Fondation MEDIC

www.fondation-medic.ch

Interrogating breast cancer heterogeneity using next generation sequencing
[22.10.2016]
Project leader – Christos Sotiriou
Christos Sotiriou

Christos Sotiriou earned a medical degree from the Université Libre de Bruxelles, Belgium in 1993. He did his internal medicine/oncology residency at the Jules Bordet Institute and he earned his specialty in internal medicine and medical oncology in July 1999 at the Université Libre de Bruxelles. From October 1999 till September 2001, he worked as basic research fellow, at the Division of Clinical Sciences, Microarray Facility, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Dr. Sotiriou earned his doctor of philosophy degree (PhD) from the Université Libre de Bruxelles, Belgium in September 2004. In October 2005, he becomes associate professor at the Université Libre de Bruxelles. In March 2010 he took the direction of the breast cancer translational research laboratory J-C Heuson at the Jules Bordet Institute. Dr. Sotiriou’s research focuses on genomics and molecular biology in breast cancer. He is a full member of ASCO, AACR, and ESMO. He is member of the biotechnology committee of TRANSBIG and of the TransALTTO committee, and also Advisory Council Member of the Susan G. Komen for the Cure and for the National foundation for research since 2010. He received several educational and research grants from the Swiss Foundation MEDIC, the National Foundation of Cancer Research, the Université Libre de Bruxelles, the “Fonds Jean-Claude Heuson”, the Fondation Lambeau-Marteau, the Belgian Federation against Cancer, and the European Union Framework VI and VII Programs. He is author of numerous publications in peer review journals and of several book chapters. He is also a reviewer for several high impact scientific journals.

Breast Cancer Research Laboratory
Institut Jules Bordet
125 Bld de Waterloo
Brussels 1000, Belgium

E-Mail: christos.sotiriou@bordet.be

Group members
 

Pierre-Yves Adnet

junior lab technician

Laurence Buisseret MD

medical oncologist, graduate student

Christine Desmedt PhD

translational research coordinator

Debora Fumagalli MD

medical oncologist, graduate student

Michail Ignatiadis MD PhD

medical oncologist

Vinu Jose

bio-informatician, graduate student

Naïma Kheddoumi

lab technician

Marion Maetens PhD

translational research project manager

Samira Majjaj

senior lab technician

David Norman Brown

bio-informatician, graduate student

Elisabetta Pietri MD

medical oncologist, graduate student

Dominique Roels

administrative assistant

Françoise Rothé PhD

lab manager

Ghizlane Rouas

lab technician

Delphine Vincent

junior lab technician

Xiaoxiao Wang

undergraduate student

Gabriele Zoppoli MD PhD

postdoctoral fellow

Project description
 

Breast cancer is the most frequently encountered type of cancer in women since 1 woman out of 9 will develop breast cancer and unfortunately one third of these women will subsequently die from this disease. As for prognostic factors, the currently used factors for predicting response to therapy are suboptimal and insufficient to explain the differences in survival and response observed in the clinical practice. Therefore, we believe that additional factors, which are still not identified, may intervene and interact together. Better understanding the biology of breast cancer and translating our findings into clinically relevant tools is the main aim of our lab.

During the last decade, our lab has mainly used the microarray technology to investigate the biology of breast cancer. Using gene expression profiling, we and others have provided: 1) a molecular classification of breast cancer into clinically relevant subtypes (Sotiriou et al. PNAS 2003), 2) new tools to predict disease recurrence and response to different treatments (Sotiriou et al. JNCI 2006, Desmedt et al. 2007, Desmedt et al. CCR 2008, Desmedt et al. JCO 2011), 3) a better characterization of the breast tumor microenvironment (Toussaint et al. PLoS One 2010; Desmedt et al. submitted); and 4) novel insight into various oncogenic pathways (Loi et al. PNAS 2010) and the process of metastatic progression (Ignatiadis et al. PLoS One 2011).

