Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2014

Open Access 01-12-2014 | Research article

Global miRNA expression analysis of serous and clear cell ovarian carcinomas identifies differentially expressed miRNAs including miR-200c-3p as a prognostic marker

Authors: Bente Vilming Elgaaen, Ole Kristoffer Olstad, Kari Bente Foss Haug, Berit Brusletto, Leiv Sandvik, Anne Cathrine Staff, Kaare M Gautvik, Ben Davidson

Published in: BMC Cancer | Issue 1/2014

Login to get access

Abstract

Background

Improved insight into the molecular characteristics of the different ovarian cancer subgroups is needed for developing a more individualized and optimized treatment regimen. The aim of this study was to a) identify differentially expressed miRNAs in high-grade serous ovarian carcinoma (HGSC), clear cell ovarian carcinoma (CCC) and ovarian surface epithelium (OSE), b) evaluate selected miRNAs for association with clinical parameters including survival and c) map miRNA-mRNA interactions.

Methods

Differences in miRNA expression between HGSC, CCC and OSE were analyzed by global miRNA expression profiling (Affymetrix GeneChip miRNA 2.0 Arrays, n = 12, 9 and 9, respectively), validated by RT-qPCR (n = 35, 19 and 9, respectively), and evaluated for associations with clinical parameters. For HGSC, differentially expressed miRNAs were linked to differentially expressed mRNAs identified previously.

Results

Differentially expressed miRNAs (n = 78) between HGSC, CCC and OSE were identified (FDR < 0.01%), of which 18 were validated (p < 0.01) using RT-qPCR in an extended cohort. Compared with OSE, miR-205-5p was the most overexpressed miRNA in HGSC. miR-200 family members and miR-182-5p were the most overexpressed in HGSC and CCC compared with OSE, whereas miR-383 was the most underexpressed. miR-205-5p and miR-200 members target epithelial-mesenchymal transition (EMT) regulators, apparently being important in tumor progression. miR-509-3-5p, miR-509-5p, miR-509-3p and miR-510 were among the strongest differentiators between HGSC and CCC, all being significantly overexpressed in CCC compared with HGSC. High miR-200c-3p expression was associated with poor progression-free (p = 0.031) and overall (p = 0.026) survival in HGSC patients. Interacting miRNA and mRNA targets, including those of a TP53-related pathway presented previously, were identified in HGSC.

