Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors

Paloma Cejas; Yotam Drier; Koen M.A. Dreijerink; Lodewijk A.A. Brosens; Vikram Deshpande; Charles B. Epstein; Elfi B. Conemans; Folkert H.M. Morsink; Mindy K. Graham; Gerlof D. Valk; Menno R. Vriens; Carlos Fernandez del Castillo; Cristina R. Ferrone; Tomer Adar; Michaela Bowden; Holly J. Whitton; Annacarolina Da Silva; Alba Font-Tello; Henry W. Long; Elizabeth Gaskell; Noam Shoresh; Christopher M. Heaphy; Ewa Sicinska; Matthew H. Kulke; Daniel C. Chung; Bradley E. Bernstein; Ramesh A. Shivdasani

doi:10.1038/s41591-019-0493-4

Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors

Paloma Cejas, Yotam Drier, Koen M.A. Dreijerink, Lodewijk A.A. Brosens, Vikram Deshpande, Charles B. Epstein, Elfi B. Conemans, Folkert H.M. Morsink, Mindy K. Graham, Gerlof D. Valk, Menno R. Vriens, Carlos Fernandez del Castillo, Cristina R. Ferrone, Tomer Adar, Michaela Bowden, Holly J. Whitton, Annacarolina Da Silva, Alba Font-Tello, Henry W. Long, Elizabeth GaskellNoam Shoresh, Christopher M. Heaphy, Ewa Sicinska, Matthew H. Kulke, Daniel C. Chung, Bradley E. Bernstein, Ramesh A. Shivdasani^*

^*Corresponding author for this work

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

Abstract

Most pancreatic neuroendocrine tumors (PNETs) do not produce excess hormones and are therefore considered ‘non-functional’^1–3. As clinical behaviors vary widely and distant metastases are eventually lethal^2,4, biological classifications might guide treatment. Using enhancer maps to infer gene regulatory programs, we find that non-functional PNETs fall into two major subtypes, with epigenomes and transcriptomes that partially resemble islet α- and β-cells. Transcription factors ARX and PDX1 specify these normal cells, respectively^5,6, and 84% of 142 non-functional PNETs expressed one or the other factor, occasionally both. Among 103 cases, distant relapses occurred almost exclusively in patients with ARX⁺PDX1⁻ tumors and, within this subtype, in cases with alternative lengthening of telomeres. These markedly different outcomes belied similar clinical presentations and histology and, in one cohort, occurred irrespective of MEN1 mutation. This robust molecular stratification provides insight into cell lineage correlates of non-functional PNETs, accurately predicts disease course and can inform postoperative clinical decisions.

Original language	English
Pages (from-to)	1260-1265
Number of pages	6
Journal	Nature Medicine
Volume	25
DOIs	https://doi.org/10.1038/s41591-019-0493-4
Publication status	Published - Aug 2019

Keywords

Cell Lineage
Enhancer Elements, Genetic
Homeodomain Proteins/analysis
Humans
Mutation
Pancreatic Neoplasms/chemistry
Proto-Oncogene Proteins/genetics
Telomere
Trans-Activators/analysis
Transcription Factors/analysis

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10.1038/s41591-019-0493-4

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Cejas, P., Drier, Y., Dreijerink, K. M. A., Brosens, L. A. A., Deshpande, V., Epstein, C. B., Conemans, E. B., Morsink, F. H. M., Graham, M. K., Valk, G. D., Vriens, M. R., Castillo, C. F. D., Ferrone, C. R., Adar, T., Bowden, M., Whitton, H. J., Da Silva, A., Font-Tello, A., Long, H. W., ... Shivdasani, R. A. (2019). Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors. Nature Medicine, 25, 1260-1265. https://doi.org/10.1038/s41591-019-0493-4