The last 5 years have witnessed the emergence of next-generation sequencing (NGS) technologies that have provided a powerful, new approach to complex genetic studies. NGS has enabled sequencing of entire transcriptomes (RNA-Seq), characterization of regulatory and chromatin protein DNA-binding sites, and whole genome sequencing, among others. Our current research makes use of the latest technological development in molecular biology, i.e. NGS as well as the recently introduced genome-wide DNA methylation profiling, to further interrogate the molecular heterogeneity of breast cancer.

figure 1

Publications
 
2016 / 10.1039/c5an01512j
Verdonck M, Denayer A, Delvaux B, Garaud S, De Wind R, Desmedt C, Sotiriou C, Willard-Gallo K, Goormaghtigh E. Characterization of human breast cancer tissues by infrared imaging. Analyst. 2016 Jan 21;141(2):606-19
» PubMed
2015 / 10.1016/j.celrep.2015.09.032
Fumagalli D, Gacquer D, Rothé F, Lefort A, Libert F, Brown D, Kheddoumi N, Shlien A, Konopka T, Salgado R, Larsimont D, Polyak K, Willard-Gallo K, Desmedt C, Piccart M, Abramowicz M, Campbell PJ, Sotiriou C, Detours V. Principles Governing A-to-I RNA Editing in the Breast Cancer Transcriptome. Cell Rep. 2015 Oct 13;13(2):277-89
» PubMed
2015 / 10.1093/annonc/mdu450
Salgado R*, Denkert C*, Demaria S*, Sirtaine N, Klauschen F, Pruneri G, Wienert S, Van den Eynden G, Baehner FL, Penault-Llorca F, Perez EA, Thompson EA, Symmans WF, Richardson AL, Brock J, Criscitiello C, Bailey H, Ignatiadis M, Floris G, Sparano J, Kos Z, Nielsen T, Rimm DL, Allison KH, Reis-Filho JS, Loibl S, Sotiriou C, Viale G, Badve S, Adams S*, Willard-Gallo K* and Loi S* (*contributed equally). The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2015 Feb;26(2):259-71
» PubMed
2013 / 10.1172/JCI67428
Gu-Trantien C, Loi S, Garaud S, Equeter C, Libin M, de Wind A, Ravoet M, Le Buanec H, Sibille C, Manfouo-Foutsop G, Veys I, Haibe-Kains B, Singhal SK, Michiels S, Rothé F, Salgado R, Duvillier H, Ignatiadis M, Desmedt C, Bron D, Larsimont D, Piccart M, Sotiriou C, Willard-Gallo K. CD4⁺ follicular helper T cell infiltration predicts breast cancer survival. J Clin Invest. 2013 Jul;123(7):2873-92
» PubMed
2012 / 10.1158/1078-0432.CCR-11-0383
Desmedt C, Majjaj S, Kheddoumi N, Singhal SK, Haibe-Kains B, El Ouriaghli F, Chaboteaux C, Michiels S, Lallemand F, Journe F, Duvillier H, Loi S, Quackenbush J, Dekoninck S, Blanpain C, Lagneaux L, Houhou N, Delorenzi M, Larsimont D, Piccart M, Sotiriou C. Characterization and clinical evaluation of CD10+ stroma cells in the breast cancer microenvironment. Clin Cancer Res. 2012 Feb 15;18(4):1004-14
» PubMed
2011 / 10.1200/JCO.2010.31.2231
Desmedt C, Di Leo A, de Azambuja E, Larsimont D, Haibe-Kains B, Selleslags J, Delaloge S, Duhem C, Kains JP, Carly B, Maerevoet M, Vindevoghel A, Rouas G, Lallemand F, Durbecq V, Cardoso F, Salgado R, Rovere R, Bontempi G, Michiels S, Buyse M, Nogaret JM, Qi Y, Symmans F, Pusztai L, D'Hondt V, Piccart-Gebhart M, Sotiriou C. Multifactorial approach to predicting resistance to anthracyclines. J Clin Oncol. 2011 Apr 20;29(12):1578-86
