Genomic analyses identify molecular subtypes of pancreatic cancer

Baile P; Chang DK; Nones K; Johns AL; Patch AM; Gingras MC; Miller DK; Christ AN; Bruxner TJC; Quinn MC; Nourse C; Murtaugh LC; Harliwong I; Idrisoglu S; Manning S; Nourbakhsh E; Wani S; Fink L; Holmes O; Chin V; Anderson MJ; Kazakoff S; Leonard C; Newell F; Waddell N; Wood S; Xu QY; Wilson PJ; Cloonan N; Kassahn KS; Taylor D; Quek K; Robertson A; Pantano L; Mincarelli L; Sanchez LN; Evers L; Wu JM; Pinese M; Cowley MJ; Jones MD; Colvin EK; Nagrial AM; Humphrey ES; Chantrill LA; Mawson A; Humphris J; Chou A; Pajic M; Scarlett CJ; Pinho AV; Giry-Laterriere M; Rooman I; Samra JS; Kench JG; Lovell JA; Merrett ND; Toon CW; Epari K; Nguyen NQ; Barbour A; Zeps N; Moran-Jones K; Jamieson NB; Graham JS; Duthie F; Oien K; Hair J; Grutzmann R; Maitra A; Iacobuzio-Donahue CA; Wolfgang CL; Morgan RA; Lawlor RT; Corbo V; Bassi C; Rusev B; Capelli P; Salvia R; Tortora G; Mukhopadhyay D; Petersen GM; Munzy DM; Fisher WE; Karim SA; Eshleman JR; Hruban RH; Pilarsky C; Morton JR; Sansom OJ; Scarpa A; Musgrove EA; Bailey UMH; Hofmann O; Sutherland RL; Wheeler DA; Gill AJ; Gibbs RA; Pearson JV; Waddell N; Biankin AV; Grimmond SM

Nature, Vol.531, No.7592, 47-47, 2016

Baile P, Chang DK, Nones K, Johns AL, Patch AM, Gingras MC, Miller DK, Christ AN, Bruxner TJC, Quinn MC, Nourse C, Murtaugh LC, Harliwong I, Idrisoglu S, Manning S, Nourbakhsh E, Wani S, Fink L, Holmes O, Chin V, Anderson MJ, Kazakoff S, Leonard C, Newell F, Waddell N, Wood S, Xu QY, Wilson PJ, Cloonan N, Kassahn KS, Taylor D, Quek K, Robertson A, Pantano L, Mincarelli L, Sanchez LN, Evers L, Wu JM, Pinese M, Cowley MJ, Jones MD, Colvin EK, Nagrial AM, Humphrey ES, Chantrill LA, Mawson A, Humphris J, Chou A, Pajic M, Scarlett CJ, Pinho AV, Giry-Laterriere M, Rooman I, Samra JS, Kench JG, Lovell JA, Merrett ND, Toon CW, Epari K, Nguyen NQ, Barbour A, Zeps N, Moran-Jones K, Jamieson NB, Graham JS, Duthie F, Oien K, Hair J, Grutzmann R, Maitra A, Iacobuzio-Donahue CA, Wolfgang CL, Morgan RA, Lawlor RT, Corbo V, Bassi C, Rusev B, Capelli P, Salvia R, Tortora G, Mukhopadhyay D, Petersen GM, Munzy DM, Fisher WE, Karim SA, Eshleman JR, Hruban RH, Pilarsky C, Morton JR, Sansom OJ, Scarpa A, Musgrove EA, Bailey UMH, Hofmann O, Sutherland RL, Wheeler DA, Gill AJ, Gibbs RA, Pearson JV, Waddell N, Biankin AV, Grimmond SM

Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-beta, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63 Delta N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.