@article{b01f83d8d7aa4c35be5e671a86ef65c2,

title = "Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors",

abstract = "Most pancreatic neuroendocrine tumors (PNETs) do not produce excess hormones and are therefore considered {\textquoteleft}non-functional{\textquoteright}1–3. As clinical behaviors vary widely and distant metastases are eventually lethal2,4, biological classifications might guide treatment. Using enhancer maps to infer gene regulatory programs, we find that non-functional PNETs fall into two major subtypes, with epigenomes and transcriptomes that partially resemble islet α- and β-cells. Transcription factors ARX and PDX1 specify these normal cells, respectively5,6, and 84% of 142 non-functional PNETs expressed one or the other factor, occasionally both. Among 103 cases, distant relapses occurred almost exclusively in patients with ARX+PDX1− tumors and, within this subtype, in cases with alternative lengthening of telomeres. These markedly different outcomes belied similar clinical presentations and histology and, in one cohort, occurred irrespective of MEN1 mutation. This robust molecular stratification provides insight into cell lineage correlates of non-functional PNETs, accurately predicts disease course and can inform postoperative clinical decisions.",

keywords = "Cell Lineage, Enhancer Elements, Genetic, Homeodomain Proteins/analysis, Humans, Mutation, Pancreatic Neoplasms/chemistry, Proto-Oncogene Proteins/genetics, Telomere, Trans-Activators/analysis, Transcription Factors/analysis",

author = "Paloma Cejas and Yotam Drier and Dreijerink, {Koen M.A.} and Brosens, {Lodewijk A.A.} and Vikram Deshpande and Epstein, {Charles B.} and Conemans, {Elfi B.} and Morsink, {Folkert H.M.} and Graham, {Mindy K.} and Valk, {Gerlof D.} and Vriens, {Menno R.} and Castillo, {Carlos Fernandez del} and Ferrone, {Cristina R.} and Tomer Adar and Michaela Bowden and Whitton, {Holly J.} and {Da Silva}, Annacarolina and Alba Font-Tello and Long, {Henry W.} and Elizabeth Gaskell and Noam Shoresh and Heaphy, {Christopher M.} and Ewa Sicinska and Kulke, {Matthew H.} and Chung, {Daniel C.} and Bernstein, {Bradley E.} and Shivdasani, {Ramesh A.}",

note = "Funding Information: The present study has been supported by the Neuroendocrine Tumor Research Foundation (R.A.S., B.E.B., M.H.K. and D.C.C.), the SPORE program in gastrointestinal cancers (P50CA127003—National Cancer Institute, R.A.S.), the North American Neuroendocrine Tumor Society (C.M.H.) and a grant (no. PI18-01604 to P.C.) from Instituto de Salud Carlos III of the Spanish Economy and Competitiveness Ministry. Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2019",

month = aug,

doi = "10.1038/s41591-019-0493-4",

language = "English",

volume = "25",

pages = "1260--1265",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Publishing Group",

}

Cejas, P, Drier, Y, Dreijerink, KMA, Brosens, LAA, Deshpande, V, Epstein, CB, Conemans, EB, Morsink, FHM, Graham, MK, Valk, GD , Vriens, MR, Castillo, CFD, Ferrone, CR, Adar, T, Bowden, M, Whitton, HJ, Da Silva, A, Font-Tello, A, Long, HW, Gaskell, E, Shoresh, N, Heaphy, CM, Sicinska, E, Kulke, MH, Chung, DC, Bernstein, BE & Shivdasani, RA 2019, 'Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors', Nature Medicine, vol. 25, pp. 1260-1265. https://doi.org/10.1038/s41591-019-0493-4

TY - JOUR

T1 - Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors

AU - Cejas, Paloma

AU - Drier, Yotam

AU - Dreijerink, Koen M.A.

AU - Brosens, Lodewijk A.A.

AU - Deshpande, Vikram

AU - Epstein, Charles B.

AU - Conemans, Elfi B.

AU - Morsink, Folkert H.M.

AU - Graham, Mindy K.

AU - Valk, Gerlof D.

AU - Vriens, Menno R.

