Gastroenterology
Volume 137, Issue 5 , Pages 1559-1562, November 2009

Synchronous Colorectal Cancer: Not Just Bad Luck?

  • Barbara A. Leggett

      Affiliations

    • Corresponding Author InformationReprint requests Address requests for reprints to: Professor Barbara Leggett, MD, Dept of Gastroenterology and Hepatology, Level 9 Ned Hanlon Building, Royal Brisbane and Womens Hospital, Herston, QLD, 4029, Australia
    • ,
  • Daniel L. Worthley

Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital and Conjoint Gastroenterology Laboratory, Royal Brisbane and Womens Hospital Research Foundation Clinical Research Centre, Queensland Institute of Medical Research, Brisbane, Queensland, Australia

published online 28 September 2009.

Article Outline

 

See “A prospective cohort study shows unique epigenetic, genetic, and prognostic features of synchronous colorectal cancers,” by Nosho K, Kure S, Irahara N, et al, on page 1609.

The paper by Nosho et al1 in this issue of Gastroenterology is important because it shows that heavily methylated colorectal cancers that arise in serrated polyps are more likely to be synchronous and that there may be an epigenetic field effect in colorectal neoplasia. This has implications for clinical practice because it helps us to understand the causes of multiple primary cancers, which are relevant to both metachronous as well as synchronous cancers. One of the most worrisome aspects of surveillance programs is the missed or interval cancer and huge resources are devoted to this problem. This study has unique advantages since it utilizes the well-defined cohort studies of the Nurses' Health Study and the Health Professionals Follow-up Study, thereby avoiding ascertainment bias and providing well-matched controls. However, the lack of information about the numbers and types of polyps in the colons of the patients with synchronous cancers and the small number of cases available for molecular analysis are limitations.

The occurrence of synchronous cancers is a natural experiment, which tests whether the molecular events of colorectal carcinogenesis are stochastic or if there is a field effect due to unique genetic and/or environmental factors in an individual. Colorectal cancer is well suited to this analysis with several distinct pathways of tumorigenesis.2, 3 The majority of sporadic colorectal cancers arise in adenomas with inactivation of the APC tumor suppressor gene. These tumors demonstrate marked chromosomal instability (CIN), which causes inactivation of other important tumor suppressors such as p53 and genes on chromosome 18q. Some sporadic cancers, however, arise in serrated polyps especially sessile serrated adenomas and traditional serrated adenomas.4 Instead of CIN, these cancers show widespread CpG island methylation (CIMP), which leads to silencing of tumor suppressor genes. Instead of APC inactivation, these serrated polyps show frequent activating mutations in the BRAF oncogene, which seems to be synergistic with CIMP.5 Some, but not all, of these CIMP cancers with BRAF mutations methylate the mismatch repair gene MLH1 at the polyp/cancer transition and develop a high level of microsatellite instability (MSI-high). Nosho et al have demonstrated that there is an overrepresentation of the CIMP-high tumor group which has BRAF mutation and often MSI-high in the synchronous cancers. This suggests that this serrated pathway predisposes to multiple primary cancers.

A priori it might have been expected that inherited forms of colorectal cancer would be a common risk factor for synchronous cancer in these cohorts. Lynch syndrome (hereditary nonpolyposis colorectal cancer) is due to inherited mutation in the mismatch repair system, leading to cancers showing MSI-high but not CIMP or BRAF mutation.2, 6 Synchronous and metachronous cancers are well-known features of this syndrome.6 The Bethesda guidelines used for the identification of possible Lynch syndrome include the “Presence of synchronous or metachronous colorectal or other HNPCC-associated tumors regardless of age” as an important indicator for MSI testing.7 There were some cases of Lynch syndrome identified in this study, such as patient 8 in Table 4 of the article, but they certainly constitute a small minority of cases of synchronous cancer. The other inherited causes of colorectal cancer predisposition which could lead to synchronous cancer are familial adenomatous polyposis, including attenuated familial adenomatous polyposis and MYH-associated polyposis.6, 8 Most cancers arising in these syndromes are characterized by CIN and APC inactivation and thus cannot be distinguished molecularly from the common CIN sporadic cancers. Because the study by Nosho et al has no information about the number and types of polyps present, no estimate of the contribution of these syndromes to synchronous cancer can be derived. Ulcerative colitis is known to be associated with synchronous cancer and a related field effect is a possibility for some of the cases in this study.9 Overall, however, the lack of association with family history and the significantly older age of the synchronous cancer cases in this study, suggests that serrated neoplasia and other field effects are possibly more common causes of synchronous colorectal cancer (Figure 1).

  • View full-size image.
  • Figure 1. 

    Relative contributions of different pathways of colorectal carcinogenesis to the occurrence of synchronous cancer. Block pink to red shading represents the relative genetic contribution and the red dots depict superimposed patchy environmental events and the typical distribution of pathology. CIN, chromosomal instability; MSI, microsatellite instability; CIMP, CpG island methylator phenotype; MSS, microsatellite stable; DALM, dysplasia-associated lesion or mass.

