The Consensus Molecular Subtypes of Colorectal Cancer

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2015 Oct 13

PMID 26457759

Citations 2365

Authors

Justin Guinney

Rodrigo Dienstmann

Xin Wang

Aurelien De Reynies

Andreas Schlicker

Charlotte Soneson

Laetitia Marisa

Paul Roepman

Gift Nyamundanda

Paolo Angelino

Brian M Bot

Jeffrey S Morris

Iris M Simon

Sarah Gerster

Evelyn Fessler

Felipe de Sousa E Melo

Edoardo Missiaglia

Hena Ramay

David Barras

Krisztian Homicsko

Dipen Maru

Ganiraju C Manyam

Bradley Broom

Valerie Boige

Beatriz Perez-Villamil

Ted Laderas

Ramon Salazar

Joe W Gray

Douglas Hanahan

Josep Tabernero

Rene Bernards

Stephen H Friend

Pierre Laurent-Puig

Jan Paul Medema

Anguraj Sadanandam

Lodewyk Wessels

Mauro Delorenzi

Scott Kopetz

Louis Vermeulen

Sabine Tejpar

Affiliations

Soon will be listed here.

Abstract

Colorectal cancer (CRC) is a frequently lethal disease with heterogeneous outcomes and drug responses. To resolve inconsistencies among the reported gene expression-based CRC classifications and facilitate clinical translation, we formed an international consortium dedicated to large-scale data sharing and analytics across expert groups. We show marked interconnectivity between six independent classification systems coalescing into four consensus molecular subtypes (CMSs) with distinguishing features: CMS1 (microsatellite instability immune, 14%), hypermutated, microsatellite unstable and strong immune activation; CMS2 (canonical, 37%), epithelial, marked WNT and MYC signaling activation; CMS3 (metabolic, 13%), epithelial and evident metabolic dysregulation; and CMS4 (mesenchymal, 23%), prominent transforming growth factor-β activation, stromal invasion and angiogenesis. Samples with mixed features (13%) possibly represent a transition phenotype or intratumoral heterogeneity. We consider the CMS groups the most robust classification system currently available for CRC-with clear biological interpretability-and the basis for future clinical stratification and subtype-based targeted interventions.

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References

Perez-Villamil B, Romera-Lopez A, Hernandez-Prieto S, Lopez-Campos G, Calles A, Lopez-Asenjo J . Colon cancer molecular subtypes identified by expression profiling and associated to stroma, mucinous type and different clinical behavior. BMC Cancer. 2012; 12:260. PMC: 3571914. DOI: 10.1186/1471-2407-12-260. View

Tamborero D, Gonzalez-Perez A, Perez-Llamas C, Deu-Pons J, Kandoth C, Reimand J . Comprehensive identification of mutational cancer driver genes across 12 tumor types. Sci Rep. 2013; 3:2650. PMC: 3788361. DOI: 10.1038/srep02650. View

Van Cutsem E, Labianca R, Bodoky G, Barone C, Aranda E, Nordlinger B . Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3. J Clin Oncol. 2009; 27(19):3117-25. DOI: 10.1200/JCO.2008.21.6663. View

Murray J, Dunson D, Carin L, Lucas J . Bayesian Gaussian Copula Factor Models for Mixed Data. J Am Stat Assoc. 2013; 108(502):656-665. PMC: 3753118. DOI: 10.1080/01621459.2012.762328. View

Johnson S, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A . RAS is regulated by the let-7 microRNA family. Cell. 2005; 120(5):635-47. DOI: 10.1016/j.cell.2005.01.014. View

Llosa N, Cruise M, Tam A, Wicks E, Hechenbleikner E, Taube J . The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 2014; 5(1):43-51. PMC: 4293246. DOI: 10.1158/2159-8290.CD-14-0863. View

Park S, Gaur A, Lengyel E, Peter M . The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev. 2008; 22(7):894-907. PMC: 2279201. DOI: 10.1101/gad.1640608. View

Kosinski C, Li V, Chan A, Zhang J, Ho C, Tsui W . Gene expression patterns of human colon tops and basal crypts and BMP antagonists as intestinal stem cell niche factors. Proc Natl Acad Sci U S A. 2007; 104(39):15418-23. PMC: 2000506. DOI: 10.1073/pnas.0707210104. View

Mlecnik B, Tosolini M, Charoentong P, Kirilovsky A, Bindea G, Berger A . Biomolecular network reconstruction identifies T-cell homing factors associated with survival in colorectal cancer. Gastroenterology. 2009; 138(4):1429-40. DOI: 10.1053/j.gastro.2009.10.057. View

10.

Wang L, Shi Z, Jiang C, Liu X, Chen Q, Qian X . MiR-143 acts as a tumor suppressor by targeting N-RAS and enhances temozolomide-induced apoptosis in glioma. Oncotarget. 2014; 5(14):5416-27. PMC: 4170647. DOI: 10.18632/oncotarget.2116. View

11.

Hoadley K, Yau C, Wolf D, Cherniack A, Tamborero D, Ng S . Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin. Cell. 2014; 158(4):929-944. PMC: 4152462. DOI: 10.1016/j.cell.2014.06.049. View

12.

Li Y, Choi P, Casey S, Dill D, Felsher D . MYC through miR-17-92 suppresses specific target genes to maintain survival, autonomous proliferation, and a neoplastic state. Cancer Cell. 2014; 26(2):262-72. PMC: 4191901. DOI: 10.1016/j.ccr.2014.06.014. View

13.

Schlicker A, Beran G, Chresta C, McWalter G, Pritchard A, Weston S . Subtypes of primary colorectal tumors correlate with response to targeted treatment in colorectal cell lines. BMC Med Genomics. 2013; 5:66. PMC: 3543849. DOI: 10.1186/1755-8794-5-66. View

14.

Marisa L, De Reynies A, Duval A, Selves J, Gaub M, Vescovo L . Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value. PLoS Med. 2013; 10(5):e1001453. PMC: 3660251. DOI: 10.1371/journal.pmed.1001453. View

15.

Johnson W, Li C, Rabinovic A . Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics. 2006; 8(1):118-27. DOI: 10.1093/biostatistics/kxj037. View

16.

Brunet J, Tamayo P, Golub T, Mesirov J . Metagenes and molecular pattern discovery using matrix factorization. Proc Natl Acad Sci U S A. 2004; 101(12):4164-9. PMC: 384712. DOI: 10.1073/pnas.0308531101. View

17.

Carter S, Cibulskis K, Helman E, McKenna A, Shen H, Zack T . Absolute quantification of somatic DNA alterations in human cancer. Nat Biotechnol. 2012; 30(5):413-21. PMC: 4383288. DOI: 10.1038/nbt.2203. View

18.

Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C . Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006; 313(5795):1960-4. DOI: 10.1126/science.1129139. View

19.

Le D, Uram J, Wang H, Bartlett B, Kemberling H, Eyring A . PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015; 372(26):2509-20. PMC: 4481136. DOI: 10.1056/NEJMoa1500596. View

20.

Qiao X, Zhang H, Liu Y, Todd M, Marron J . Weighted Distance Weighted Discrimination and Its Asymptotic Properties. J Am Stat Assoc. 2010; 105(489):401-414. PMC: 2996856. DOI: 10.1198/jasa.2010.tm08487. View