© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 15, 1267-1269,
August 4, 1999
© 1999 Oxford University Press
EDITORIALS |
Molecular Markers of Prognosis in Colorectal Cancer
Affiliations of authors: Colon Cancer Genetics Group, University of Edinburgh Division of Molecular and Clinical Medicine, and Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, U.K.
Correspondence to: Malcolm G. Dunlop, M.D., Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, U.K. (e-mail: Malcolm.Dunlop{at}hgu.mrc.ac.uk).
Characterization of molecular and cellular alterations involved in the initiation and progression of colorectal cancer is the focus of intense research activity, and this activity is not misdirected. In the United States, around 130 000 patients are diagnosed with colorectal cancer annually (1), and the incidence is rising rapidly in developing countries, particularly in Asia. Gaining new insight into the molecular pathogenesis of colorectal cancer will allow progress in many facets of disease control, including primary prevention on a population basis, identification of genetically predisposed groups for targeted surveillance and/or chemoprevention, prognosis for patients with established cancer, prediction of tumor response to treatment, and rational development of novel treatment approaches. Descriptive and mechanistic molecular studies of colorectal cancer are moving on apace, and we are now challenged with applying the wealth of available information for clinical benefit.
In this issue of the Journal, Halling et al. (2) report statistical associations between tumor molecular genetic status and patient outcome. In a retrospective study of 508 patients who were a subset of those recruited to the North Central Cancer Treatment Group adjuvant chemotherapy trials, they have confirmed and refined the findings of previous smaller studies (3-6) showing that high microsatellite instability (MSI-H) in tumors is an independent prognostic indicator in colorectal cancer. In addition, they make a novel observation that loss of heterozygosity (LOH) at a chromosome 8p marker (termed "allelic imbalance") is associated with poor outcome. For both microsatellite instability (MSI) and 8p allelic imbalance, the difference in survival reached statistical significance only for stage C tumors (Astler-Coller modification of Dukes' staging). Nonetheless, these parameters were of independent prognostic value and so may allow stratification of patients within tumor stage in order to inform therapeutic intervention and the design of future adjuvant chemotherapy trials. For all stage C tumors, overall 5-year survival was 58%, whereas 5-year survival stratified on the basis of molecular phenotype was 45% for tumors with allelic imbalance compared with 68% for tumors with no allelic imbalance and 55% for tumors with microsatellite stability compared with 74% for tumors with MSI-H. Thus, the refinement in prognosis of stage C tumors provided by these molecular parameters is of potential practical clinical utility. It is now important to confirm these findings in a large independent patient cohort, homogeneous with respect to the adjuvant treatment that they receive, and where there has been universal, prospective collection of tumor material. Such a cohort would also allow study of molecular determinants of response to treatment, which Halling et al. (2) were not able to study in detail because of the low power to detect a benefit of the magnitude imparted by chemotherapy regimens included in the trials.
The findings of Halling et al. (2), like much good science, bring into sharp focus a number of issues—What is the molecular basis of the association between alleleic imbalance on chromosome 8p and poor prognosis, and why does MSI-H confer improved patient postoperative survival?
There is strong evidence to suggest that the association of 8p alleleic imbalance and poor prognosis reported by Halling et al. (2) is a specific event related to loss of function of specific target gene(s). A number of studies in different tumor systems indicate that one or more tumor suppressor genes are present on chromosome 8p and that these genes are involved in the later stages of tumorigenesis. LOH at 8p has been observed in around 50% of colorectal, bladder, prostate, head and neck, lung, and hepatocellular cancers (7,8). Furthermore, colorectal carcinomas exhibit 8p LOH significantly more commonly than do adenomas (9,10). The article by Halling et al. (2) extends previous reports of an association between prognosis and 8p status in head and neck cancer (11) and in prostate cancer (12). It is intriguing that suppression of metastasis has been reported when human chromosome 8 was introduced into rat prostate cancer cells (13).
