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 - Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2019/8/1
Y1 - 2019/8/1
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.
UR - http://www.scopus.com/inward/record.url?scp=85068563478&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.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 - 1264
EP - 1269
JO - Nature medicine
JF - Nature medicine
IS - 8
ER -