AU - Castillo, Carlos Fernandez del

AU - Ferrone, Cristina R.

AU - Adar, Tomer

AU - Bowden, Michaela

AU - Whitton, Holly J.

AU - Da Silva, Annacarolina

AU - Font-Tello, Alba

AU - Long, Henry W.

AU - Gaskell, Elizabeth

AU - Shoresh, Noam

AU - Heaphy, Christopher M.

AU - Sicinska, Ewa

AU - Kulke, Matthew H.

AU - Chung, Daniel C.

AU - Bernstein, Bradley E.

AU - Shivdasani, Ramesh A.

N1 - Funding Information: The present study has been supported by the Neuroendocrine Tumor Research Foundation (R.A.S., B.E.B., M.H.K. and D.C.C.), the SPORE program in gastrointestinal cancers (P50CA127003—National Cancer Institute, R.A.S.), the North American Neuroendocrine Tumor Society (C.M.H.) and a grant (no. PI18-01604 to P.C.) from Instituto de Salud Carlos III of the Spanish Economy and Competitiveness Ministry. Publisher Copyright: © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2019/8

Y1 - 2019/8

N2 - Most pancreatic neuroendocrine tumors (PNETs) do not produce excess hormones and are therefore considered ‘non-functional’1–3. As clinical behaviors vary widely and distant metastases are eventually lethal2,4, biological classifications might guide treatment. Using enhancer maps to infer gene regulatory programs, we find that non-functional PNETs fall into two major subtypes, with epigenomes and transcriptomes that partially resemble islet α- and β-cells. Transcription factors ARX and PDX1 specify these normal cells, respectively5,6, and 84% of 142 non-functional PNETs expressed one or the other factor, occasionally both. Among 103 cases, distant relapses occurred almost exclusively in patients with ARX+PDX1− tumors and, within this subtype, in cases with alternative lengthening of telomeres. These markedly different outcomes belied similar clinical presentations and histology and, in one cohort, occurred irrespective of MEN1 mutation. This robust molecular stratification provides insight into cell lineage correlates of non-functional PNETs, accurately predicts disease course and can inform postoperative clinical decisions.

AB - Most pancreatic neuroendocrine tumors (PNETs) do not produce excess hormones and are therefore considered ‘non-functional’1–3. As clinical behaviors vary widely and distant metastases are eventually lethal2,4, biological classifications might guide treatment. Using enhancer maps to infer gene regulatory programs, we find that non-functional PNETs fall into two major subtypes, with epigenomes and transcriptomes that partially resemble islet α- and β-cells. Transcription factors ARX and PDX1 specify these normal cells, respectively5,6, and 84% of 142 non-functional PNETs expressed one or the other factor, occasionally both. Among 103 cases, distant relapses occurred almost exclusively in patients with ARX+PDX1− tumors and, within this subtype, in cases with alternative lengthening of telomeres. These markedly different outcomes belied similar clinical presentations and histology and, in one cohort, occurred irrespective of MEN1 mutation. This robust molecular stratification provides insight into cell lineage correlates of non-functional PNETs, accurately predicts disease course and can inform postoperative clinical decisions.

KW - Cell Lineage

KW - Enhancer Elements, Genetic

KW - Homeodomain Proteins/analysis

KW - Humans

KW - Mutation

KW - Pancreatic Neoplasms/chemistry

KW - Proto-Oncogene Proteins/genetics

KW - Telomere

KW - Trans-Activators/analysis

KW - Transcription Factors/analysis

UR - http://www.scopus.com/inward/record.url?scp=85068563478&partnerID=8YFLogxK

U2 - 10.1038/s41591-019-0493-4

DO - 10.1038/s41591-019-0493-4

M3 - Article

C2 - 31263286

AN - SCOPUS:85068563478

SN - 1078-8956

VL - 25

SP - 1260

EP - 1265

JO - Nature Medicine

JF - Nature Medicine

ER -

Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors

Abstract

Keywords

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