Integrative multi-omics analysis identifies a prognostic miRNA signature and a targetable miR-21-3p/TSC2/mTOR axis in metastatic pheochromocytoma/paraganglioma

被引：58

作者：

Calsina, Bruna ^{[1
]}

Jaime Castro-Vega, Luis ^{[2
,3
]}

Torres-Perez, Rafael ^{[1
]}

Inglada-Perez, Lucia ^{[1
,4
]}

Curras-Freixes, Maria ^{[1
]}

Maria Roldan-Romero, Juan ^{[1
]}

Mancikova, Veronika ^{[1
]}

Leton, Rocio ^{[1
]}

Remacha, Laura ^{[1
]}

Santos, Maria ^{[1
]}

Burnichon, Nelly ^{[2
,3
,5
]}

Lussey-Lepoutre, Charlotte ^{[2
,6
]}

Rapizzi, Elena ^{[7
]}

Grana, Osvaldo ^{[8
]}

Alvarez-Escola, Cristina ^{[9
]}

de Cubas, Aguirre A. ^{[1
]}

Lanillos, Javier ^{[1
]}

Cordero-Barreal, Alfonso ^{[1
]}

Martinez-Montes, Angel M. ^{[1
]}

Bellucci, Alexandre ^{[10
]}

Amar, Laurence ^{[2
,3
,11
]}

Luiz Fernandes-Rosa, Fabio ^{[2
,3
]}

Calatayud, Maria ^{[12
,13
]}

Aller, Javier ^{[14
]}

Lamas, Cristina ^{[15
]}

Sastre-Marcos, Julia ^{[16
]}

Canu, Letizia ^{[7
]}

Korpershoek, Esther ^{[17
]}

Timmers, Henri J. ^{[18
]}

Lenders, Jacques W. M. ^{[18
,19
,20
]}

Beuschlein, Felix ^{[21
,22
]}

Fassnacht-Capeller, Martin ^{[23
,24
]}

Eisenhofer, Graeme ^{[25
]}

Mannelli, Massimo ^{[7
]}

Al-Shahrour, Fatima ^{[8
]}

Favier, Judith ^{[25
]}

Rodriguez-Antona, Cristina ^{[1
,4
]}

Cascon, Alberto ^{[1
,4
]}

Montero-Conde, Cristina ^{[1
]}

Gimenez-Roqueplo, Anne-Paule ^{[2
,3
,5
]}

Robledo, Mercedes ^{[1
,4
]}

机构：

[1] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Hereditary Endocrine Canc Grp, Madrid, Spain

[2] Paris Cardiovasc Res Ctr, INSERM, UMR970, Equipe Labellisee Ligue Canc, Paris, France

[3] Univ Paris 05, Sorbonne Paris Cite, PRES, Fac Med, Paris, France

[4] Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid, Spain

[5] Hop Europeen Georges Pompidou, AP HP, Serv Genet, Paris, France

[6] Sorbonne Univ, Pitie Salpetriere Hosp, Dept Nucl Med, Paris, France

[7] Univ Florence, Dept Expt & Clin Biomed Sci, Florence, Italy

[8] Spanish Natl Canc Res Ctr CNIO, Struct Biol Program, Bioinformat Unit, Madrid, Spain

[9] Hosp Univ La Paz, Serv Endocrinol & Nutr, Madrid, Spain

[10] Hop Europeen Georges Pompidou, AP HP, Serv Radiol, Paris, France

[11] Hop Europeen Georges Pompidou, AP HP, Hypertens Unit, Paris, France

[12] Hosp Univ 12 Octubre, Dept Endocrinol, Madrid, Spain

[13] Hosp Univ 12 Octubre, Nutr Serv, Madrid, Spain

[14] Puerta Hierro Univ Hosp, Dept Endocrinol, Madrid, Spain

[15] Albacete Univ Hosp Complex, Dept Endocrinol, Albacete, Spain

[16] Toledo Hosp Complex, Virgen Salud Hosp, Dept Endocrinol, Toledo, Spain

[17] Univ Med Ctr Rotterdam, Erasmus Med Ctr, Canc Inst, Dept Pathol, Rotterdam, Netherlands

[18] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, NL-6525 HP Nijmegen, Netherlands

[19] Tech Univ Dresden, Univ Hosp, Dept Med 3, Dresden, Germany

[20] Tech Univ Dresden, Med Fac Carl Gustav Carus, Dresden, Germany

[21] Klinikum Univ Munchen, Med Klin & Poliklin IV, Munich, Germany

[22] Univ Spital Zurich, Klin Endokrinol Diabetol & Klin Ernahrung, Zurich, Switzerland

[23] Univ Wurzburg, Univ Hosp Wurzburg, Endocrine & Diabet Unit, Dept Internal Med 1, Wurzburg, Germany

[24] Univ Wurzburg, Comprehens Canc Ctr Mainfranken, Wurzburg, Germany

[25] Tech Univ Dresden, Med Univ Hosp Carl Gustav Carus, Med Fac Carl Gustav Carus, Inst Clin Chem & Lab Med, Dresden, Germany

来源：

THERANOSTICS | 2019年 / 9卷 / 17期

关键词：

multi-omic integration; pheochromocytoma/paraganglioma; miR-21-3p; liquid biopsy; prognostic biomarker; MALIGNANT PHEOCHROMOCYTOMA; CELL-METABOLISM; SDHB GENE; EVEROLIMUS; MUTATIONS; BENIGN; PARAGANGLIOMAS; PROFILES; THERAPY; MARKERS;

D O I：

10.7150/thno.35458

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Rationale: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that present variable outcomes. To date, no effective therapies or reliable prognostic markers are available for patients who develop metastatic PPGL (mPPGL). Our aim was to discover robust prognostic markers validated through in vitro models, and define specific therapeutic options according to tumor genomic features. Methods: We analyzed three PPGL miRNome datasets (n=443), validated candidate markers and assessed them in serum samples (n=36) to find a metastatic miRNA signature. An integrative study of miRNome, transcriptome and proteome was performed to find miRNA targets, which were further characterized in vitro. Results: A signature of six miRNAs (miR-21-3p, miR-183-5p, miR-182-5p, miR-96-5p, miR-551b-3p, and miR-202-5p) was associated with metastatic risk and time to progression. A higher expression of five of these miRNAs was also detected in PPGL patients' liquid biopsies compared with controls. The combined expression of miR-21-3p/miR-183-5p showed the best power to predict metastasis (AUC=0.804, P=4.67.10(-18)), and was found associated in vitro with pro-metastatic features, such as neuroendocrine-mesenchymal transition phenotype, and increased cell migration rate. A pan-cancer multi-omic integrative study correlated miR-21-3p levels with TSC2 expression, mTOR pathway activation, and a predictive signature for mTOR inhibitor-sensitivity in PPGLs and other cancers. Likewise, we demonstrated in vitro a TSC2 repression and an enhanced rapamycin sensitivity upon miR-21-3p expression. Conclusions: Our findings support the assessment of miR-21-3p/miR-183-5p, in tumors and liquid biopsies, as biomarkers for risk stratification to improve the PPGL patients' management. We propose miR-21-3p to select mPPGL patients who may benefit from mTOR inhibitors.

引用

页码：4946 / 4958

页数：13