Isolated Loss of PMS2 Expression in Colorectal Cancers: Frequency, Patient Age, and Familial Aggregation

Abstract

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.Tumor DNA microsatellite instability (MSI) is a consequence of defects in DNA mismatch repair. A high level of microsatellite instability (MSI-H) is recognized in a subset of patients diagnosed with Hereditary Nonpolyposis Colorectal Cancer (HNPCC) by pedigree, and in 10% to 15% of all colorectal cancers in most unselected series (1 -3). Both somatic and germ line mutations have been identified in several putative genes from the mutS (MSH2, MSH3, and MSH6) and mutL (MLH1, MLH3, PMS1, and PMS2) gene families in colon cancer with defective mismatch repair (4 -7).

The Clinical Phenotype of Lynch Syndrome Due to Germ-Line PMS2 Mutations

“…Thus, general population screening recommendations for colon cancer surveillance beginning at age 50 would not be sufficient for families with a PMS2 gene mutation. However, the standard LS cancer screening guidelines (colonoscopy every 1-2 years beginning at age [20][21][22][23][24][25] 47 for carriers of MLH1 or MSH2 mutations may be extreme given the lower penetrance. Our data suggest that PMS2 mutation carriers should probably follow an intermediate screening regimen such as beginning colonoscopy every 1-2 years at 30, as was recommended by Lindor et al for individuals with MSH6 mutations.…”

“…22 IHC showing isolated loss of PMS2 protein is suggestive of a germline PMS2 mutation. Two large studies have shown that loss of PMS2 protein and retention of MLH1, MSH2, and MSH6 mismatch repair proteins occurs in 4.3% of colorectal tumors exhibiting a high degree of microsatellite instability (95% CI 2.7% -6.4%), 23 and 11.5% of colorectal tumors with abnormal mismatch repair IHC (95% CI 6.7% -18.0%). 24 Baudhuin et al found loss of PMS2 protein in <1% of colorectal tumors with abnormal IHC from cases unselected for family history of cancer and 4% of colorectal tumors with abnormal IHC that were classified as "moderate to high risk patients" based on "being referred for routine clinical molecular testing for Lynch syndrome at the Mayo Clinic."…”

Frequency of Deletions of EPCAM (TACSTD1) in MSH2-Associated Lynch Syndrome Cases

“…Immunohistochemistry was performed according to previously described and standard protocols. 16,27 Germline …”

Higher frequency of isolated PMS2 loss in colorectal tumors in Colombian population: preliminary results

“…17,18 These findings were similar to the findings of this study. Similarly, Gill et al 19 showed that the majority of MSI-H colon cancers (499 of 535, 93%) had loss of expression for at least one of the proteins for MLH1, MSH2, and/or MSH6. However, the selective loss of PMS2 (with normal expression of MLH1, MSH2, and/or MSH6) was detected in 4.3% (23 of 529) of all MSI-H colon cancer.…”

“…However, the selective loss of PMS2 (with normal expression of MLH1, MSH2, and/or MSH6) was detected in 4.3% (23 of 529) of all MSI-H colon cancer. 19 According to Gill et al 19 , PMS2 negative cancer occurs mostly in males (64%) aged 28-67 years and is more common in the right colon (52%). In our study, PMS2 negative colon cancers were more common in males (75%) aged 29-83 years as well.…”