Gastroenterology

Gastroenterology

Volume 158, Issue 8, June 2020, Pages 2158-2168.e4
Gastroenterology

Original Research
Full Report: Clinical—Alimentary Tract
Association Between Molecular Subtypes of Colorectal Tumors and Patient Survival, Based on Pooled Analysis of 7 International Studies

https://doi.org/10.1053/j.gastro.2020.02.029Get rights and content

Background and Aims

The heterogeneity among colorectal tumors is probably due to differences in developmental pathways and might associate with patient survival times. We studied the relationship among markers of different subtypes of colorectal tumors and patient survival.

Methods

We pooled data from 7 observational studies, comprising 5010 patients with colorectal cancer. All the studies collected information on microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and mutations in KRAS and BRAF in tumors. Tumors with complete marker data were classified as type 1 (MSI-high, CIMP-positive, with pathogenic mutations in BRAF but not KRAS), type 2 (not MSI-high, CIMP-positive, with pathogenic mutations in BRAF but not KRAS), type 3 (not MSI-high or CIMP, with pathogenic mutations in KRAS but not BRAF), type 4 (not MSI-high or CIMP, no pathogenic mutations in BRAF or KRAS), or type 5 (MSI-high, no CIMP, no pathogenic mutations in BRAF or KRAS). We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CIs) for associations of these subtypes and tumor markers with disease-specific survival (DSS) and overall survival times, adjusting for age, sex, stage at diagnosis, and study population.

Results

Patients with type 2 colorectal tumors had significantly shorter time of DSS than patients with type 4 tumors (HRDSS 1.66; 95% CI 1.33–2.07), regardless of sex, age, or stage at diagnosis. Patients without MSI-high tumors had significantly shorter time of DSS compared with patients with MSI-high tumors (HRDSS 0.42; 95% CI 0.27–0.64), regardless of other tumor markers or stage, or patient sex or age.

Conclusions

In a pooled analysis of data from 7 observational studies of patients with colorectal cancer, we found that tumor subtypes, defined by combinations of 4 common tumor markers, were associated with differences in survival time. Colorectal tumor subtypes might therefore be used in determining patients’ prognoses.

Section snippets

Study Populations

We pooled data from the Cancer Prevention Study-II Nutrition cohort (CPS-II),7,8 the German Darmkrebs: Chancen der Verhutung durch Screening Study (DACHS),9,10 the Diet Activity and Lifestyle Study (DALS),11 the Health Professionals Follow-up Study (HPFS),12 the Melbourne Collaborative Cohort Study (MCCS),13 the Nurses’ Health Study (NHS),14,15 and population-based sites from the CCFR.16 These studies, including the CCFR, participate in the Genetics and Epidemiology of Colorectal Cancer

Results

Study population characteristics are provided in Table 1. Although the distribution of individual tumor markers differed across studies, the prevalence of each tumor marker was consistent with previous estimates when combined across studies: 14.3% of tumors were MSI-high (study-specific range 7%–22%), 17.6% were CIMP-positive (range 9%–27%), 33.0% were KRAS-mutated (range 31%–52%), and 11.8% were BRAF-mutated (range 2%–19%).

In analyses of previously specified tumor marker combinations,

Discussion

In this large pooled analysis of survival in patients with CRC, we observed significant differences in outcomes according to established tumor markers, when considered in prespecified combinations and individually. Patients with type 2 CRC had the poorest prognosis, particularly with respect to DSS. Regardless of other tumor markers, patients with MSI-high colorectal tumors had a favorable prognosis; however, this survival benefit was most evident when combined with CIMP-positive and BRAF

Acknowledgments

CPS-II Nutrition Cohort: The authors thank the CPS-II participants and Study Management Group for their invaluable contributions to this research. The authors also acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, and cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program.

DACHS: We thank all participants and

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    Conflict of interest The authors disclose no conflicts.

    Funding Grant support: Genetics and Epidemiology of Colorectal Cancer Consortium: National Cancer Institute (NCI), National Institutes of Health (NIH), US Department of Health and Human Services (U01 CA137088 and R01 CA176272). This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA015704. The Colon Cancer Family Registry (CCFR) Illumina Genome-Wide Association Study was supported by funding from NCI, NIH (grant numbers U01 CA122839, R01 CA143247 to Dr. Graham Casey). The CCFR participant recruitment and collection of data and biospecimens used in this study were supported by NCI, NIH (grant number U01 CA167551). Additional funding toward molecular characterization and analyses included the following grants from NCI, NIH: K05CA152715 (to Polly A. Newcomb) and K07CA172298 (to Amanda I. Phipps). The content of this article does not necessarily reflect the views or policies of NCI or any of the collaborating centers in the CCFR, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government, any cancer registry, or the CCFR. CPS-II: The American Cancer Society funds the creation, maintenance, and updating of the Cancer Prevention Study-II (CPS-II) cohort. This study was conducted with institutional review board approval. DACHS: This work was supported by the German Research Council (BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, HO 5117/2-1, HE 5998/2-1, KL 2354/3-1, RO 2270/8-1, and BR 1704/17-1), the Interdisciplinary Research Program of the National Center for Tumor Diseases (NCT), Germany, and the German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815, 01ER1505A, and 01ER1505B). Diet Activity and Lifestyle Study: NIH (R01 CA48998 to Martha L. Slattery). The Health Professionals Follow-up Study is supported by NIH P01 CA055075, UM1 CA167552, U01 CA167552, R01 CA137178, R01 CA151993, R35CA197735, K07 CA190673, and P50 CA127003; and Nurses’ Health Study by NIH (R01 CA137178, P01 CA087969, UM1 CA186107, R01 CA151993, R35 CA197735, K07CA190673, and P50 CA127003). The Melbourne Collaborative Cohort Study (MCCS) recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian National Health and Medical Research Council grants 209057, 396414, and 1074383, and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the National Death Index and the Australian Cancer Database. Ontario Familial Colorectal Cancer Registry (OFCCR): NIH, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); see the preceding CCFR section. Additional funding toward genetic analyses of OFCCR includes the Ontario Research Fund, the Canadian Institutes of Health Research, and the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation. Andrew T. Chan is a Stuart and Suzanne Steele MGH Research Scholar.

    Author names in bold designate shared co-first authoship.

    ∗

    Authors share co-first authorship.

    §

    Authors share co-last authorship.

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