Recurrent loss of heterozygosity correlates with clinical outcome in pancreatic neuroendocrine cancer

Abstract

Pancreatic neuroendocrine tumors (pNETs) are uncommon cancers arising from pancreatic islet cells. Here we report the analysis of gene mutation, copy number, and RNA expression of 57 sporadic well-differentiated pNETs. pNET genomes are dominated by aneuploidy, leading to concordant changes in RNA expression at the level of whole chromosomes and chromosome segments. We observed two distinct patterns of somatic pNET aneuploidy that are associated with tumor pathology and patient prognosis. Approximately 26% of the patients in this series had pNETs with genomes characterized by recurrent loss of heterozygosity (LoH) of 10 specific chromosomes, accompanied by bi-allelic MEN1 inactivation and generally poor clinical outcome. Another ~40% of patients had pNETs that lacked this recurrent LoH pattern but had chromosome 11 LoH, bi-allelic MEN1 inactivation, and universally good clinical outcome. The somatic aneuploidy allowed pathogenic germline variants (e.g., ATM) to be expressed unopposed, with RNA expression patterns showing inactivation of downstream tumor suppressor pathways. No prognostic associations were found with tumor morphology, single gene mutation, or expression of RNAs reflecting the activity of immune, differentiation, proliferative or tumor suppressor pathways. In pNETs, single gene mutations appear to be less important than aneuploidy, with MEN1 the only statistically significant recurrently mutated driver gene. In addition, only one pNET in the series had clearly actionable single nucleotide variants (SNVs) (in PTEN and FLCN) confirmed by corroborating RNA expression changes. The two clinically relevant patterns of LoH described here define a novel oncogenic mechanism and a plausible route to genomic precision oncology for this tumor type.

The evolving (epi)genetic landscape of pancreatic neuroendocrine tumours

“…However, in this study series, G2 tumours (coinciding with the RPCL cluster) harbouring mutations in DAXX/ATRX and correlating with mutations in mTOR genes were associated with poor prognosis. Another recent targeted/whole-genome sequencing study reported three CN-based clusters (Lawrence et al 2018) similar to those identified in the Scarpa study. Correlation with clinical data demonstrated that tumours in cluster 1 had the poorest prognosis, cluster 2 tumours had more favourable clinical/pathological outcomes, while those in cluster 3 had variable clinical outcomes.…”

“…However, their penetrance among PanNET cases is currently unknown and warrants further investigation possibly within a clinical genetic referral context. This list has recently been expanded through the identification of novel non-synonymous germline mutations in PIF1 (n = 2), involved in transcriptional regulation and chromatin remodelling, MAPKBP1 (n = 1), a member of the MAPK/ERK signalling pathway (Vandamme et al 2019) known to be co-activated with the PI3K/Akt/mTOR pathway in neuroendocrine tumours through PI3K (Carracedo et al 2008), and identification of a pathogenic germline variant leading to somatic loss of ATM (Lawrence et al 2018).…”

DNA methylation reveals distinct cells of origin for pancreatic neuroendocrine carcinomas (PanNECs) and pancreatic neuroendocrine tumors (PanNETs)

“…The cohort includes tumors of grades NET G1 (27) and NET G2 (25) NET G3 (4), and NEC (3), 45 samples were primary PanNENs and 14 were metastases (8 liver, 6 lymph nodes). As healthy control we used matched adjacent healthy (24) or distant healthy tissue (27) or blood (4) from the same patient.…”

“…In addition to driver mutations affecting individual genes, copy number aberrations (CNA) have been used to characterize these tumors 16,[24][25][26] . Recent work has revealed four distinct subtypes based on chromosome arm length CNA patterns: i) recurring copy number losses of specific chromosomes, ii) limited copy number events with mostly loss of chromosome 11, iii) polyploidy tumors and iv) aneuploidy tumors 16 .…”

“…Recent work has revealed four distinct subtypes based on chromosome arm length CNA patterns: i) recurring copy number losses of specific chromosomes, ii) limited copy number events with mostly loss of chromosome 11, iii) polyploidy tumors and iv) aneuploidy tumors 16 . In addition, the first two groups harbor MEN1 mutations in combination with loss of chromosome 11, resulting in a bi-allelic inactivation of this tumor suppressor gene 24 . The aneuploid tumors also show frequent DAXX/ATRX loss of expression along with an alternative telomerase lengthening phenotype 25 .…”