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Updated: Jul 9, 2026
Deficient Pms2, ERCC1, Ku86, CcOI in Field Defects During Progression to Colon Cancer
Published on: July 28, 2010
Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer
Kaspar Truninger1, Mirco Menigatti, Judith Luz
1Institute of Molecular Cancer Research, University of Zurich, Switzerland.
Background & Aims:
Germline mutations in the DNA mismatch repair (MMR) genes MSH2, MSH6, or MLH1 predispose to colorectal cancer (CRC) with an autosomal dominant inheritance pattern. The protein encoded by PMS2 is also essential for MMR; however, alterations in this gene have been documented only in extremely rare cases. We addressed this unexpected finding by analyzing a large series of CRCs.
Methods:
Expression of MSH2, MSH6, MLH1, and PMS2 was studied by immunohistochemistry in 1048 unselected, consecutive CRCs. Where absence of MMR proteins was detected, microsatellite instability and cytosine methylation of the respective gene promoter were analyzed. The DNA of patients presenting with PMS2-deficient cancers was examined for germline and somatic alterations in the PMS2 gene.
Results:
An aberrant pattern of MMR protein expression was detected in 13.2% of CRCs. Loss of expression of MSH2, MSH6, or MLH1 was found in 1.4%, 0.5%, and 9.8%, respectively. PMS2 deficiency accompanied by microsatellite instability was found in 16 cases (1.5%) with a weak family history of cancer. The PMS2 promoter was not hypermethylated in these cases. Despite interference of the PMS2 pseudogenes, we identified several heterozygous germline mutations in the PMS2 gene.
Conclusions:
PMS2 defects account for a small but significant proportion of CRCs and for a substantial fraction of tumors with microsatellite instability. However, the penetrance of heterozygous germline mutations in PMS2 is considerably lower than that of mutations in other MMR genes. The possible underlying causes of this unorthodox inheritance pattern are discussed.
Insights
DNA mismatch repair gene PMS2 defects cause a small but significant portion of colorectal cancers (CRCs). Heterozygous germline mutations in PMS2 show lower penetrance than other MMR genes, impacting CRC inheritance patterns.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- Germline mutations in DNA mismatch repair (MMR) genes MSH2, MSH6, and MLH1 are linked to hereditary colorectal cancer (CRC).
- The PMS2 gene is crucial for MMR, but its role in CRC predisposition is exceptionally rare, prompting further investigation.
Purpose of the Study:
- To investigate the frequency and characteristics of PMS2 gene alterations in a large cohort of colorectal cancers.
- To understand the inheritance patterns and penetrance of PMS2 mutations in CRC.
Main Methods:
- Immunohistochemistry was used to assess MMR protein expression (MSH2, MSH6, MLH1, PMS2) in 1048 CRCs.
- Microsatellite instability and gene promoter methylation were analyzed in MMR-deficient tumors.
- Germline and somatic mutations in the PMS2 gene were identified in affected patients.
Main Results:
- Aberrant MMR protein expression was observed in 13.2% of CRCs, with PMS2 deficiency in 1.5% of cases.
- PMS2-deficient tumors showed microsatellite instability and were associated with a weak family cancer history.
- Heterozygous germline mutations in PMS2 were identified, despite challenges posed by PMS2 pseudogenes.
Conclusions:
- PMS2 defects contribute to a notable subset of CRCs and a significant fraction of microsatellite-instability-high tumors.
- Heterozygous PMS2 mutations exhibit considerably lower penetrance compared to other MMR gene mutations.
- The study discusses potential reasons for the atypical inheritance pattern of PMS2 mutations in CRC.
