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Cold Spring Harb Mol Case Stud. 2018 Feb 1;4(1). pii: a002329. doi: 10.1101/mcs.a002329. Print 2018 Feb.

Molecular characterization of metastatic pancreatic neuroendocrine tumors (PNETs) using whole-genome and transcriptome sequencing.

Author information

1
Division of Medical Oncology, BC Cancer Agency, Vancouver, British Columbia V5Z 4E6, Canada.
2
Pancreas Centre BC, Vancouver, British Columbia V5Z 4E6, Canada.
3
Department of Molecular Biology and Biochemistry, Simon Fraser University, Vancouver, British Columbia V5A 1S6, Canada.
4
Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 4S6, Canada.
5
Division of Anatomical Pathology, Vancouver General Hospital, Vancouver, British Columbia V5Z 1M9, Canada.
6
Vancouver Island Centre, British Columbia Cancer Agency, Vancouver, British Columbia V8R 6V5, Canada.
7
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
#
Contributed equally

Abstract

Pancreatic neuroendocrine tumors (PNETs) are a genomically and clinically heterogeneous group of pancreatic neoplasms often diagnosed with distant metastases. Recurrent somatic mutations, chromosomal aberrations, and gene expression signatures in PNETs have been described, but the clinical significance of these molecular changes is still poorly understood, and the clinical outcomes of PNET patients remain highly variable. To help identify the molecular factors that contribute to PNET progression and metastasis, and as part of an ongoing clinical trial at the BC Cancer Agency (clinicaltrials.gov ID: NCT02155621), the genomic and transcriptomic profiles of liver metastases from five patients (four PNETs and one neuroendocrine carcinoma) were analyzed. In four of the five cases, we identified biallelic loss of MEN1 and DAXX as well as recurrent regions with loss of heterozygosity. Several novel findings were observed, including focal amplification of MYCN concomitant with loss of APC and TP53 in one sample with wild-type MEN1 and DAXX Transcriptome analyses revealed up-regulation of MYCN target genes in this sample, confirming a MYCN-driven gene expression signature. We also identified a germline NTHL1 fusion event in one sample that resulted in a striking C>T mutation signature profile not previously reported in PNETs. These varying molecular alterations suggest different cellular pathways may contribute to PNET progression, consistent with the heterogeneous clinical nature of this disease. Furthermore, genomic profiles appeared to correlate well with treatment response, lending support to the role of prospective genotyping efforts to guide therapy in PNETs.

KEYWORDS:

neoplasm of the gastrointestinal tract; neuroendocrine neoplasm

PMID:
29092957
PMCID:
PMC5793777
DOI:
10.1101/mcs.a002329
[Indexed for MEDLINE]
Free PMC Article

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