Subtyping of Microsatellite Instability-high Colorectal Cancer

Overview

Journal Cell Commun Signal

Publisher Biomed Central

Specialties Biochemistry
Cell Biology

Date 2019 Jul 24

PMID 31331345

Citations 29

Authors

Wangxiong Hu

Yanmei Yang

Lina Qi

Jiani Chen

Weiting Ge

Shu Zheng

Affiliations

Soon will be listed here.

Abstract

Background: Patients with microsatellite instability-high (MSI-H) colorectal cancer (CRC) generally have a better prognosis than patients with microsatellite stable (MSS) CRC. However, some MSI-H CRC patients do not gain overall survival benefits from immune checkpoint-blockade treatment. In other words, heterogeneity within the subgroup of MSI-H tumors remains poorly understood. Thus, an in-depth molecular characterization of MSI-H tumors is urgently required.

Methods: Here, we use nonnegative matrix factorization (NMF)-based consensus clustering to define CRC MSI-H subtypes in The Cancer Genome Atlas and a French multicenter cohort GSE39582. CIBERSORT was used to calculate the proportions of 22 lymphocytes in tumor tissue in MSI-H subtypes.

Results: MSI-H CRC samples basically clustered into two subgroups (MSI-H1 and MSI-H2). MSI-H1 was characterized by a lower BRAF mutational status, higher frequency of chromosomal instability, global hypomethylation, and worse survival than MSI-H2. Further examination of the immune landscape showed that macrophages of the M2 phenotype were enriched in MSI-H1, which may be associated with poor prognosis in this subgroup.

Conclusions: Our results illustrate the genetic heterogeneity in MSI-H CRCs and macrophages may serve as good targets for anticancer therapy in MSI-H1.

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References

Ogino S, Nowak J, Hamada T, Milner Jr D, Nishihara R . Insights into Pathogenic Interactions Among Environment, Host, and Tumor at the Crossroads of Molecular Pathology and Epidemiology. Annu Rev Pathol. 2018; 14:83-103. PMC: 6345592. DOI: 10.1146/annurev-pathmechdis-012418-012818. View

Cremolini C, Di Bartolomeo M, Amatu A, Antoniotti C, Moretto R, Berenato R . BRAF codons 594 and 596 mutations identify a new molecular subtype of metastatic colorectal cancer at favorable prognosis. Ann Oncol. 2015; 26(10):2092-7. DOI: 10.1093/annonc/mdv290. View

Sveen A, Johannessen B, Tengs T, Danielsen S, Eilertsen I, Lind G . Multilevel genomics of colorectal cancers with microsatellite instability-clinical impact of JAK1 mutations and consensus molecular subtype 1. Genome Med. 2017; 9(1):46. PMC: 5442873. DOI: 10.1186/s13073-017-0434-0. View

Barras D, Missiaglia E, Wirapati P, Sieber O, Jorissen R, Love C . BRAF V600E Mutant Colorectal Cancer Subtypes Based on Gene Expression. Clin Cancer Res. 2016; 23(1):104-115. DOI: 10.1158/1078-0432.CCR-16-0140. View

Gaujoux R, Seoighe C . A flexible R package for nonnegative matrix factorization. BMC Bioinformatics. 2010; 11:367. PMC: 2912887. DOI: 10.1186/1471-2105-11-367. View

Tran B, Kopetz S, Tie J, Gibbs P, Jiang Z, Lieu C . Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer. 2011; 117(20):4623-32. PMC: 4257471. DOI: 10.1002/cncr.26086. View

Binnewies M, Roberts E, Kersten K, Chan V, Fearon D, Merad M . Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med. 2018; 24(5):541-550. PMC: 5998822. DOI: 10.1038/s41591-018-0014-x. View

Yamaguchi T, Fushida S, Yamamoto Y, Tsukada T, Kinoshita J, Oyama K . Tumor-associated macrophages of the M2 phenotype contribute to progression in gastric cancer with peritoneal dissemination. Gastric Cancer. 2015; 19(4):1052-1065. PMC: 5034006. DOI: 10.1007/s10120-015-0579-8. View

Langfelder P, Horvath S . WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics. 2008; 9:559. PMC: 2631488. DOI: 10.1186/1471-2105-9-559. View

10.

Hu W, Yang Y, Li X, Huang M, Xu F, Ge W . Multi-omics Approach Reveals Distinct Differences in Left- and Right-Sided Colon Cancer. Mol Cancer Res. 2017; 16(3):476-485. DOI: 10.1158/1541-7786.MCR-17-0483. View

11.

Phipps A, Limburg P, Baron J, Burnett-Hartman A, Weisenberger D, Laird P . Association between molecular subtypes of colorectal cancer and patient survival. Gastroenterology. 2014; 148(1):77-87.e2. PMC: 4274235. DOI: 10.1053/j.gastro.2014.09.038. View

12.

Svensson S, Abrahamsson A, Rodriguez G, Olsson A, Jensen L, Cao Y . CCL2 and CCL5 Are Novel Therapeutic Targets for Estrogen-Dependent Breast Cancer. Clin Cancer Res. 2015; 21(16):3794-805. DOI: 10.1158/1078-0432.CCR-15-0204. View

13.

Taieb J, Le Malicot K, Shi Q, Penault-Llorca F, Bouche O, Tabernero J . Prognostic Value of BRAF and KRAS Mutations in MSI and MSS Stage III Colon Cancer. J Natl Cancer Inst. 2017; 109(5). PMC: 6075212. DOI: 10.1093/jnci/djw272. 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.

Guinney J, Dienstmann R, Wang X, De Reynies A, Schlicker A, Soneson C . The consensus molecular subtypes of colorectal cancer. Nat Med. 2015; 21(11):1350-6. PMC: 4636487. DOI: 10.1038/nm.3967. View

16.

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

17.

Germano G, Lamba S, Rospo G, Barault L, Magri A, Maione F . Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth. Nature. 2017; 552(7683):116-120. DOI: 10.1038/nature24673. View

18.

Hutchins L, Murphy S, Singh P, Graber J . Position-dependent motif characterization using non-negative matrix factorization. Bioinformatics. 2008; 24(23):2684-90. PMC: 2639279. DOI: 10.1093/bioinformatics/btn526. View

19.

Yu G, Wang L, Han Y, He Q . clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012; 16(5):284-7. PMC: 3339379. DOI: 10.1089/omi.2011.0118. View

20.

Gautier L, Cope L, Bolstad B, Irizarry R . affy--analysis of Affymetrix GeneChip data at the probe level. Bioinformatics. 2004; 20(3):307-15. DOI: 10.1093/bioinformatics/btg405. View