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Published on: July 28, 2010
Isolated loss of PMS2 expression in colorectal cancers: frequency, patient age, and familial aggregation
Sharlene Gill1, Noralane M Lindor, Lawrence J Burgart
1British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
Purpose:
Most colorectal cancers that have high levels of microsatellite instability (MSI-H) show loss of immunohistochemical expression of proteins that participate in the DNA mismatch repair process, most often involving MLH1 and MSH2. Less commonly, a third DNA mismatch repair protein, MSH6, may also be lost as the primary event. Rarely, tumors with MSI-H show normal expression of these three proteins. The genetic deficiency leading to the MSI-H phenotype in such cases is unknown. PMS2 is another member of the DNA mismatch repair complex. Its expression is generally lost in tumors with MLH1 loss of expression. Rarely, there is selective loss of PMS2 expression. We sought to describe the frequency and clinical correlates of selective loss of expression of PMS2 with the MSI-H tumor phenotype.
Experimental Design:
Two thousand seven hundred nineteen colorectal cancers from both clinic- and research-based ascertainment were studied. Tumor MSI testing and immunohistochemistry for MLH1, MSH2, MSH6, and PMS2 were conducted. Medical records were abstracted for age at diagnosis, gender, colorectal cancer site, and family history.
Results:
Five hundred thirty-five of the 2,719 tumors were MSI-H. Of these, 93% showed loss of expression of MLH1, MSH2, and/or MSH6. Thirty-eight showed normal expression for these proteins. PMS2 immunohistochemical staining was successful in 32 of 38 of these tumors. Of the 32, 23 showed selective loss of expression of PMS2. This was associated with young age of diagnosis and right-sided location but not with a striking family history of cancer.
Conclusions:
Overall, 97% of the MSI-H tumors showed loss of expression for one or more of these four mismatch repair proteins. Selective loss of expression of PMS2 was present in 72% of cases in which colorectal cancers had an MSI-H phenotype but no alteration of expression of MLH1, MSH2, and MSH6. The underlying mechanism involved cannot be determined from this study but could involve point mutations in other DNA mismatch repair genes with retention of immunohistochemical expression, somatic inactivation of PMS2, or germ line mutation of PMS2.
Insights
Selective loss of PMS2 expression is a key finding in colorectal cancers with high microsatellite instability (MSI-H) but normal MLH1, MSH2, and MSH6. This suggests novel mechanisms for DNA mismatch repair deficiency.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- High microsatellite instability (MSI-H) in colorectal cancer (CRC) usually results from loss of DNA mismatch repair (MMR) proteins MLH1, MSH2, or MSH6.
- Selective loss of PMS2 expression, a component of the MMR complex, is rarely observed in MSI-H CRC with intact MLH1, MSH2, and MSH6.
Purpose of the Study:
- To determine the frequency of selective PMS2 loss in MSI-H CRC.
- To identify clinical correlates associated with selective PMS2 loss in MSI-H CRC.
Main Methods:
- Studied 2,719 colorectal cancers using MSI testing and immunohistochemistry for MLH1, MSH2, MSH6, and PMS2.
- Abstracted medical records for patient demographics and cancer characteristics.
Main Results:
- Of 535 MSI-H tumors, 38 showed normal MLH1, MSH2, and MSH6 expression.
- Selective PMS2 loss was observed in 23 of 32 (72%) of these cases.
- Selective PMS2 loss was associated with younger age at diagnosis and right-sided tumor location.
Conclusions:
- Selective PMS2 loss accounts for a significant proportion of MSI-H CRC cases with intact MLH1, MSH2, and MSH6.
- The underlying genetic mechanisms require further investigation, potentially involving PMS2 point mutations or germline alterations.
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