Microsatellite Instability in Colorectal Cancer
Microsatellite Instability in Colorectal Cancer
abstract & commentary
Synopsis: The presence of high-frequency microsatellite instability in colorectal cancer was found to be associated with proximal location, a medullary or mucinous histologic pattern, infrequent p53 expression, and an improved survival compared with tumors that had low-frequency microsatellite instability.
Source: Gafa R, et al. Cancer 2000;89:2025-2037.
Colorectal carcinomas with high-frequency microsatellite instability (HF-MSI) are believed to possess unique biologic properties compared with tumors that have low-frequency microsatellite instability (LF-MSI) or tumors that are microsatellite stable (MSS). The aim of this study was to correlate the presence of HF-MSI with clinicopathologic information.
Gafa and colleagues evaluated 216 surgically resected specimens half of which were proximal to the splenic flexure and half of which were distal. Tumors of any stage were included but not from patients with known inherited colorectal cancer syndromes. In addition to standard histopathologic evaluation, the tissue also underwent microsatellite analysis, immunohistochemical analysis, and flow cytometric DNA ploidy analysis. Tumors were designated as having HF-MSI if three or more of the six analyzed microsatellite loci demonstrated instability, which occurred in 20% of the cases. Immunohistochemistry was used to define the expression of the p53, hMLH1, and hMSH2 proteins.
When the clinicopathologic characteristics of HF-MSI and LF-MSI/MSS tumors were compared, a number of observations were made concerning tumor location, pathologic subtypes, patterns of local growth, and the likelihood of distant metastases. For example, HF-MSI tumors were localized to the right and transverse colon 90% of the time, whereas LF-MSI/MSS tumors were localized to the distal colon 60% of the time. Furthermore, these HF-MSI tumors were much more likely than LF-MSI/MSS tumors to have a medullary or mucinous pattern or a conspicuous lymphoid reaction. Furthermore, the HF-MSI tumors were far less likely to demonstrate an infiltrating growth pattern or extramural venous invasion. All of these observations were highly statistically significant.
Other interesting pathologic observations were presented. For example, 82% of the HF-MSI tumors were diploid with infrequent p53 overexpression (23%) suggesting that these tumors would have a better prognosis. On the other hand, 80% of the LF-MSI/MSS adenocarcinomas were aneuploid with 54% overexpressing p53.
These pathological observations were supported by clinical findings as well. Considering only those tumors located proximally, distant metastases were present at diagnosis in only 5% of tumors with HF-MSI vs. 24% of tumors with LF-MSI/MSS. Furthermore, only 16% of patients with HF-MSI tumors died of colorectal cancer compared with 44% of patients with LF-MSI/MSS tumors. Considering just the poorly differentiated cancers, the prognosis was markedly improved if the tumor had HF-MSI. This is illustrated by the five-year survival for poorly differentiated tumors of only 37% for cases with LF-MSI/MSS, which jumped to 79% for cases with HF-MSI.
COMMENT by Kenneth W. Kotz, MD
There are two genetic pathways that can lead to colorectal cancer. The most common is the "suppressor pathway" characterized by the sequential inactivation of tumor-suppressor genes such as APC, p53, and DCC. This pathway involves marked chromosomal changes with frequent cytogenetic abnormalities.
The other genetic pathway leading to colorectal carcinoma is characterized by widespread microsatellite instability. This "mutator" pathway leads to an accumulation of somatic alterations of simple, repeated sequences called microsatellites. When greater than 30% of microsatellites demonstrate instability, this is called high-frequency microsatellite instability, a consequence of defects in the DNA mismatch repair system. These defects are usually caused by inactivation of the DNA mismatch repair genes. The well-described hereditary nonpolyposis colon cancer syndrome is caused by mutations (rather than inactivation) of DNA mismatch repair genes. Like tumors with HF-MSI, proximal orientation in the bowel has also been noted in this syndrome.
The study by Gafa et al has provided some interesting clinicopathologic findings. First, the majority (86%) of tumors with a medullary pattern had HF-MSI. Second, the HF-MSI tumors were highly likely (90%) to occur in the proximal colon. Third, despite the poor differentiation, patients with HF-MSI tumors actually had a better prognosis than LF-MSI/MSS tumors.
The mechanism behind the improved prognosis afforded HF-MSI tumors is unknown. Perhaps the multiple mutational changes lead to an immune response against new tumor-associated antigens or alternatively these multiple genetic changes might simultaneously place these malignant cells at a growth disadvantage. Whereas loss of classic tumor suppressor genes is often associated with tumor progression and an increased ability to spread (which requires angiogenesis and breakdown of the cell membrane), it may be that HF-MSI predominantly imparts a local growth advantage to the tumor.
The ultimate clinical significance of measuring microsatellite instability in colorectal cancer remains to be determined. However, important questions include whether tumors with HF-MSI require chemotherapy and whether they would respond to chemotherapy in the same way as other colorectal tumors.
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