Projects per year
Introduction: Small intestinal neuroendocrine tumours (siNETs) are rare neoplasms which present with low mutational burden and can be subtyped based on copy number variation (CNV). Currently, siNETs can be molecularly classified as having chromosome 18 loss of heterozygosity (18LOH), multiple CNVs (MultiCNV), or no CNVs. 18LOH tumours have better progression-free survival when compared to MultiCNV and NoCNV tumours, however, the mechanism underlying this is unknown, and clinical practice does not currently consider CNV status.
Methods: Here, we use genome-wide tumour DNA methylation (n = 54) and gene expression (n = 20 matched to DNA methylation) to better understand how gene regulation varies by 18LOH status. We then use multiple cell deconvolution methods to analyse how cell composition varies between 18LOH status and determine potential associations with progression-free survival.
Results: We identified 27,464 differentially methylated CpG sites and 12 differentially expressed genes between 18LOH and non-18LOH (MultiCNV + NoCNV) siNETs. Although few differentially expressed genes were identified, these genes were highly enriched with the differentially methylated CpG sites compared to the rest of the genome. We identified differences in tumour microenvironment between 18LOH and non-18LOH tumours, including CD14+ infiltration in a subset of non-18LOH tumours which had the poorest clinical outcomes.
Conclusions: We identify a small number of genes which appear to be linked to the 18LOH status of siNETs, and find evidence of potential epigenetic dysregulation of these genes. We also find a potential prognostic marker for worse progression-free outcomes in the form of higher CD14 infiltration in non-18LOH siNETs.
Bibliographical noteFunding Information:
S.W. is supported by Cancer Research UK (C18281/A30905). P.Y., C.R., M.S., and S.W. are supported via the following: Medical Research Council Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/5) and the Cancer Research UK Integrative cancer epidemiology programme (C18281/A29019). CT was supported via the Cancer Research UK – Clinician Scientist Grant (2011–2016) for the duration in which the data were procured and processed.
© 2023 The Author(s).
FingerprintDive into the research topics of 'Chromosome 18 Loss of Heterozygosity in Small Intestinal Neuroendocrine Tumours: Multi-Omic and Tumour Composition Analyses'. Together they form a unique fingerprint.
- 1 Active
Sadaf R Alam (Manager), Steven A Chapman (Manager), Polly E Eccleston (Other), Simon H Atack (Other) & D A G Williams (Manager)