DNA Microsatellite Instability: A Favorable Indicator in Colon Cancer
ABSTRACT & COMMENTARY
Source: Gryfe R, et al. N Engl J Med 2000;342:69-77.
Recently, it has become apparent that colorectal cancer may evolve through two distinct DNA mutational mechanisms: microsatellite instability or chromosomal instability. It had been proposed that cancers arising from microsatellite instability have a more indolent course and the purpose of this research was to determine if there was a detectable clinical difference between the two pathways.
Specimens from 607 patients with colorectal cancer who were 50 years of age or younger at diagnosis were analyzed for microsatellite instability. The results were correlated with their clinical course and survival. High-frequency microsatellite instability was found in 17% of the 607 patients; and in multivariate analysis, microsatellite instability was associated with a significant survival advantage independently of all standard prognostic factors, including tumor stage. Furthermore, regardless of the depth of tumor invasion, colorectal cancers with high-frequency microsatellite instability had a decreased likelihood of metastasizing to regional lymph nodes or distant organs.
Gryfe and colleagues conclude that high-frequency microsatellite instability in colorectal cancer is an independent predictor of more favorable clinical outcome.
COMMENT BY WILLIAM B. ERSHLER, MD
It is now believed that most cancers occur as a result of an accumulation of genetic alterations that favor cell growth. For colon cancer, these DNA alterations may include features that suggest either chromosomal or microsatellite instability. Microsatellites are short, tandemly repeated DNA sequences that result from defective DNA repair due, most frequently, to dysfunction of certain DNA repair enzymes.1 The abnormal DNA sequences are termed microsatellites and they are detected by amplification of certain key sequences by polymerase chain reaction (PCR). A high frequency of microsatellite instability (i.e., instability ³ 40% of the tested microsatellite loci) has been found in the majority of hereditary nonpolyposis colorectal cancer and in about 15% of sporadic cases of colorectal cancer.2 High-frequency microsatellite instability is also found in specimens from tumors proximal to the splenic flexure.3
It had been previously suggested that tumors demonstrating high-frequency microsatellite instability were clinically different, with more favorable clinical outcomes.4-6 However, the data upon which these predictions were based are limited. Thus, it was the purpose of this investigation to examine a larger number of tumor specimens and correlate the presence of high-frequency microsatellite instability with clinical features such as metastases and survival.
The series included young (< 50 years at diagnosis) individuals with colorectal cancer for whom archival tissue was available. Of the 607 evaluable patients, high-frequency microsatellite instability was found in 17%. These individuals tended to have more undifferentiated tumors and a significantly greater depth of tumor invasion at the time of diagnosis. Yet, the survival of those with high-frequency microsatellite instability was much better. Five-year survival of patients without microsatellite instability was 54%, compared with 76% with this genetic marker. Using a step-down multivariate analysis, the microsatellite status, pathological stage, tumor grade, and histologic type were found to be significantly and independently associated with survival. The survival advantage conferred by high-frequency microsatellite instability could be seen at all stages.
These are intriguing findings for which the clinical significance (i.e., common applicability) is yet to be established. Certainly, prognostic markers (in this case, high-frequency microsatellite instability) are useful in determining treatment strategies and providing prognostic information, but it may be too early to formulate a plan of treatment for an individual patient based upon this information. It is also not clear as to what extent clinical laboratories are prepared to provide this evaluation at present, although it is likely, based on this report and others, to be made available soon.
The development of colon cancer is, perhaps, the best understood at the molecular level of all solid tumors. The findings from this report support the impression that destabilization of the genome, in addition to the randomly accumulated DNA lesions, account for the pathogenesis of the disease, and that this destabilization process accounts for some of the heterogeneity observed in tumor growth and spread.
References
1. Aaltonen LA, et al. Science 1993;260:812-816.
2. Aaltonen LA, et al. N Engl J Med 1998;338:1481-1487.
3. Ionov Y, et al. Nature 1993;363:558-561.
4. Lothe RA, et al. Cancer Res 1993;53:5849-5852.
5. Lukish JR, et al. Ann Surg 1998;227:51-56.
6. Halling KC, et al. J Natl Cancer Inst 1999;91:295-303.
Which of the following statements about the demonstration of high-frequency microsatellite instability in colonic tumor tissue has been shown to be true?
a. It occurs more frequently in tumor samples from the distal colon or rectum.
b. It is associated with a more benign appearing histology with less evidence for local invasion.
c. It is associated with less metastases and longer survival.
d. It is found more frequently in tumors taken from older individuals.
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