Conclusions

Several miRNAs differentially expressed between HGSC, CCC and OSE have been identified, suggesting a carcinogenetic role for these miRNAs. miR-200 family members, targeting EMT drivers, were mostly overexpressed in both subgroups, among which miR-200c-3p was associated with survival in HGSC patients. A set of miRNAs differentiates CCC from HGSC, of which miR-509-3-5p and miR-509-5p are the strongest classifiers. Several interactions between miRNAs and mRNAs in HGSC were mapped.
Appendix
Available only for authorised users
Literature
1.
Cancer Registry of Norway: Cancer in Norway 2010 - Cancer incidence, mortality, survival and prevalence in Norway. 2012, Oslo: Cancer Registry of Norway
2.
Siegel R, Naishadham D, Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 2012, 62: 10-29. 10.3322/caac.20138.CrossRefPubMed
3.
Prat J: Ovarian carcinomas: five distinct diseases with different origins, genetic alterations, and clinicopathological features. Virchows Arch. 2012, 460: 237-249. 10.1007/s00428-012-1203-5.CrossRefPubMed
4.
Anglesio MS, Carey MS, Kobel M, Mackay H, Huntsman DG: Clear cell carcinoma of the ovary: a report from the first ovarian clear cell symposium, June 24th, 2010. Gynecol Oncol. 2011, 121: 407-415. 10.1016/j.ygyno.2011.01.005.CrossRefPubMed
5.
Vang R, Shih I, Kurman RJ: Ovarian low-grade and high-grade serous carcinoma: pathogenesis, clinicopathologic and molecular biologic features, and diagnostic problems. Adv Anat Pathol. 2009, 16: 267-282. 10.1097/PAP.0b013e3181b4fffa.CrossRefPubMedPubMedCentral
6.
Shih I, Kurman RJ: Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis. Am J Pathol. 2004, 164: 1511-1518. 10.1016/S0002-9440(10)63708-X.CrossRefPubMedPubMedCentral
7.
Huntzinger E, Izaurralde E: Gene silencing by microRNAs: contributions of translational repression and mRNA decay. Nat Rev Genet. 2011, 12: 99-110. 10.1038/nrg2936.CrossRefPubMed
8.
Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, Downing JR, Jacks T, Horvitz HR, Golub TR: MicroRNA expression profiles classify human cancers. Nature. 2005, 435: 834-838. 10.1038/nature03702.CrossRefPubMed
9.
Torres A, Torres K, Maciejewski R, Harvey WH: MicroRNAs and their role in gynecological tumors. Med Res Rev. 2011, 31: 895-923. 10.1002/med.20205.CrossRefPubMed
10.
Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M, Prueitt RL, Yanaihara N, Lanza G, Scarpa A, Vecchione A, Negrini M, Harris CC, Croce CM: A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci U S A. 2006, 103: 2257-2261. 10.1073/pnas.0510565103.CrossRefPubMedPubMedCentral
11.
Kuhlmann JD, Rasch J, Wimberger P: Kasimir-Bauer S: microRNA and the pathogenesis of ovarian cancer–a new horizon for molecular diagnostics and treatment?. Clin Chem Lab Med. 2012, 50: 601-615.PubMed
12.
13.
Vaksman O, Stavnes HT, Kaern J, Trope CG, Davidson B, Reich R: miRNA profiling along tumour progression in ovarian carcinoma. J Cell Mol Med. 2011, 15: 1593-1602. 10.1111/j.1582-4934.2010.01148.x.CrossRefPubMedPubMedCentral
14.
Li SD, Zhang JR, Wang YQ, Wan XP: The role of microRNAs in ovarian cancer initiation and progression. J Cell Mol Med. 2010, 14: 2240-2249. 10.1111/j.1582-4934.2010.01058.x.CrossRefPubMedPubMedCentral
15.
Dahiya N, Sherman-Baust CA, Wang TL, Davidson B, Shih I, Zhang Y, Wood W, Becker KG, Morin PJ: MicroRNA expression and identification of putative miRNA targets in ovarian cancer. PLoS One. 2008, 3: e2436-10.1371/journal.pone.0002436.CrossRefPubMedPubMedCentral
16.
Zhang L, Volinia S, Bonome T, Calin GA, Greshock J, Yang N, Liu CG, Giannakakis A, Alexiou P, Hasegawa K, Johnstone CN, Megraw MS, Adams S, Lassus H, Huang J, Kaur S, Liang S, Sethupathy P, Leminen A, Simossis VA, Sandaltzopoulos R, Naomoto Y, Katsaros D, Gimotty PA, DeMichele A, Huang Q, Butzow R, Rustgi AK, Weber BL, Birrer MJ, et al: Genomic and epigenetic alterations deregulate microRNA expression in human epithelial ovarian cancer. Proc Natl Acad Sci U S A. 2008, 105: 7004-7009. 10.1073/pnas.0801615105.CrossRefPubMedPubMedCentral
17.
