Gastroenterology

Gastroenterology

Volume 148, Issue 1, January 2015, Pages 77-87.e2
Gastroenterology

Original Research
Full Report: Clinical—Alimentary Tract
Association Between Molecular Subtypes of Colorectal Cancer and Patient Survival

https://doi.org/10.1053/j.gastro.2014.09.038Get rights and content

Background and Aims

Colorectal cancer (CRC) is a heterogeneous disease that can develop via several pathways. Different CRC subtypes, identified based on tumor markers, have been proposed to reflect these pathways. We evaluated the significance of these previously proposed classifications to survival.

Methods

Participants in the population-based Seattle Colon Cancer Family Registry were diagnosed with invasive CRC from 1998 through 2007 in western Washington State (N = 2706), and followed for survival through 2012. Tumor samples were collected from 2050 participants and classified into 5 subtypes based on combinations of tumor markers: type 1 (microsatellite instability [MSI]–high, CpG island methylator phenotype [CIMP] –positive, positive for BRAF mutation, negative for KRAS mutation); type 2 (microsatellite stable [MSS] or MSI-low, CIMP-positive, positive for BRAF mutation, negative for KRAS mutation); type 3 (MSS or MSI low, non-CIMP, negative for BRAF mutation, positive for KRAS mutation); type 4 (MSS or MSI-low, non-CIMP, negative for mutations in BRAF and KRAS); and type 5 (MSI-high, non-CIMP, negative for mutations in BRAF and KRAS). Multiple imputation was used to impute tumor markers for those missing data on 1–3 markers. We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations of subtypes with disease-specific and overall mortality, adjusting for age, sex, body mass, diagnosis year, and smoking history.

Results

Compared with participants with type 4 tumors (the most predominant), participants with type 2 tumors had the highest disease-specific mortality (HR = 2.20, 95% CI: 1.47–3.31); subjects with type 3 tumors also had higher disease-specific mortality (HR = 1.32, 95% CI: 1.07–1.63). Subjects with type 5 tumors had the lowest disease-specific mortality (HR = 0.30, 95% CI: 0.14–0.66). Associations with overall mortality were similar to those with disease-specific mortality.

Conclusions

Based on a large, population-based study, CRC subtypes, defined by proposed etiologic pathways, are associated with marked differences in survival. These findings indicate the clinical importance of studies into the molecular heterogeneity of CRC.

Section snippets

Study Population

A description of the study populations has been published elsewhere.24, 25 Briefly, SCCFR study participants included persons diagnosed with incident invasive CRC between January 1998 and June 2002 who, at the time of diagnosis, were aged 20–74 years and resided in King, Pierce, or Snohomish counties of Washington State (Supplementary Table 1). During this same period, women aged 50–74 years at CRC diagnosis and residing in 10 surrounding counties were also recruited for participation in the

Results

Among the 2080 cases with available tumor tissue, 99% (n = 2050) had information on at least one tumor marker and were included in the analysis; 65% (n = 1344) had complete data on all tumor markers. Approximately 16% of cases had tumors that were MSI-high, 13% had tumors that were BRAF-mutated, 31% had KRAS-mutated tumors, and 18% had CIMP-positive tumors. Among those with complete tumor marker data, 7% (n = 100) were classified as having the type 1 subtype, 4% (n = 55) had type 2 CRC, 26%

Discussion

In this large population-based cohort of individuals with incident invasive CRC, we found important differences in survival across CRC subtypes defined on the basis of prespecified combinations of MSI, CIMP, BRAF-mutation, and KRAS-mutation status. Patients with MSI-high subtypes of disease (ie, types 1 and 5) had the most favorable survival, and those with type 2 CRC (MSS/MSI-low, CIMP-positive, BRAF-mutated, KRAS-mutation–negative) had the highest mortality. Observed survival differences were

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    Conflicts of interest These authors disclose the following: Paul J. Limburg reported grant support received or pending from Olympus America, BENEO-Orafti Group, Bayer Healthcare, Fujinon, Inc., Boston Scientific, Astra Zeneca, and Ironwood Pharmaceuticals; he also reported having received payment for lectures from the American School of Oncology and Imedex, and royalties and stock from Exact Sciences. Daniel J. Weisenberger reported serving as a consultant to Zymo Research and receiving payment for patents and royalties from Epigenomics. Peter W. Laird also reported receiving royalties from Epigenomics, as well as receiving payment for lectures from the American Society for Clinical Oncology and for travel from the American Association for Cancer Research. The remaining authors disclose no conflicts.

    Funding This work was supported by the National Cancer Institute at the National Institutes of Health (K07CA172298 to A.I.P., U01CA74794, R01CA076366, R01CA118699, R01CA107333, K05CA142885 to P.A.N.), the National Center for Advancing Translational Science at the National Institutes of Health (KL2TR000421 to A.N.B.-H.), and through cooperative agreements with members of the Colon Cancer Family Registry and Principal Investigators. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The sponsors had no role in the design and conduct of the study; no role in the collection, management, analysis, and interpretation of data; no role in preparation, review, or approval of the manuscript; and no role in the decision to submit the manuscript for publication.

    Author names in bold designate shared co-first authorship.

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