.85; 95% CI = 1.40–5.81). NETs from different anatomical locations must be regarded as different biological entities with diverging molecular prognosticators, and epigenetic changes being important to the pathogenesis of these tumours. This review underpins the prognostic drivers of pancreatic NET which lie in mutations of DAXX/ATRX and ALT pathways. However, there is reaffirmation that prognostic molecular biomarkers of small bowel NETs should be sought in copy number variations (CNVs) rather than in single nucleotide variations (SNVs). This review also reveals how little is known about the prognostic significance of epigenetics in NETs.

Molecular Classification of Gastrointestinal and Pancreatic Neuroendocrine Neoplasms: Are We Ready for That?

“…This is related not only to the alteration of specific genes involved in the pathogenesis but also to genome-wide differences, including tumor mutational burden (TMB), the number of single-nucleotide variants (SNV) and multiple nucleotide variants (MNV), microsatellite instability (MSI), and ploidy and copy number variations (CNV) [ 32 – 36 ]. Moreover, epigenetic alterations are also differentially involved in NET and NEC [ 37 ]. In general, NEC of the digestive sites and NEC of other anatomical sites are most frequently characterized by mutations of TP53 and RB1 , together with other key driver genes, including, but not limited to, RAS family, APC , CDKN2A , and MYC [ 13 , 14 , 32 – 34 , 36 , 37 ].…”

“…Moreover, epigenetic alterations are also differentially involved in NET and NEC [ 37 ]. In general, NEC of the digestive sites and NEC of other anatomical sites are most frequently characterized by mutations of TP53 and RB1 , together with other key driver genes, including, but not limited to, RAS family, APC , CDKN2A , and MYC [ 13 , 14 , 32 – 34 , 36 , 37 ]. In addition, NEC display high genome instability, with diploid to triploid genome, a median TMB comparable to that of non-neuroendocrine aggressive carcinomas, high numbers of SNV and MNV, and frequent structural chromosomal alterations, including, in a subset of cases, the catastrophic event of chromothripsis [ 32 , 33 , 36 ].…”

“…There is increasing evidence supporting the view that the specific site of insurgence of a NEN, whether a NET or a NEC, is related to distinct pathogenetic events, possibly related to different local microenvironment and acting risk factors. This is detectable at a molecular level, with the involvement of specific genomic alterations [ 10 , 14 , 32 , 37 , 46 ], but also non-genomic mechanisms have been invoked, including, but not limited to, the composition of local microbiota [ 47 ], the interactions with stromal and inflammatory cells [ 48 ], and the action of specific local growth factors and growth factors receptors [ 49 ]. Details will be addressed in the paragraphs dedicated to each type of NEN.…”

Epigenetic developmental mechanisms underlying sex differences in cancer

“…In order to maintain their telomeres and immortality, 15% of cancers utilize a telomerase-independent mechanism, the ALT pathway, and ATRX is important in suppressing this pathway ( 53 ). ATRX mutations are more commonly present in male cancer overall ( 158 ) and in a number of cancers with sex differences in incidence and outcomes, including, glioblastoma, oligodendroglioma ( 159 , 160 ), gastric cancer ( 161 ), and nonfunctional neuroendocrine tumors of the pancreas and other sites ( 162 , 163 ), suggesting that biallelic ATRX expression may endow female cells with cancer protection.…”