Whole-genome landscape of pancreatic neuroendocrine tumours
Scarpa A., Chang DK., Nones K., Corbo V., Patch AM., Bailey P., Lawlor RT., Johns AL., Miller DK., Mafficini A., Rusev B., Scardoni M., Antonello D., Barbi S., Sikora KO., Cingarlini S., Vicentini C., McKay S., Quinn MCJ., Bruxner TJC., Christ AN., Harliwong I., Idrisoglu S., McLean S., Nourse C., Nourbakhsh E., Wilson PJ., Anderson MJ., Fink JL., Newell F., Waddell N., Holmes O., Kazakoff SH., Leonard C., Wood S., Xu Q., Nagaraj SH., Amato E., Dalai I., Bersani S., Cataldo I., Dei Tos AP., Capelli P., Davì MV., Landoni L., Malpaga A., Miotto M., Whitehall VLJ., Leggett BA., Harris JL., Harris J., Jones MD., Humphris J., Chantrill LA., Chin V., Nagrial AM., Pajic M., Scarlett CJ., Pinho A., Rooman I., Toon C., Wu J., Pinese M., Cowley M., Barbour A., Mawson A., Humphrey ES., Colvin EK., Chou A., Lovell JA., Jamieson NB., Duthie F., Gingras MC., Fisher WE., Dagg RA., Lau LMS., Lee M., Pickett HA., Reddel RR., Samra JS., Kench JG., Merrett ND., Epari K., Nguyen NQ., Zeps N., Falconi M., Simbolo M., Butturini G., Van Buren G., Partelli S., Fassan M., Khanna KK., Gill AJ., Wheeler DA., Gibbs RA., Musgrove EA., Bassi C., Tortora G., Pederzoli P., Pearson JV.
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.