DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association

Vanessa Lakis; Rita T. Lawlor; Felicity Newell; Ann Marie Patch; Andrea Mafficini; Anguraj Sadanandam; Lambros T. Koufariotis; Rebecca L. Johnston; Conrad Leonard; Scott Wood; Borislav Rusev; Vincenzo Corbo; Claudio Luchini; Sara Cingarlini; Luca Landoni; Roberto Salvia; Michele Milella; David Chang; Peter Bailey; Nigel B. Jamieson; Fraser Duthie; Marie Claude Gingras; Donna M. Muzny; David A. Wheeler; Richard A. Gibbs; Massimo Milione; Australian Pancreatic Genome Initiative (APGI); ARC-Net; Paolo Pederzoli; Jaswinder S. Samra; Anthony J. Gill; Amber L. Johns; John V. Pearson; Andrew V. Biankin; Sean M. Grimmond; Nicola Waddell; Katia Nones; Aldo Scarpa

doi:10.1038/s42003-020-01469-0

DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association

Vanessa Lakis, Rita T. Lawlor, Felicity Newell, Ann Marie Patch, Andrea Mafficini, Anguraj Sadanandam, Lambros T. Koufariotis, Rebecca L. Johnston, Conrad Leonard, Scott Wood, Borislav Rusev, Vincenzo Corbo, Claudio Luchini, Sara Cingarlini, Luca Landoni, Roberto Salvia, Michele Milella, David Chang, Peter Bailey, Nigel B. JamiesonFraser Duthie, Marie Claude Gingras, Donna M. Muzny, David A. Wheeler, Richard A. Gibbs, Massimo Milione, Australian Pancreatic Genome Initiative (APGI), ARC-Net, Paolo Pederzoli, Jaswinder S. Samra, Anthony J. Gill, Amber L. Johns, John V. Pearson, Andrew V. Biankin, Sean M. Grimmond, Nicola Waddell, Katia Nones^*, Aldo Scarpa

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Here we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent loss and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent loss of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs.

Original language	English
Article number	155
Pages (from-to)	1-11
Number of pages	11
Journal	Communications Biology
Volume	4
Issue number	1
DOIs	https://doi.org/10.1038/s42003-020-01469-0
Publication status	Published - 3 Feb 2021
Externally published	Yes

Bibliographical note

Copyright the Author(s) 2021. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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Lakis, V., Lawlor, R. T., Newell, F., Patch, A. M., Mafficini, A., Sadanandam, A., Koufariotis, L. T., Johnston, R. L., Leonard, C., Wood, S., Rusev, B., Corbo, V., Luchini, C., Cingarlini, S., Landoni, L., Salvia, R., Milella, M., Chang, D., Bailey, P., ... Scarpa, A. (2021). DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association. Communications Biology, 4(1), 1-11. Article 155. https://doi.org/10.1038/s42003-020-01469-0

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title = "DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association",

abstract = "Here we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent loss and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent loss of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs.",