Yang H, Kong W, He L, Zhao JJ, O’Donnell JD, Wang J, Wenham RM, Coppola D, Kruk PA, Nicosia SV, Cheng JQ: MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN. Cancer Res. 2008, 68: 425-433. 10.1158/0008-5472.CAN-07-2488.CrossRefPubMed
18.
Shih KK, Qin LX, Tanner EJ, Zhou Q, Bisogna M, Dao F, Olvera N, Viale A, Barakat RR, Levine DA: A microRNA survival signature (MiSS) for advanced ovarian cancer. Gynecol Oncol. 2011, 121: 444-450. 10.1016/j.ygyno.2011.01.025.CrossRefPubMed
19.
Kim TH, Kim YK, Kwon Y, Heo JH, Kang H, Kim G, An HJ: Deregulation of miR-519a, 153, and 485-5p and its clinicopathological relevance in ovarian epithelial tumours. Histopathology. 2010, 57: 734-743. 10.1111/j.1365-2559.2010.03686.x.CrossRefPubMed
20.
Wurz K, Garcia RL, Goff BA, Mitchell PS, Lee JH, Tewari M, Swisher EM: MiR-221 and MiR-222 alterations in sporadic ovarian carcinoma: relationship to CDKN1B, CDKNIC and overall survival. Genes Chromosomes Cancer. 2010, 49: 577-584.PubMedPubMedCentral
21.
Hu X, Macdonald DM, Huettner PC, Feng Z, El Naqa IM, Schwarz JK, Mutch DG, Grigsby PW, Powell SN, Wang X: A miR-200 microRNA cluster as prognostic marker in advanced ovarian cancer. Gynecol Oncol. 2009, 114: 457-464. 10.1016/j.ygyno.2009.05.022.CrossRefPubMed
22.
Nam EJ, Yoon H, Kim SW, Kim H, Kim YT, Kim JH, Kim JW, Kim S: MicroRNA expression profiles in serous ovarian carcinoma. Clin Cancer Res. 2008, 14: 2690-2695. 10.1158/1078-0432.CCR-07-1731.CrossRefPubMed
23.
Eitan R, Kushnir M, Lithwick-Yanai G, David MB, Hoshen M, Glezerman M, Hod M, Sabah G, Rosenwald S, Levavi H: Tumor microRNA expression patterns associated with resistance to platinum based chemotherapy and survival in ovarian cancer patients. Gynecol Oncol. 2009, 114: 253-259. 10.1016/j.ygyno.2009.04.024.CrossRefPubMed
24.
Yang N, Kaur S, Volinia S, Greshock J, Lassus H, Hasegawa K, Liang S, Leminen A, Deng S, Smith L, Johnstone CN, Chen XM, Liu CG, Huang Q, Katsaros D, Calin GA, Weber BL, Butzow R, Croce CM, Coukos G, Zhang L: MicroRNA microarray identifies Let-7i as a novel biomarker and therapeutic target in human epithelial ovarian cancer. Cancer Res. 2008, 68: 10307-10314. 10.1158/0008-5472.CAN-08-1954.CrossRefPubMedPubMedCentral
25.
Boren T, Xiong Y, Hakam A, Wenham R, Apte S, Chan G, Kamath SG, Chen DT, Dressman H, Lancaster JM: MicroRNAs and their target messenger RNAs associated with ovarian cancer response to chemotherapy. Gynecol Oncol. 2009, 113: 249-255. 10.1016/j.ygyno.2009.01.014.CrossRefPubMed
26.
Iorio MV, Visone R, Di LG, Donati V, Petrocca F, Casalini P, Taccioli C, Volinia S, Liu CG, Alder H, Calin GA, Menard S, Croce CM: MicroRNA signatures in human ovarian cancer. Cancer Res. 2007, 67: 8699-8707. 10.1158/0008-5472.CAN-07-1936.CrossRefPubMed
27.
Elgaaen BV, Haug KB, Wang J, Olstad OK, Fortunati D, Onsrud M, Staff AC, Sauer T, Gautvik KM: POLD2 and KSP37 (FGFBP2) correlate strongly with histology, stage and outcome in ovarian carcinomas. PLoS One. 2010, 5: e13837-10.1371/journal.pone.0013837.CrossRefPubMedPubMedCentral
28.
Zorn KK, Jazaeri AA, Awtrey CS, Gardner GJ, Mok SC, Boyd J, Birrer MJ: Choice of normal ovarian control influences determination of differentially expressed genes in ovarian cancer expression profiling studies. Clin Cancer Res. 2003, 9: 4811-4818.PubMed
29.
Elgaaen BV, Olstad OK, Sandvik L, Odegaard E, Sauer T, Staff AC, Gautvik KM: ZNF385B and VEGFA are strongly differentially expressed in serous ovarian carcinomas and correlate with survival. PLoS One. 2012, 7: e46317-10.1371/journal.pone.0046317.CrossRefPubMedPubMedCentral
30.
Edgar R, Domrachev M, Lash AE: Gene expression omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 2002, 30: 207-210. 10.1093/nar/30.1.207.CrossRefPubMedPubMedCentral
31.
Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001, 25: 402-408. 10.1006/meth.2001.1262.CrossRefPubMed
32.
Schmittgen TD, Livak KJ: Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008, 3: 1101-1108. 10.1038/nprot.2008.73.CrossRefPubMed
33.
Elson-Schwab I, Lorentzen A, Marshall CJ: MicroRNA-200 family members differentially regulate morphological plasticity and mode of melanoma cell invasion. PLoS One. 2010, 5:  -doi: 10.1371/journal.pone.0013176