In colorectal tumors, at least two regions on chromosome 8p harboring potential tumor suppressor genes have been identified (14,15). Candidate 8p tumor suppressor genes include the platelet-derived growth factor receptor beta-like tumor suppressor (PRLTS) gene, located on 8p21.3-p22 (16,17), although few mutations have been identified to date. Recently, positional cloning efforts have identified the FEZ1 gene located on 8p22, and preliminary data suggest that it is an attractive candidate tumor suppressor gene (18). It encodes a leucine-zipper protein exhibiting homology to the cyclic adenosine monophosphate-responsive Atf-5 DNA-binding protein. Aberrant messenger RNA transcripts were identified in a number of epithelial tumor cell lines, including esophageal cancer, gastric cancer, colorectal cancer, prostate cancer, and melanoma cell lines. However, corroborative data confirming frequent FEZ1 inactivation in colorectal tumor tissue are eagerly awaited. It is clear that defining loss of function of tumor suppressor genes on 8p has substantial immediate relevance to understanding progression in colorectal cancers as well as to such alterations' clinical utility as a prognostic marker.
With previous work (3-6,19), the study by Halling et al. (2) establishes the association between tumor MSI and prolonged postoperative survival in patients with sporadic colorectal cancer. Most sporadic tumors exhibit MSI as a result of defective DNA mismatch repair (MMR) consequent upon methylation silencing of the hMLH1 promoter (20-22). However, it is not clear whether the mechanism responsible for defective MMR repair has a bearing on the natural history of the tumor. Patients from hereditary nonpolyposis colorectal cancer (HNPCC) families carry germline mutations in DNA MMR genes. The second MMR gene allele is inactivated in the tumor, frequently by alleleic imbalance (23) and mutation or in a minority of cases by methylation silencing (21). Hence, there are fundamental molecular differences between sporadic tumors and those from HNPCC families with respect to the mechanism underlying the MSI phenotype. Therefore, it is not clear whether the observed survival associated with MSI-H in sporadic tumors can be translated to HNPCCs. There are a number of survival studies in empirically defined HNPCC families (24,25) as well as families defined by mutation status (26). However, these studies are subject to ascertainment bias by the nature of reproductive fitness because of recruitment to surveillance programs and subsequent prolonged survival affording greater opportunity for contact with researchers interested in HNPCC. Thus, there is a real need for contemporary, prospective case-control and cohort survival studies of systematically collected colorectal cancer patients defined by MMR germline status. Such studies would provide crucial data on which to estimate cost-effectiveness of population approaches to identifying MMR gene carriers.
It is not immediately apparent why patients with tumors exhibiting MSI-H should have increased relative survival rates because it might be supposed that a mutator phenotype might actually enhance mutation rates in cancer genes and accelerate tumor progression. One apparently paradoxical explanation for these observations is that genetic instability contributes to tumor initiation but not to tumor progression because MSI results in a spectrum of genetic modification that acts as a barrier to cellular stability. In support of this notion, Bocker et al. (27) reported a significantly lower proliferative capacity in microsatellite-unstable sporadic colorectal carcinomas. Tumors with MSI have been shown to carry frequent mutations in genes containing simple repeat sequences such as tumor growth factor-ßRII (28) and BAX (29), and it has been shown that such mutations select for tumor growth. Thus, it seems likely that other genes containing target repeats are mutated at high rates, but such defects are cell lethal and, therefore, defective MMR might be seen as a brake on tumor progression. Defective MMR might result in the production of dysfunctional cell-cycle proteins or novel soluble and cell-associated neoantigens, activating an immune response. Concordant with this suggestion, conspicuous peritumoral lymphocytic infiltration has been observed in microsatellite-unstable colorectal tumors and is indicated as a positive prognostic indicator in colorectal cancer. In sporadic gastric carcinomas, MSI was shown to be associated with marked T-cell lymphatic infiltration (30). Furthermore, survival of patients with gastric tumors exhibiting MSI also appears to parallel the better outlook seen in colorectal cancer.
There are conflicting clinical and molecular data on the nature of the influence of MSI on prognosis. While it has been shown that mutation of ß2-microglobulin is frequent in tumors exhibiting MSI (31), the "neoantigen-immune recognition" hypothesis alluded to above is confounded by the finding that colorectal adenocarcinoma cell lines exhibiting a mutator phenotype exclusively fail to express surface ß2-microglobulin (32). Thus, such tumors are likely to have been selected by host T-cell surveillance. Clinical observations also serve to confound understanding, since there is some evidence to indicate that tumor progression from adenoma to carcinoma may be accelerated in HNPCC with MSI (33).
It is clear that we have much to learn about the fundamental basis of colorectal cancer, but translational research is already bearing fruit and will doubtless make a growing contribution to clinical practice.
NOTE
M. G. Dunlop is funded by a Medical Research Council Clinician Scientist Fellowship, and I. D. Nicholl is supported by Cancer Research Campaign grant SP2326/0201.
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