In this study approximately one third of cases of synchronous cancer were CIMP-high, BRAF mutant tumors arising through the serrated neoplastic pathway. The most extreme form of this pathway is hyperplastic polyposis. In this condition there are large numbers of serrated polyps in a pancolonic distribution with many of the polyps being sessile serrated adenomas.10 Synchronous cancer seems to be a common feature of hyperplastic polyposis with many reports in the literature.11, 12, 13, 14 Indeed, we have reported a case of a 66-year-old woman with 6 synchronous cancers and have observed another case of a 65-year-old woman with 5 cancers.11

The high prevalence of MSI-high and older age amongst the synchronous cancers in the present study is consistent with other research. It has been argued that the elevated incidence of MSI-high simply reflects the increasing frequency of synchronous cancer at older ages because there is a well-established association between sporadic MSI-high and older age.15, 16 These studies were limited by small numbers and the study by Dykes et al17 of 77 patients with synchronous cancer clearly shows not only the association with MSI-high but also that there is strong concordance in MSI status among cancers of the same individual. This supports the contention that synchronous cancers in a given patient develop preferentially along the same genetic pathway. None of these studies incorporated the new knowledge concerning CIMP and BRAF mutation, and thus, did not identify the CIMP cancers without methylated MLH1. This is an important contribution made by the Nosho et al study and in fact the strongest association they demonstrate is with CIMP and BRAF mutation rather than MSI-high. Their study is limited by the fact that in only 10 cases were both cancers available for analysis to demonstrate concordance in individual patients. Nonetheless, the strong concordance of LINE-1 methylation between cancer pairs strengthens the case for a pathway preference in these individuals.

This potential field effect could have both genetic and environmental causes. There is evidence that there may be a genetic predisposition to serrated neoplasia in some families.18, 19 Smoking may also be an important factor predisposing to BRAF mutated colorectal cancer.20 It is reasonable to hypothesize that a tendency to CIMP may be demonstrable in macroscopically normal mucosa of individuals predisposed to serrated polyps and cancer. In the present study, there was “no substantial CIMP” in the normal mucosal samples examined. However, more detailed studies suggest that DNA methylation within histologically normal mucosa is associated with colorectal carcinogenesis. One study showed that MGMT methylation was more frequently detected within the peritumoral mucosa of MGMT methylated cancers.21 Others have detected more frequent MLH1 methylation in the peritumoral mucosa of patients with sporadic MSI-high colorectal cancers.22 MLH1 methylation is also more frequent in the normal mucosa of older women, a potential explanation for this group's predisposition to CIMP colorectal cancer.23 When applying MethyLight to cancer-specific markers in normal mucosa, the detection of any methylation (PMR > 0) may reflect patches of epigenetically disturbed epithelium primed to develop into CIMP pathway tumors.

The finding by Nosho et al that the prognosis of patients with synchronous cancer is worse needs to be interpreted with caution and may not necessarily mean that synchronous cancers are biologically more aggressive. Most previous studies have not supported this notion. In particular, a large, population-based study that included 596 cases of synchronous colorectal cancer found no difference in survival once the adverse effect of the older age at diagnosis was adjusted.24 Although multivariate analysis was performed in the Nosho et al study, the numbers were small and only overall mortality, not cancer specific mortality, was significant after adjustment for age. As the authors point out, there could be an element of “double jeopardy” with increased cancer burden and postoperative complications. It seems unlikely that the molecular characteristics made the cancers biologically more aggressive because there is strong evidence that MSI-high is a good prognostic feature.25, 26 It is true that CIMP cancers without MSI-high probably have a worse prognosis but these constitute the minority of serrated pathway cancers.25

In conclusion, this paper has contributed to the body of evidence showing that synchronous cancers are more likely to have arisen via the serrated neoplastic pathway although the traditional CIN pathway still underlies the majority of cancers. It has been recognized for some time that the presence of multiple adenomas predisposes to synchronous cancer and it is now clear sessile serrated adenomas and serrated adenomas are at least as significant in this regard.24 Furthermore, interval colon cancers have also been shown to be more likely to be MSI-high.27, 28 One of the key research questions regarding surveillance of the colon after resection of colorectal cancer is the identification of clinical, genetic, or biologic markers that predict development of metachronous cancer. If an epigenetic field effect can be proven to exist, it may constitute such a marker.

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References 

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 Conflicts of interest The authors disclose no conflicts.

PII: S0016-5085(09)01666-7

doi:10.1053/j.gastro.2009.09.025

Refers to article:

  • Additional Online Content AvailableEditorial Accompanies this Article A Prospective Cohort Study Shows Unique Epigenetic, Genetic, and Prognostic Features of Synchronous Colorectal Cancers , 17 August 2009

    Katsuhiko Nosho, Shoko Kure, Natsumi Irahara, Kaori Shima, Yoshifumi Baba, Donna Spiegelman, Jeffrey A. Meyerhardt, Edward L. Giovannucci, Charles S. Fuchs, Shuji Ogino
    Gastroenterology November 2009 (Vol. 137, Issue 5, Pages 1609-1620.e3)

Gastroenterology
Volume 137, Issue 5 , Pages 1559-1562, November 2009

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