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

被引：139

作者：

Cejas, Paloma ^{[1
,2
,3
,17
]}

Drier, Yotam ^{[4
,5
,6
,17
]}

Dreijerink, Koen M. A. ^{[7
,8
]}

Brosens, Lodewijk A. A. ^{[9
]}

Deshpande, Vikram ^{[5
,6
]}

Epstein, Charles B. ^{[4
]}

Conemans, Elfi B. ^{[7
,8
]}

Morsink, Folkert H. M. ^{[9
]}

Graham, Mindy K. ^{[10
]}

Valk, Gerlof D. ^{[7
]}

Vriens, Menno R. ^{[6
,11
]}

Fernandez-del Castillo, Carlos ^{[12
]}

Ferrone, Cristina R. ^{[12
]}

Adar, Tomer ^{[6
,13
]}

Bowden, Michaela ^{[1
]}

Whitton, Holly J. ^{[4
]}

Da Silva, Annacarolina ^{[14
]}

Font-Tello, Alba ^{[2
]}

Long, Henry W. ^{[2
]}

Gaskell, Elizabeth ^{[4
]}

Shoresh, Noam ^{[4
]}

Heaphy, Christopher M. ^{[10
]}

Sicinska, Ewa ^{[14
]}

Kulke, Matthew H. ^{[1
,15
,16
]}

Chung, Daniel C. ^{[6
,13
]}

Bernstein, Bradley E. ^{[4
,5
,6
]}

Shivdasani, Ramesh A. ^{[1
,2
,15
,16
]}

机构：

[1] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[2] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02115 USA

[3] Hosp La Paz, Inst Hlth Res, Translat Oncol Lab, Madrid, Spain

[4] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[5] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[6] Harvard Med Sch, Boston, MA 02115 USA

[7] UMC Utrecht Canc Ctr, Dept Endocrine Oncol, Utrecht, Netherlands

[8] Amsterdam UMC, Dept Internal Med, Amsterdam, Netherlands

[9] UMC Utrecht Canc Ctr, Dept Pathol, Utrecht, Netherlands

[10] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

[11] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA

[12] UMC Utrecht Canc Ctr, Dept Surg Oncol, Utrecht, Netherlands

[13] Massachusetts Gen Hosp, Dept Gastroenterol, Boston, MA 02114 USA

[14] Dana Farber Canc Inst, Dept Oncol Pathol, Boston, MA 02115 USA

[15] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA

[16] Harvard Med Sch, Dept Med, Boston, MA 02115 USA

[17] Hebrew Univ Jerusalem, Fac Med, Lautenberg Ctr Immunol & Canc Res, Jerusalem, Israel

来源：

NATURE MEDICINE | 2019年 / 25卷 / 08期

关键词：

ALPHA-CELL; TRANSCRIPTION FACTORS; ENDOCRINE PANCREAS; SUPER-ENHANCERS; BETA-CELLS; PAX4; ARX; DIFFERENTIATION; EPIDEMIOLOGY; IDENTITY;

D O I：

10.1038/s41591-019-0493-4

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 alpha- and beta-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.

引用

页码：1260 / +

页数：14

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