author = "Vanessa Lakis and Lawlor, {Rita T.} and Felicity Newell and Patch, {Ann Marie} and Andrea Mafficini and Anguraj Sadanandam and Koufariotis, {Lambros T.} and Johnston, {Rebecca L.} and Conrad Leonard and Scott Wood and Borislav Rusev and Vincenzo Corbo and Claudio Luchini and Sara Cingarlini and Luca Landoni and Roberto Salvia and Michele Milella and David Chang and Peter Bailey and Jamieson, {Nigel B.} and Fraser Duthie and Gingras, {Marie Claude} and Muzny, {Donna M.} and Wheeler, {David A.} and Gibbs, {Richard A.} and Massimo Milione and {Australian Pancreatic Genome Initiative (APGI)} and Chantrill, {Lorraine A.} and Paul Timpson and Angela Chou and Marina Pajic and Angela Murphy and Tanya Dwarte and David Hermann and Claire Vennin and Cox, {Thomas R.} and Brooke Pereira and Shona Ritchie and Reed, {Daniel A.} and Chambers, {Cecilia R.} and Xanthe Metcalf and Max Nobis and Pamela Mukhopadhyay and Venkateswar Addala and Stephen Kazakoff and Oliver Holmes and Qinying Xu and Oliver Hofmann and Nick Pavlakis and Jennifer Arena and High, {Hilda A.} and Ray Asghari and Merrett, {Neil D.} and Darren Pavey and Amitabha Das and Cosman, {Peter H.} and Kasim Ismail and Chelsie O{\textquoteright}Connnor and Alina Stoita and David Williams and Allan Spigellman and Lam, {Vincent W.} and Duncan McLeod and Judy Kirk and Kench, {James G.} and Peter Grimison and Charbel Sandroussi and Annabel Goodwin and Mead, {R. Scott} and Katherine Tucker and Lesley Andrews and Michael Texler and Cindy Forest and Mo Ballal and Fletcher, {David R.} and Nikolajs Zeps and Nguyen, {Nan Q.} and Ruszkiewicz, {Andrew R.} and Chris Worthley and John Chen and Brooke-Smith, {Mark E.} and Virginia Papangelis and Clouston, {Andrew D.} and Barbour, {Andrew P.} and O{\textquoteright}Rourke, {Thomas J.} and Fawcett, {Jonathan W.} and Kellee Slater and Michael Hatzifotis and Peter Hodgkinson and Mehrdad Nikfarjam and Eshleman, {James R.} and Hruban, {Ralph H.} and Wolfgang, {Christopher L.} and Judith Dixon and ARC-Net and Maria Scardoni and Claudio Bassi and Sonia Grimaldi and Cinzia Cant{\`u} and Giada Bonizzato and Samantha Bersani and Davide Antonello and Liliana Piredda and Nicola Sperandio and Stefano Barbi and Paola Merlini and Paolo Pederzoli and Samra, {Jaswinder S.} and Gill, {Anthony J.} and Johns, {Amber L.} and Pearson, {John V.} and Biankin, {Andrew V.} and Grimmond, {Sean M.} and Nicola Waddell and Katia Nones and Aldo Scarpa",

note = "Copyright the Author(s) 2021. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",

year = "2021",

month = feb,

day = "3",

doi = "10.1038/s42003-020-01469-0",

language = "English",

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Lakis, V, Lawlor, RT, Newell, F, Patch, AM, Mafficini, A, Sadanandam, A, Koufariotis, LT, Johnston, RL, Leonard, C, Wood, S, Rusev, B, Corbo, V, Luchini, C, Cingarlini, S, Landoni, L, Salvia, R, Milella, M, Chang, D, Bailey, P, Jamieson, NB, Duthie, F, Gingras, MC, Muzny, DM, Wheeler, DA, Gibbs, RA, Milione, M, Australian Pancreatic Genome Initiative (APGI), ARC-Net, Pederzoli, P, Samra, JS, Gill, AJ, Johns, AL, Pearson, JV, Biankin, AV, Grimmond, SM, Waddell, N, Nones, K & Scarpa, A 2021, 'DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association', Communications Biology, vol. 4, no. 1, 155, pp. 1-11. https://doi.org/10.1038/s42003-020-01469-0

TY - JOUR

T1 - DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association

AU - Lakis, Vanessa

AU - Lawlor, Rita T.

AU - Newell, Felicity

AU - Patch, Ann Marie

AU - Mafficini, Andrea

AU - Sadanandam, Anguraj

AU - Koufariotis, Lambros T.

AU - Johnston, Rebecca L.

AU - Leonard, Conrad

AU - Wood, Scott

AU - Rusev, Borislav

AU - Corbo, Vincenzo

AU - Luchini, Claudio

AU - Cingarlini, Sara

AU - Landoni, Luca

AU - Salvia, Roberto

AU - Milella, Michele

AU - Chang, David

AU - Bailey, Peter

AU - Jamieson, Nigel B.

