Progressive epigenetic dysregulation in neuroendocrine tumour liver metastases
- Anna Karpathakis1,2,
- Harpreet Dibra1,
- Christodoulos Pipinikas1,
- Andrew Feber1,
- Tiffany Morris1,
- Joshua Francis3,
- Dahmane Oukrif1,
- Dalvinder Mandair1,2,
- Marinos Pericleous2,
- Mullan Mohmaduvesh2,
- Stefano Serra4,
- Olagunju Ogunbiyi2,
- Marco Novelli1,
- TuVinh Luong2,
- Sylvia L Asa4,
- Matthew Kulke5,
- Christos Toumpanakis2,
- Tim Meyer1,2,
- Martyn Caplin2,
- Stephan Beck1 and
- Christina Thirlwell1,2⇑
- 1University College London, London, UK
- 22The Royal Free Hospital, London, UK
- 3The Broad Institute, Boston, Massachusetts, USA
- 4UHN Princess Margaret Cancer Centre, Toronto, Ontario, Canada
- 5DanaFaber Cancer Institute, Boston, Massachusetts, USA
- Correspondence should be addressed to C Thirlwell; email: christina.thirlwell{at}ucl.ac.uk
Dear Editor,
The incidence of small intestinal neuroendocrine tumours (SINETs) is increasing and distant metastases are present at diagnosis in 70% of cases, the liver being the commonest site of metastasis (Yao et al. 2008). Despite this, our understanding of the mechanisms underlying metastatic progression of SINETs is currently limited, and prior studies of the molecular biology of SINET liver metastases (LM) have been performed predominantly in small cohorts utilising candidate-based techniques.
SINETs have a low rate of mutations compared to most cancers. The most frequently mutated gene is CDKN1B (encoding p27, a cell cycle regulator); however, mutations in this gene occur in only 8% of tumours, and there is no characteristic mutational hotspot (Francis et al. 2013). Furthermore, mutation of CDKN1B does not correlate with the expression of p27 (Crona et al. 2015). We previously identified that SINETs are epigenetically dysregulated, and a panel of candidate driver epimutation genes has been identified (Karpathakis et al. 2016). Therefore, we postulated that metastatic progression in SINETs may also be epigenetically regulated. Here, we present the findings from the largest molecular profiling study of SINET LM performed to date, integrating copy number variance (CNV), DNA methylation, and RNA expression profiling to characterise the mechanisms underlying metastatic progression.
Experimental details of DNA methylation, CNV and RNA expression profiling are as previously published (Karpathakis et al. 2016). Patients provided informed consent for their tissue to be analysed in this study, which was Research Ethics Committee approved (Ref: 09/H0722/27). All cases were reviewed by two expert NET histopathologists (TVL/MN). Nucleic acids were extracted using standard methods (Qiagen, QIAamp DNA Mini kit; Roche, High Pure RNA Paraffin kit). H&E-stained sections were evaluated to ensure >80% purity of tumour specimens. Methylation profiling was performed on the HumanMethylation450 BeadChip (HM450) (Illumina). Methylation data were analysed …
