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. 2019 Jul 11;19(1):681.
doi: 10.1186/s12885-019-5842-7.

External validation of molecular subtype classifications of colorectal cancer based on microsatellite instability, CIMP, BRAF and KRAS

Elizabeth Alwers  1 , Hendrik Bläker  2 , Viola Walter  1 , Lina Jansen  1 , Matthias Kloor  3 , Alexander Arnold  2 , Julia Sieber-Frank  3 , Esther Herpel  4   5 , Katrin E Tagscherer  4   6 , Wilfried Roth  4   6 , Jenny Chang-Claude  7   8 , Hermann Brenner  1   9   10 , Michael Hoffmeister  11
Affiliations

External validation of molecular subtype classifications of colorectal cancer based on microsatellite instability, CIMP, BRAF and KRAS

Elizabeth Alwers et al. BMC Cancer. .

Abstract

Background: Competing molecular classification systems have been proposed to complement the TNM staging system for a better prediction of survival in colorectal cancer (CRC). However, validation studies are so far lacking. The aim of this study was to validate and extend previously published molecular classifications of CRC in a large independent cohort of CRC patients.

Methods: CRC patients were recruited into a population-based cohort study (DACHS). Molecular subtypes were categorized based on three previously published classifications. Cox-proportional hazard models, based on the same set of patients and using the same confounders as reported by the original studies, were used to determine overall, cancer-specific, or relapse-free survival for each subtype. Hazard ratios and confidence intervals, as well as Kaplan-Meier plots were compared to those reported by the original studies.

Results: We observed similar patterns of worse survival for the microsatellite stable (MSS)/BRAF-mutated and MSS/KRAS-mutated subtypes in our validation analyses, which were included in two of the validated classifications. Of the two MSI subtypes, one defined by additional presence of CIMP-high and BRAF-mutation and the other by tumors negative for CIMP, BRAF and KRAS-mutations, we could not confirm associations with better prognosis as suggested by one of the classifications. For two of the published classifications, we were able to provide results for additional subgroups not included in the original studies (men, other disease stages, other locations).

Conclusions: External validation of three previously proposed classifications confirmed findings of worse survival for CRC patients with MSS subtypes and BRAF or KRAS mutations. Regarding MSI subtypes, other patient characteristics such as stage of the tumor, may influence the potential survival benefit. Further integration of methylation, genetic, and immunological information is needed to develop and validate a comprehensive classification that will have relevance for use in clinical practice.

Keywords: Cancer-specific survival; Colorectal cancer; External validation; Molecular subtypes.

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Conflict of interest statement

The authors declare that they have no competing interests. Author MK is an Editorial Board member for the journal.

Figures

Fig. 1
Fig. 1
Kaplan-Meier curves for each classification within DACHS patient cohort. A. Cancer-specific survival for the classification by Samadder et al. [20] B. Cancer-specific survival for the classification by Phipps et al. [21] C. Relapse-free survival for the classification by Sinicrope et al. [16]
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References

    1. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al. GLOBOCAN 2012. v1.0, Cancer incidence and mortality worldwide: IARC CancerBase no.11. Lyon: International Agency for Research on Cancer; 2013.
    1. Siegel R, Miller KD, Fedewa SA, Ahnen DJ, Meester RG, Barzi A, et al. Colorectal Cancer statistics, 2017. CA Cancer J Clin. 2017;67:177–193. doi: 10.3322/caac.21395. - DOI - PubMed
    1. Kawakami H, Zaanan A, Sinicrope FA. Microsatellite instability testing and its role in the management of colorectal cancer. Curr Treat Options in Oncol. 2015;16(7):30. doi: 10.1007/s11864-015-0348-2. - DOI - PMC - PubMed
    1. Hutchins G, Southward K, Handley K, Magill L, Beaumont C, Stahlschmidt J, et al. Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer. J Clin Oncol. 2011;29(10):1261–1270. doi: 10.1200/JCO.2010.30.1366. - DOI - PubMed
    1. Guastadisegni C, Colafranceschi M, Ottini L, Dogliotti E. Microsatellite instability as a marker of prognosis and response to therapy: a meta-analysis of colorectal cancer survival data. Eur J Cancer. 2010;46(15):2788–2798. doi: 10.1016/j.ejca.2010.05.009. - DOI - PubMed

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