Gastroenterology

Gastroenterology

Volume 137, Issue 5, November 2009, Pages 1609-1620.e3
Gastroenterology

Clinical—Alimentary Tract
A Prospective Cohort Study Shows Unique Epigenetic, Genetic, and Prognostic Features of Synchronous Colorectal Cancers

https://doi.org/10.1053/j.gastro.2009.08.002Get rights and content

Background & Aims

Synchronous colorectal neoplasias (2 or more primary carcinomas identified in the same patient) are caused by common genetic and environmental factors and can be used to study the field effect. Synchronous colon cancers have not been compared with control solitary cancers in a prospective study.

Methods

We analyzed data collected from 47 patients with synchronous colorectal cancers and 2021 solitary colorectal cancers (controls) in 2 prospective cohort studies. Tumors samples were analyzed for methylation in LINE-1 and 16 CpG islands (CACNA1G, CDKN2A [p16], CRABP1, IGF2, MLH1, NEUROG1, RUNX3, SOCS1, CHFR, HIC1, IGFBP3, MGMT, MINT1, MINT31, p14 [ARF], and WRN); microsatellite instability (MSI); the CpG island methylator phenotype (CIMP); 18q loss of heterozygosity; KRAS, BRAF, and PIK3CA mutations; and expression of β-catenin, p53, p21, p27, cyclin D1, fatty acid synthase, and cyclooxygenase-2.

Results

Compared with patients with solitary colorectal cancer, synchronous colorectal cancer patients had reduced overall survival time (log-rank, P = .0048; hazard ratio [HR], 1.71; 95% confidence interval [CI]: 1.17–2.50; P = .0053; multivariate HR, 1.47; 95% CI: 1.00–2.17; P = .049). Compared with solitary tumors, synchronous tumors more frequently contained BRAF mutations (P = .0041), CIMP-high (P = .013), and MSI-high (P = .037). Methylation levels of LINE-1 (Spearman r = 0.82; P = .0072) and CpG island methylation (P < .0001) correlated between synchronous cancer pairs from the same individuals.

Conclusions

Synchronous colorectal cancers had more frequent mutations in BRAF, were more frequently CIMP- and MSI-high, and had a worse prognosis than solitary colorectal cancers. Similar epigenomic and epigenetic events were frequently observed within a synchronous cancer pair, suggesting the presence of a field defect.

Section snippets

Study Population

We utilized 2 prospective cohort studies: the Nurses' Health Study (121,701 women followed since 1976)27 and the Health Professionals Follow-up Study (51,529 men followed since 1986).27 Every 2 years, participants have been sent follow-up questionnaires to identify newly diagnosed cancer and other diseases in themselves and their first-degree relatives. For nonresponders, we searched the National Death Index to discover deaths and ascertain any diagnosis of colorectal cancer that contributed to

Clinical Features of Synchronous Colorectal Cancer Cases

During follow-up of the 2 prospective cohort studies (the Nurses' Health Study and the Health Professionals Follow-up Study), there were 2068 eligible colorectal cancer patients diagnosed up to 2004. Among the 2068 patients, we identified 47 cases of synchronous colorectal cancers (Figure 1). The remaining 2021 solitary colorectal cancers had arisen in the same cohort population that had given rise to the 47 synchronous cases and thus constituted an optimal control group. We assessed clinical

Discussion

In this study, we examined genetic and epigenetic features as well as clinical outcome of synchronous colorectal cancer cases. To date, no previous study has examined global DNA methylation levels within synchronous colorectal cancer pairs. In addition, no previous study has compared clinical and molecular features of synchronous colorectal cancers with those of solitary colorectal cancers that had occurred in the same background population as the synchronous cancers in a prospective cohort

Acknowledgments

The authors thank the Nurses' Health Study and Health Professionals Follow-up Study cohort participants who have generously agreed to provide us with biological specimens and information through responses to questionnaires; hospitals and pathology departments throughout the United States for providing us with tumor tissue materials; Frank Speizer, Walter Willett, Susan Hankinson, Meir Stampfer, and many other staff members who implemented and maintained the cohort studies.

K.N., S.K., and N.I.

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    Conflicts of interest The authors disclose no conflicts.

    Funding Supported by the US National Institutes of Health (P01 CA87969 to S. Hankinson, P01 CA55075 to W. Willett, P50 CA127003 to C.S.F., K07 CA122826 to S.O.); the Bennett Family Fund; the Entertainment Industry Foundation National Colorectal Cancer Research Alliance; and a fellowship grant from the Japan Society for Promotion of Science (to K.N.).

    The content is solely the responsibility of the authors and does not necessarily represent the official views of NCI or NIH. Funding agencies did not have any role in the design of the study; the collection, analysis, or interpretation of the data; the decision to submit the manuscript for publication; or the writing of the manuscript.

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