Whole-genome landscape of pancreatic neuroendocrine tumours

Abstract

The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

“…Patients with loss of DAXX or ATRX expression in PanNET have a poorer prognosis in surgical series (Marinoni et al 2014, Singhi et al 2017. Additionally, loss of DAXX or ATRX is associated with chromosome instability (CIN) possibly explaining the presence of chromosomal instability in a subset of more aggressive PanNET (Marinoni et al 2014, Pipinikas et al 2015, Scarpa et al 2017. DAXX/ATRX loss is found almost exclusively in sporadic PanNET >2 cm (Marinoni et al 2014) and the same is true for DAXX/ATRX mutations in MEN1 patients (de Wilde et al 2012).…”

“…All these PanNET were apparently sporadic and no data on penetrance of these germline mutations in PanNET are available. All tumours showed mutation profiles typical for repair gene deficiency, a phenotype only observed in this familial setting (Scarpa et al 2017). Clinically, these new finding open the way to new treatment options for these PanNET patients, possibly including PARP inhibitors.…”

“…Notably, mutually exclusive mutations were found in PTEN (7.1%), TSC1 (2.0%), TSC2 (2.0%) and for the first time, in DEPDC5 (2.0%) (Scarpa et al 2017). EWSR translocations also lead to an altered mTOR signalling (Scarpa et al 2017).…”

“…H3.3 is important in chromatin modification, replication and repair of DNA, regulation of gene expression as well as maintenance of centromeres and telomeres. Very recently, with the histone modifier SETD2 (5 samples out of 98 mutated), an additional epigenetic modifier was described in PanNET (Scarpa et al 2017).…”

“…Mutations of PTEN were found in 7.3% of PanNET and more recently mutations in TSC2, 8.8%; PIK3CA, 1.4% were also described (Perren et al 2000. TP53 mutations are rare in PanNET Jiao et al 2011, Cao et al 2013, Francis et al 2013, Cancer Genome Atlas Research 2014, Fernandez-Cuesta et al 2014, Cromer et al 2015, Lichtenauer et al 2015, Witkiewicz et al 2015, Scarpa et al 2017.…”