AU - Duthie, Fraser

AU - Gingras, Marie Claude

AU - Muzny, Donna M.

AU - Wheeler, David A.

AU - Gibbs, Richard A.

AU - Milione, Massimo

AU - Australian Pancreatic Genome Initiative (APGI)

AU - Chantrill, Lorraine A.

AU - Timpson, Paul

AU - Chou, Angela

AU - Pajic, Marina

AU - Murphy, Angela

AU - Dwarte, Tanya

AU - Hermann, David

AU - Vennin, Claire

AU - Cox, Thomas R.

AU - Pereira, Brooke

AU - Ritchie, Shona

AU - Reed, Daniel A.

AU - Chambers, Cecilia R.

AU - Metcalf, Xanthe

AU - Nobis, Max

AU - Mukhopadhyay, Pamela

AU - Addala, Venkateswar

AU - Kazakoff, Stephen

AU - Holmes, Oliver

AU - Xu, Qinying

AU - Hofmann, Oliver

AU - Pavlakis, Nick

AU - Arena, Jennifer

AU - High, Hilda A.

AU - Asghari, Ray

AU - Merrett, Neil D.

AU - Pavey, Darren

AU - Das, Amitabha

AU - Cosman, Peter H.

AU - Ismail, Kasim

AU - O’Connnor, Chelsie

AU - Stoita, Alina

AU - Williams, David

AU - Spigellman, Allan

AU - Lam, Vincent W.

AU - McLeod, Duncan

AU - Kirk, Judy

AU - Kench, James G.

AU - Grimison, Peter

AU - Sandroussi, Charbel

AU - Goodwin, Annabel

AU - Mead, R. Scott

AU - Tucker, Katherine

AU - Andrews, Lesley

AU - Texler, Michael

AU - Forest, Cindy

AU - Ballal, Mo

AU - Fletcher, David R.

AU - Zeps, Nikolajs

AU - Nguyen, Nan Q.

AU - Ruszkiewicz, Andrew R.

AU - Worthley, Chris

AU - Chen, John

AU - Brooke-Smith, Mark E.

AU - Papangelis, Virginia

AU - Clouston, Andrew D.

AU - Barbour, Andrew P.

AU - O’Rourke, Thomas J.

AU - Fawcett, Jonathan W.

AU - Slater, Kellee

AU - Hatzifotis, Michael

AU - Hodgkinson, Peter

AU - Nikfarjam, Mehrdad

AU - Eshleman, James R.

AU - Hruban, Ralph H.

AU - Wolfgang, Christopher L.

AU - Dixon, Judith

AU - ARC-Net

AU - Scardoni, Maria

AU - Bassi, Claudio

AU - Grimaldi, Sonia

AU - Cantù, Cinzia

AU - Bonizzato, Giada

AU - Bersani, Samantha

AU - Antonello, Davide

AU - Piredda, Liliana

AU - Sperandio, Nicola

AU - Barbi, Stefano

AU - Merlini, Paola

AU - Pederzoli, Paolo

AU - Samra, Jaswinder S.

AU - Gill, Anthony J.

AU - Johns, Amber L.

AU - Pearson, John V.

AU - Biankin, Andrew V.

AU - Grimmond, Sean M.

AU - Waddell, Nicola

AU - Nones, Katia

AU - Scarpa, Aldo

N1 - Copyright the Author(s) 2021. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2021/2/3

Y1 - 2021/2/3

N2 - Here we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent loss and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent loss of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs.

AB - Here we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent loss and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent loss of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs.

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UR - http://purl.org/au-research/grants/nhmrc/631701

UR - http://purl.org/au-research/grants/nhmrc/535903

U2 - 10.1038/s42003-020-01469-0

DO - 10.1038/s42003-020-01469-0

M3 - Article

C2 - 33536587

AN - SCOPUS:85100523728

SN - 2399-3642

VL - 4

SP - 1

EP - 11

JO - Communications Biology

JF - Communications Biology

IS - 1

M1 - 155

ER -

DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association

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