34.
Volinia S, Galasso M, Sana ME, Wise TF, Palatini J, Huebner K, Croce CM: Breast cancer signatures for invasiveness and prognosis defined by deep sequencing of microRNA. Proc Natl Acad Sci U S A. 2012, 109: 3024-3029. 10.1073/pnas.1200010109.CrossRefPubMedPubMedCentral
35.
Slaby O, Svoboda M, Michalek J, Vyzula R: MicroRNAs in colorectal cancer: translation of molecular biology into clinical application. Mol Cancer. 2009, 8: 102-10.1186/1476-4598-8-102.CrossRefPubMedPubMedCentral
36.
37.
Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, Vadas MA, Khew-Goodall Y, Goodall GJ: The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 2008, 10: 593-601. 10.1038/ncb1722.CrossRefPubMed
38.
Hurteau GJ, Carlson JA, Roos E, Brock GJ: Stable expression of miR-200c alone is sufficient to regulate TCF8 (ZEB1) and restore E-cadherin expression. Cell Cycle. 2009, 8: 2064-2069. 10.4161/cc.8.13.8883.CrossRefPubMed
39.
Li Y, VandenBoom TG, Kong D, Wang Z, Ali S, Philip PA, Sarkar FH: Up-regulation of miR-200 and let-7 by natural agents leads to the reversal of epithelial-to-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells. Cancer Res. 2009, 69: 6704-6712. 10.1158/0008-5472.CAN-09-1298.CrossRefPubMedPubMedCentral
40.
Kent OA, Mullendore M, Wentzel EA, Lopez-Romero P, Tan AC, Alvarez H, West K, Ochs MF, Hidalgo M, Arking DE, Maitra A, Mendell JT: A resource for analysis of microRNA expression and function in pancreatic ductal adenocarcinoma cells. Cancer Biol Ther. 2009, 8: 2013-2024. 10.4161/cbt.8.21.9685.CrossRefPubMedPubMedCentral
41.
42.
Huynh C, Segura MF, Gaziel-Sovran A, Menendez S, Darvishian F, Chiriboga L, Levin B, Meruelo D, Osman I, Zavadil J, Marcusson EG, Hernando E: Efficient in vivo microRNA targeting of liver metastasis. Oncogene. 2011, 30: 1481-1488. 10.1038/onc.2010.523.CrossRefPubMed
43.
Muinos-Gimeno M, Guidi M, Kagerbauer B, Martin-Santos R, Navines R, Alonso P, Menchon JM, Gratacos M, Estivill X, Espinosa-Parrilla Y: Allele variants in functional MicroRNA target sites of the neurotrophin-3 receptor gene (NTRK3) as susceptibility factors for anxiety disorders. Hum Mutat. 2009, 30: 1062-1071. 10.1002/humu.21005.CrossRefPubMed
44.
Hidaka H, Seki N, Yoshino H, Yamasaki T, Yamada Y, Nohata N, Fuse M, Nakagawa M, Enokida H: Tumor suppressive microRNA-1285 regulates novel molecular targets: aberrant expression and functional significance in renal cell carcinoma. Oncotarget. 2012, 3: 44-57.PubMedPubMedCentral
45.
Findlay VJ, Turner DP, Moussa O, Watson DK: MicroRNA-mediated inhibition of prostate-derived Ets factor messenger RNA translation affects prostate-derived Ets factor regulatory networks in human breast cancer. Cancer Res. 2008, 68: 8499-8506. 10.1158/0008-5472.CAN-08-0907.CrossRefPubMedPubMedCentral
46.
Stavnes HT, Nymoen DA, Langerod A, Holth A, Borresen Dale AL, Davidson B: AZGP1 and SPDEF mRNA expression differentiates breast carcinoma from ovarian serous carcinoma. Virchows Arch. 2013, 462: 163-173. 10.1007/s00428-012-1347-3.CrossRefPubMed
47.
Marchini S, Cavalieri D, Fruscio R, Calura E, Garavaglia D, Nerini IF, Mangioni C, Cattoretti G, Clivio L, Beltrame L, Katsaros D, Scarampi L, Menato G, Perego P, Chiorino G, Buda A, Romualdi C, D’Incalci M: Association between miR-200c and the survival of patients with stage I epithelial ovarian cancer: a retrospective study of two independent tumour tissue collections. Lancet Oncol. 2011, 12: 273-285. 10.1016/S1470-2045(11)70012-2.CrossRefPubMed
48.
Leskela S, Leandro-Garcia LJ, Mendiola M, Barriuso J, Inglada-Perez L, Munoz I, Martinez-Delgado B, Redondo A, de Santiago J, Robledo M, Hardisson D, Rodriguez-Antona C: The miR-200 family controls beta-tubulin III expression and is associated with paclitaxel-based treatment response and progression-free survival in ovarian cancer patients. Endocr Relat Cancer. 2011, 18: 85-95.CrossRefPubMed
49.