» PubMed
2011 / 10.1371/journal.pone.0015624
Ignatiadis M, Rothé F, Chaboteaux C, Durbecq V, Rouas G, Criscitiello C, Metallo J, Kheddoumi N, Singhal SK, Michiels S, Veys I, Rossari J, Larsimont D, Carly B, Pestrin M, Bessi S, Buxant F, Liebens F, Piccart M, Sotiriou C. HER2-positive circulating tumor cells in breast cancer. PLoS One. 2011 Jan 10;6(1):e15624
» PubMed
2011 / 10.1371/journal.pone.0020980
Rothé F, Ignatiadis M, Chaboteaux C, Haibe-Kains B, Kheddoumi N, Majjaj S, Badran B, Fayyad-Kazan H, Desmedt C, Harris AL, Piccart M, Sotiriou C. Global microRNA expression profiling identifies MiR-210 associated with tumor proliferation, invasion and poor clinical outcome in breast cancer. PLoS One. 2011;6(6):e20980
» PubMed
2011 / 10.1002/emmm.201100121
Sircoulomb F, Nicolas N, Ferrari A, Finetti P, Bekhouche I, Rousselet E, Lonigro A, Adélaïde J, Baudelet E, Esteyriès S, Wicinski J, Audebert S, Charafe-Jauffret E, Jacquemier J, Lopez M, Borg JP, Sotiriou C, Popovici C, Bertucci F, Birnbaum D, Chaffanet M, Ginestier C. ZNF703 gene amplification at 8p12 specifies luminal B breast cancer. EMBO Mol Med. 2011 Mar;3(3):153-66
» PubMed
2010 / 10.1002/emmm.200900054
Bedard PL, Sotiriou C. Decoding the evolution of a breast cancer genome. EMBO Mol Med. 2010 Jan;2(1):3-5
» PubMed
2010 / 10.1097/CCO.0b013e32833de186
Criscitiello C, Sotiriou C, Ignatiadis M. Circulating tumor cells and emerging blood biomarkers in breast cancer. Curr Opin Oncol. 2010 Nov;22(6):552-8
» PubMed
2010 / 10.1016/S1470-2045(10)70018-8
Juul N, Szallasi Z, Eklund AC, Li Q, Burrell RA, Gerlinger M, Valero V, Andreopoulou E, Esteva FJ, Symmans WF, Desmedt C, Haibe-Kains B, Sotiriou C, Pusztai L, Swanton C. Assessment of an RNA interference screen-derived mitotic and ceramide pathway metagene as a predictor of response to neoadjuvant paclitaxel for primary triple-negative breast cancer: a retrospective analysis of five clinical trials. Lancet Oncol. 2010 Apr;11(4):358-65
» PubMed
2010 / 10.1038/nm.2090
Li Y, Zou L, Li Q, Haibe-Kains B, Tian R, Li Y, Desmedt C, Sotiriou C, Szallasi Z, Iglehart JD, Richardson AL, Wang ZC. Amplification of LAPTM4B and YWHAZ contributes to chemotherapy resistance and recurrence of breast cancer. Nat Med. 2010 Feb;16(2):214-8
» PubMed
2010 / 10.1073/pnas.0907011107
Loi S, Haibe-Kains B, Majjaj S, Lallemand F, Durbecq V, Larsimont D, Gonzalez-Angulo AM, Pusztai L, Symmans WF, Bardelli A, Ellis P, Tutt AN, Gillett CE, Hennessy BT, Mills GB, Phillips WA, Piccart MJ, Speed TP, McArthur GA, Sotiriou C. PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer. Proc Natl Acad Sci U S A. 2010 Jun 1;107(22):10208-13
» PubMed
2010 / 10.1126/scitranslmed.3001329
Reis-Filho JS, Weigelt B, Fumagalli D, Sotiriou C. Molecular profiling: moving away from tumor philately. Sci Transl Med. 2010 Sep 1;2(47):47ps43
» PubMed
2010 / 10.1200/JCO.2010.28.4273
Symmans WF, Hatzis C, Sotiriou C, Andre F, Peintinger F, Regitnig P, Daxenbichler G, Desmedt C, Domont J, Marth C, Delaloge S, Bauernhofer T, Valero V, Booser DJ, Hortobagyi GN, Pusztai L. Genomic index of sensitivity to endocrine therapy for breast cancer. J Clin Oncol. 2010 Sep 20;28(27):4111-9
» PubMed
2010 / 10.1371/journal.pone.0012100
Toussaint J, Durbecq V, Altintas S, Doriath V, Rouas G, Paesmans M, Bedard P, Haibe-Kains B, Tjalma WA, Larsimont D, Piccart M, Sotiriou C. Low CD10 mRNA expression identifies high-risk ductal carcinoma in situ (DCIS). PLoS One. 2010 Aug 10;5(8). pii: e12100
» PubMed
2009 / 10.1158/1078-0432.CCR-08-1844
Ignatiadis M, Desmedt C, Sotiriou C, de Azambuja E, Piccart M. HER-2 as a target for breast cancer therapy. Clin Cancer Res. 2009 Mar 15;15(6):1848-52
» PubMed
2009 / 10.1200/JCO.2008.18.5934
Liedtke C, Hatzis C, Symmans WF, Desmedt C, Haibe-Kains B, Valero V, Kuerer H, Hortobagyi GN, Piccart-Gebhart M, Sotiriou C, Pusztai L. Genomic grade index is associated with response to chemotherapy in patients with breast cancer. J Clin Oncol. 2009 Jul 1;27(19):3185-91
» PubMed
2009 / 10.1056/NEJMra0801289
Sotiriou C, Pusztai L. Gene-expression signatures in breast cancer. N Engl J Med. 2009 Feb 19;360(8):790-800
» PubMed
2008 / 10.1158/1078-0432.CCR-07-1755
Camps C, Buffa FM, Colella S, Moore J, Sotiriou C, Sheldon H, Harris AL, Gleadle JM, Ragoussis J. hsa-miR-210 Is induced by hypoxia and is an independent prognostic factor in breast cancer. Clin Cancer Res. 2008 Mar 1;14(5):1340-8
» PubMed
2008 / 10.1186/1471-2164-9-239
Loi S, Haibe-Kains B, Desmedt C, Wirapati P, Lallemand F, Tutt AM, Gillet C, Ellis P, Ryder K, Reid JF, Daidone MG, Pierotti MA, Berns EM, Jansen MP, Foekens JA, Delorenzi M, Bontempi G, Piccart MJ, Sotiriou C. Predicting prognosis using molecular profiling in estrogen receptor-positive breast cancer treated with tamoxifen. BMC Genomics. 2008 May 22;9:239
» PubMed
2008 / 10.1158/1078-0432.CCR-07-5026
Ma XJ, Salunga R, Dahiya S, Wang W, Carney E, Durbecq V, Harris A, Goss P, Sotiriou C, Erlander M, Sgroi D. A five-gene molecular grade index and HOXB13:IL17BR are complementary prognostic factors in early stage breast cancer. Clin Cancer Res. 2008 May 1;14(9):2601-8
» PubMed
2007
Andre F, Hatzis C, Anderson K, Sotiriou C, Mazouni C, Mejia J, Wang B, Hortobagyi GN, Symmans WF, Pusztai L. Microtubule-associated protein-tau is a bifunctional predictor of endocrine sensitivity and chemotherapy resistance in estrogen receptor-positive breast cancer. Clin Cancer Res. 2007 Apr 1;13(7):2061-7
» PubMed
2007
Desmedt C, Piette F, Loi S, Wang Y, Lallemand F, Haibe-Kains B, Viale G, Delorenzi M, Zhang Y, d'Assignies MS, Bergh J, Lidereau R, Ellis P, Harris AL, Klijn JG, Foekens JA, Cardoso F, Piccart MJ, Buyse M, Sotiriou C; TRANSBIG Consortium. Strong time dependence of the 76-gene prognostic signature for node-negative breast cancer patients in the TRANSBIG multicenter independent validation series. Clin Cancer Res. 2007 Jun 1;13(11):3207-14
» PubMed
2007
Gong Y, Yan K, Lin F, Anderson K, Sotiriou C, Andre F, Holmes FA, Valero V, Booser D, Pippen JE Jr, Vukelja S, Gomez H, Mejia J, Barajas LJ, Hess KR, Sneige N, Hortobagyi GN, Pusztai L, Symmans WF. Determination of oestrogen-receptor status and ERBB2 status of breast carcinoma: a gene-expression profiling study. Lancet Oncol. 2007 Mar;8(3):203-11
» PubMed
2007 / 10.3816/CBC.2007.n.054
Ignatiadis M, Perraki M, Apostolaki S, Politaki E, Xenidis N, Kafousi M, Stathopoulos E, Lianidou E, Sotiriou C, Georgoulias V, Mavroudis D. Molecular detection and prognostic value of circulating cytokeratin-19 messenger RNA-positive and HER2 messenger RNA-positive cells in the peripheral blood of women with early-stage breast cancer. Clin Breast Cancer. 2007 Dec;7(11):883-9
» PubMed
2007
Ignatiadis M, Xenidis N, Perraki M, Apostolaki S, Politaki E, Kafousi M, Stathopoulos EN, Stathopoulou A, Lianidou E, Chlouverakis G, Sotiriou C, Georgoulias V, Mavroudis D. Different prognostic value of cytokeratin-19 mRNA positive circulating tumor cells according to estrogen receptor and HER2 status in early-stage breast cancer. J Clin Oncol. 2007 Nov 20;25(33):5194-202
» PubMed
2007
Loi S, Haibe-Kains B, Desmedt C, Lallemand F, Tutt AM, Gillet C, Ellis P, Harris A, Bergh J, Foekens JA, Klijn JG, Larsimont D, Buyse M, Bontempi G, Delorenzi M, Piccart MJ, Sotiriou C. Definition of clinically distinct molecular subtypes in estrogen receptor-positive breast carcinomas through genomic grade. J Clin Oncol. 2007 Apr 1;25(10):1239-46
» PubMed
2007
Sotiriou C, Piccart MJ. Taking gene-expression profiling to the clinic: when will molecular signatures become relevant to patient care? Nat Rev Cancer. 2007 Jul;7(7):545-53
» PubMed
2006
Buyse M, Loi S, van't Veer L, Viale G, Delorenzi M, Glas AM, d'Assignies MS, Bergh J, Lidereau R, Ellis P, Harris A, Bogaerts J, Therasse P, Floore A, Amakrane M, Piette F, Rutgers E, Sotiriou C, Cardoso F, Piccart MJ; TRANSBIG Consortium. Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer. J Natl Cancer Inst. 2006 Sep 6;98(17):1183-92
» PubMed
2006
Sotiriou C, Wirapati P, Loi S, Harris A, Fox S, Smeds J, Nordgren H, Farmer P, Praz V, Haibe-Kains B, Desmedt C, Larsimont D, Cardoso F, Peterse H, Nuyten D, Buyse M, Van de Vijver MJ, Bergh J, Piccart M, Delorenzi M. Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis. J Natl Cancer Inst. 2006 Feb 15;98(4):262-72
» PubMed
2003
Sotiriou C, Neo SY, McShane LM, Korn EL, Long PM, Jazaeri A, Martiat P, Fox SB, Harris AL, Liu ET. Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10393-8
» PubMed