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; Lorraine A. Chantrill; Paul Timpson; Angela Chou; Marina Pajic; Angela Murphy; Tanya Dwarte; David Hermann; Claire Vennin; Thomas R. Cox; Brooke Pereira; Shona Ritchie; Daniel A. Reed; Cecilia R. Chambers; Xanthe Metcalf; Max Nobis; Pamela Mukhopadhyay; Venkateswar Addala; Stephen Kazakoff; Oliver Holmes; Qinying Xu; Scott Wood; Oliver Hofmann; Jaswinder S. Samra; Nick Pavlakis; Jennifer Arena; Hilda A. High; Ray Asghari; Neil D. Merrett; et al

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. Jamieson

Fraser Duthie, Marie-Claude Gingras, Donna M. Muzny, David A. Wheeler, Richard A. Gibbs, Massimo Milione, Lorraine A. Chantrill, Paul Timpson, Angela Chou, Marina Pajic, Angela Murphy, Tanya Dwarte, David Hermann, Claire Vennin, Thomas R. Cox, Brooke Pereira, Shona Ritchie, Daniel A. Reed, Cecilia R. Chambers, Xanthe Metcalf, Max Nobis, Pamela Mukhopadhyay, Venkateswar Addala, Stephen Kazakoff, Oliver Holmes, Qinying Xu, Scott Wood, Oliver Hofmann, Jaswinder S. Samra, Nick Pavlakis, Jennifer Arena, Hilda A. High, Ray Asghari, Neil D. Merrett, et al

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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
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 - Dec 2021

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© 2021, The Author(s).

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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., ... et al (2021). DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association. Communications Biology, 4(1), Article 155. https://doi.org/10.1038/s42003-020-01469-0

@article{796d2228f82f41e095b194dc2e15d170,

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 Ann-Marie Patch 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 Marie-Claude Gingras and Muzny, \{Donna M.\} and Wheeler, \{David A.\} and Gibbs, \{Richard A.\} and Massimo Milione 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 Scott Wood and Oliver Hofmann and Samra, \{Jaswinder S.\} and Nick Pavlakis and Jennifer Arena and High, \{Hilda A.\} and Ray Asghari and Merrett, \{Neil D.\} and \{et al\}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

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

language = "English",

volume = "4",

journal = "Communications Biology",

issn = "2399-3642",

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}

Lakis, V, Lawlor, RT, Newell, F, Patch, A-M, 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, M-C, Muzny, DM, Wheeler, DA, Gibbs, RA, Milione, M, Chantrill, LA, Timpson, P, Chou, A, Pajic, M, Murphy, A, Dwarte, T, Hermann, D, Vennin, C, Cox, TR, Pereira, B, Ritchie, S, Reed, DA, Chambers, CR, Metcalf, X, Nobis, M, Mukhopadhyay, P, Addala, V, Kazakoff, S, Holmes, O, Xu, Q, Wood, S, Hofmann, O, Samra, JS, Pavlakis, N, Arena, J, High, HA, Asghari, R, Merrett, ND & et al 2021, 'DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association', Communications Biology, vol. 4, no. 1, 155. 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 - 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 - Wood, Scott

AU - Hofmann, Oliver

AU - Samra, Jaswinder S.

AU - Pavlakis, Nick

AU - Arena, Jennifer

AU - High, Hilda A.

AU - Asghari, Ray

AU - Merrett, Neil D.

AU - et al, null

PY - 2021/12

Y1 - 2021/12

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.

UR - http://hdl.handle.net/1959.7/uws:63094

U2 - 10.1038/s42003-020-01469-0

DO - 10.1038/s42003-020-01469-0

M3 - Article

C2 - 33536587

SN - 2399-3642

VL - 4

JO - Communications Biology

JF - Communications Biology

IS - 1

M1 - 155

ER -

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

Abstract

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