Kan CW, Hahn MA, Gard GB, Maidens J, Huh JY, Marsh DJ, Howell VM: Elevated levels of circulating microRNA-200 family members correlate with serous epithelial ovarian cancer. BMC Cancer. 2012, 12: 627-10.1186/1471-2407-12-627.CrossRefPubMedPubMedCentral
50.
Vasudevan S, Tong Y, Steitz JA: Switching from repression to activation: microRNAs can up-regulate translation. Science. 2007, 318: 1931-1934. 10.1126/science.1149460.CrossRefPubMed
51.
Mortensen RD, Serra M, Steitz JA, Vasudevan S: Posttranscriptional activation of gene expression in Xenopus laevis oocytes by microRNA-protein complexes (microRNPs). Proc Natl Acad Sci U S A. 2011, 108: 8281-8286. 10.1073/pnas.1105401108.CrossRefPubMedPubMedCentral
52.
Vasudevan S: Posttranscriptional upregulation by microRNAs. Wiley Interdiscip Rev RNA. 2012, 3: 311-330. 10.1002/wrna.121.CrossRefPubMed
53.
Auersperg N, Wong AS, Choi KC, Kang SK, Leung PC: Ovarian surface epithelium: biology, endocrinology, and pathology. Endocr Rev. 2001, 22: 255-288.PubMed
54.
Piek JM, van Diest PJ, Zweemer RP, Jansen JW, Poort-Keesom RJ, Menko FH, Gille JJ, Jongsma AP, Pals G, Kenemans P, Verheijen RH: Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer. J Pathol. 2001, 195: 451-456. 10.1002/path.1000.CrossRefPubMed
55.
Medeiros F, Muto MG, Lee Y, Elvin JA, Callahan MJ, Feltmate C, Garber JE, Cramer DW, Crum CP: The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome. Am J Surg Pathol. 2006, 30: 230-236. 10.1097/01.pas.0000180854.28831.77.CrossRefPubMed
56.
Kindelberger DW, Lee Y, Miron A, Hirsch MS, Feltmate C, Medeiros F, Callahan MJ, Garner EO, Gordon RW, Birch C, Berkowitz RS, Muto MG, Crum CP: Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: evidence for a causal relationship. Am J Surg Pathol. 2007, 31: 161-169. 10.1097/01.pas.0000213335.40358.47.CrossRefPubMed
57.
Lee Y, Miron A, Drapkin R, Nucci MR, Medeiros F, Saleemuddin A, Garber J, Birch C, Mou H, Gordon RW, Cramer DW, McKeon FD, Crum CP: A candidate precursor to serous carcinoma that originates in the distal fallopian tube. J Pathol. 2007, 211: 26-35. 10.1002/path.2091.CrossRefPubMed
58.
Jarboe E, Folkins A, Nucci MR, Kindelberger D, Drapkin R, Miron A, Lee Y, Crum CP: Serous carcinogenesis in the fallopian tube: a descriptive classification. Int J Gynecol Pathol. 2008, 27: 1-9. 10.1097/pgp.0b013e31814b191f.CrossRefPubMed
59.
Folkins AK, Jarboe EA, Saleemuddin A, Lee Y, Callahan MJ, Drapkin R, Garber JE, Muto MG, Tworoger S, Crum CP: A candidate precursor to pelvic serous cancer (p53 signature) and its prevalence in ovaries and fallopian tubes from women with BRCA mutations. Gynecol Oncol. 2008, 109: 168-173. 10.1016/j.ygyno.2008.01.012.CrossRefPubMedPubMedCentral
60.
Auersperg N: The origin of ovarian carcinomas: a unifying hypothesis. Int J Gynecol Pathol. 2011, 30: 12-21. 10.1097/PGP.0b013e3181f45f3e.CrossRefPubMed
Metadata
Title
Global miRNA expression analysis of serous and clear cell ovarian carcinomas identifies differentially expressed miRNAs including miR-200c-3p as a prognostic marker
Authors
Bente Vilming Elgaaen
Ole Kristoffer Olstad
Kari Bente Foss Haug
Berit Brusletto
Leiv Sandvik
Anne Cathrine Staff
Kaare M Gautvik
Ben Davidson
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2014
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-14-80

Other articles of this Issue 1/2014

BMC Cancer 1/2014 Go to the issue

Research article

Estrogen receptor α and aryl hydrocarbon receptor independent growth inhibitory effects of aminoflavone in breast cancer cells

Case report

Leptomeningeal metastasis from hepatocellular carcinoma with other unusual metastases: a case report

Research article

Closing the global cancer divide- performance of breast cancer care services in a middle income developing country

Case report

Large cell anaplastic medulloblastoma metastatic to the scalp: tumor and derived stem-like cells features

Research article

Amyloid-β precursor protein promotes cell proliferation and motility of advanced breast cancer

Research article

Cyr61 Expression is associated with prognosis in patients with colorectal cancer
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits