Fondation MEDIC

www.fondation-medic.ch

Comprehensive molecular characterization of colorectal liver metastases: a step towards personalized medicine in stage IV colon cancer
[13.09.2015]
Project leader – Arnaud Roth
Arnaud Roth

Prof. A. Roth received his medical degree from the Faculty of Medicine, University of Geneva, Switzerland. He received his training in internal medicine at the University Hospital of Geneva and at the Hammersmith Hospital in London (UK). He then trained as a fellow in hemato-oncology for three years at the Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA. He is presently in charge of the Digestive Tumors Unit in the Department of Medical specialties, at Geneva University Hospital.

As part of his scientific activities Prof. A. Roth served as chairman of the GI project group of the Swiss Group for Clinical Cancer Research (SAKK) from 1997 to 2005. He is also an active member of the European Organization for Research and Treatment of Cancer (EORTC), where he served as chairman of the EORTC-GI project group from 2010 to 2014. His scientific interests are centered on translational research programs on prognostic/predictive molecular biomarkers in colon cancer, new treatment strategy for the management of liver metastasis from colorectal cancers, and development of new systemic therapy in gastric cancer.

Department of Internal Medicine Specialties
Division of Oncology
HUG
4 rue Gabrielle-Perret-Gentil
CH-1211 Genčve 14

E-Mail: arnaud.roth@hcuge.ch
Phone: +41 22 372 77 44

HUG website - Division of Oncology

Group members
 

Tom McKee MD, PhD

Pathologist

Mauro Delorenzi, PhD

Bio-statistician

Sabine Tejpar MD, PhD

Digestive tract oncologist

Petro Tsantoulis MD, PhD

Oncologist

Wulfran Cacheux MD, PhD

Digestive tract oncologist

Laura Rubbia-Brandt MD, PhD

Pathologist

Project description
 

Comprehensive molecular characterization of colorectal cancer liver metastases, a step towards personalized medicine in advanced colorectal cancer (CRC).

The project proposes to perform detailed comparative analysis of primary colorectal carcinomas and their liver metastases focusing on gene expression and digital morphologic analysis. It is part of a larger international collaborative effort to characterize liver metastases relative to the primary tumor, including DNA copy number aberrations and gene mutations, initially using fresh frozen tissue samples, which will subsequently be expanded to a large series of formalin-fixed, paraffin-embedded tissue sample pairs of untreated cases.

The first part of the project will extend to this group of metastatic (stage IV) carcinomas gene expression analyses already performed on a large group of stage II and III colorectal carcinomas. Questions are whether all previously identified molecular subtypes are also found in more advanced cancers and their metastases? Are there molecular subtype changes between primary tumor and metastasis? How do low-risk primary colon carcinomas progress into high-risk liver metastases?

In the second part we will integrate quantitative morphologic data with gene expression and clinical data. The high spatial resolution of morphology allows us to separately analyze the malignant epithelial component and reactive stroma as well as the center of the tumor relative to the invasion front. The fundamental question here is how different elements of the tissue contribute to the genomic and transcriptomic data. This potentially will provide novel information allowing us to refine prognostic or predictive parameters and include novel elements such as the role of the immune system in prognosis and therapy response.

Publications
 
2015 / doi: 10.1016/j.molonc.2015.02.008. PMID: 25759163.
Jensen NF, Stenvang J, Beck MK, Hanáková B, Belling KC, Do KN, Viuff B, Nygĺrd SB, Gupta R, Rasmussen MH, Tarpgaard LS, Hansen TP, Budinská E, Pfeiffer P, Bosman F, Tejpar S, Roth A, Delorenzi M, Andersen CL, Rřmer MU, Brünner N, Moreira JM. Establishment and characterization of models of chemotherapy resistance in colorectal cancer: Towards a predictive signature of chemoresistance. Mol Oncol. 2015 Feb 24
» PubMed
2015 / 10.1016/j.clcc.2014.11.002
Gustavsson B, Carlsson G, Machover D, Petrelli N, Roth A, Schmoll HJ, Tveit KM, Gibson F. A review of the evolution of systemic chemotherapy in the management of colorectal cancer. Clin Colorectal Cancer. 2015 Mar;14(1):1-10
» PubMed
2015 / PMID: 25361982.
Klingbiel D, Saridaki Z, Roth AD, Bosman F, Delorenzi M, Tejpar S. Prognosis of stage II and III colon carcinoma treated with adjuvant 5-FU or FOLFIRI in relation to microsatellite status, results of the PETACC-3 trial. Ann Oncol. 2015 Jan;26(1):126-32 2014 Oct 30.
» PubMed
2014 / doi: 10.1093/annonc/mdu275. PMID: 25057166.
Missiaglia E, Jacobs B, D'Ario G, F. Di Narzo AF, Soneson C, Eva Budinska E, Popovici V, Vecchione L, Gerster S, Pu Yan P, Roth AD, Dirk D, Bosman F, Delorenzi M, Tejpar S. Distal and proximal colon cancers differ in terms of molecular, pathological and clinical features. Ann Oncol. 2014 Oct;25(10):1995-2001
» PubMed
2014 / doi: 10.1093/jnci/dju247. PMID: 25246611
Di Narzo AF, Tejpar S, Rossi S, Yan P, Popovici V, Wirapati P, Budinska E, Xie T, Estrella H, Pavlicek A, Mao M, Martin E, Scott W, Bosman F, Roth A, Delorenzi M. Test of four Colon Cancer Risk-Scores in FFPE Microarray Gene Expression data. J Natl Cancer Inst. 2014: Sep 22: 106(10).
» PubMed
2013 / 10.1002/path.4212
Budinska E, Popovici V, Tejpar S, D'Ario G, Lapique N, Sikora KO, Di Narzo AF, Yan P, Hodgson JG, Weinrich S, Bosman F, Roth A, Delorenzi M. Gene expression patterns unveil a new level of molecular heterogeneity in colorectal cancer. J Pathol. 2013 Jul 8
» PubMed
2013 / doi: 10.1186/1471-2407-13-439
Popovici V, Budinska E, Bosman FT, Tejpar S, Roth AD, Delorenzi M. Context-dependent interpretation of the prognostic value of BRAF and KRAS mutations in colorectal cancer. BMC Cancer. 2013 Sep 27;13:439
» PubMed
2012
Rossi S, Di Narzo AF, Mestdagh P, Jacobs B, Bosman FT, Gustavsson B, Majoie B, Roth A, Vandesompele J, Rigoutsos I, Delorenzi M, Tejpar S. microRNAs in colon cancer: a roadmap for discovery. FEBS Lett. 2012 Sep 21;586(19):3000-7
» PubMed
2012 / 10.1200/JCO.2011.39.5814
Popovici V, Budinska E, Tejpar S, Weinrich S, Estrella H, Hodgson G, Van Cutsem E, Xie T, Bosman FT, Roth AD, Delorenzi M. Identification of a poor-prognosis BRAF-mutant-like population of patients with colon cancer. J Clin Oncol. 2012 Apr 20;30(12):1288-95
» PubMed
2012 / 10.1093/jnci/djs427
Roth AD, Delorenzi M, Tejpar S, Yan P, Klingbiel D, Fiocca R, d'Ario G, Cisar L, Labianca R, Cunningham D, Nordlinger B, Bosman F, Van Cutsem E. Integrated analysis of molecular and clinical prognostic factors in stage II/III colon cancer. J Natl Cancer Inst. 2012 Nov 7;104(21):1635-46
» PubMed
2012 / 10.1371/journal.pone.0042001
Xie T, D' Ario G, Lamb JR, Martin E, Wang K, Tejpar S, Delorenzi M, Bosman FT, Roth AD, Yan P, Bougel S, Di Narzo AF, Popovici V, Budinská E, Mao M, Weinrich SL, Rejto PA, Hodgson JG. A comprehensive characterization of genome-wide copy number aberrations in colorectal cancer reveals novel oncogenes and patterns of alterations. PLoS One. 2012;7(7):e42001
» PubMed
2011 / 10.1093/jnci/djr170
Tejpar S, Saridaki Z, Delorenzi M, Bosman F, Roth AD. Microsatellite instability, prognosis and drug sensitivity of stage II and III colorectal cancer: more complexity to the puzzle. J Natl Cancer Inst. 2011 Jun 8;103(11):841-4
» PubMed
2010 / 10.1200/JCO.2009.23.3452
Roth AD, Tejpar S, Delorenzi M, Yan P, Fiocca R, Klingbiel D, Dietrich D, Biesmans B, Bodoky G, Barone C, Aranda E, Nordlinger B, Cisar L, Labianca R, Cunningham D, Van Cutsem E, Bosman F. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol. 2010 Jan 20;28(3):466-74
» PubMed
2010 / 10.1634/theoncologist.2009-0233
Tejpar S, Bertagnolli M, Bosman F, Lenz HJ, Garraway L, Waldman F, Warren R, Bild A, Collins-Brennan D, Hahn H, Harkin DP, Kennedy R, Ilyas M, Morreau H, Proutski V, Swanton C, Tomlinson I, Delorenzi M, Fiocca R, Van Cutsem E, Roth A. Prognostic and predictive biomarkers in resected colon cancer: current status and future perspectives for integrating genomics into biomarker discovery. Oncologist. 2010;15(4):390-404
» PubMed