Heterozygous Mutations in PMS2 Cause Hereditary Nonpolyposis Colorectal Carcinoma (Lynch Syndrome)

Center for Human and Clinical Genetics, Leiden University Medical Center, The Netherlands.
Gastroenterology (Impact Factor: 16.72). 02/2006; 130(2):312-22. DOI: 10.1053/j.gastro.2005.10.052
Source: PubMed

ABSTRACT The role of the mismatch repair gene PMS2 in hereditary nonpolyposis colorectal carcinoma (HNPCC) is not fully clarified. To date, only 7 different heterozygous truncating PMS2 mutations have been reported in HNPCC-suspected families. Our aim was to further assess the role of PMS2 in HNPCC.
We performed Southern blot analysis in 112 patients from MLH1-, MSH2-, and MSH6-negative HNPCC-like families. A subgroup (n = 38) of these patients was analyzed by denaturing gradient gel electrophoresis (DGGE). In a second study group consisting of 775 index patients with familial colorectal cancer, we performed immunohistochemistry using antibodies against MLH1, MSH2, MSH6, and PMS2 proteins. In 8 of 775 tumors, only loss of PMS2 expression was found. In these cases, we performed Southern blot analysis and DGGE. Segregation analysis was performed in the families with a (possibly) deleterious mutation.
Seven novel mutations were identified: 4 genomic rearrangements and 3 truncating point mutations. Three of these 7 families fulfill the Amsterdam II criteria. The pattern of inheritance is autosomal dominant with a milder phenotype compared with families with pathogenic MLH1 or MSH2 mutations. Microsatellite instability and immunohistochemical analysis performed in HNPCC-related tumors from proven carriers showed a microsatellite instability high phenotype and loss of PMS2 protein expression in all tumors.
We show that heterozygous truncating mutations in PMS2 do play a role in a small subset of HNPCC-like families. PMS2 mutation analysis is indicated in patients diagnosed with a colorectal tumor with absent staining for the PMS2 protein.

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    • "The PMS2 gene was the last of the four MMR genes to be identified as a cause of LS [1]. It has been suggested that PMS2 mutations may be associated with a later age of onset of cancer than MLH1 and MSH2 mutations [1]. "
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    ABSTRACT: Using immunohistochemistry (IHC) to select cases for mismatch repair (MMR) genetic testing, we failed to identify a large kindred with the deleterious PMS2 mutation c.989-1G > T. The purpose of the study was to examine the sensitivity of IHC and microsatellite instability-analysis (MSI) to identify carriers of the mutation, and to estimate its penetrance and expressions. All carriers and obligate carriers of the mutation were identified. All cancer diagnoses were confirmed. IHC and MSI-analysis were performed on available tumours. Penetrances of cancers included in the Amsterdam and the Bethesda Criteria, for MSI-high tumours and MSI-high and low tumours were calculated by the Kaplan-Meier algorithm. Probability for co-segregation of the mutation and cancers by chance was 0.000004. Fifty-six carriers or obligate carriers were identified. There was normal staining for PMS2 in 15/18 (83.3%) of tumours included in the AMS1/AMS2/Bethesda criteria. MSI-analysis showed that 15/21 (71.4%) of tumours were MSI-high and 4/21 (19.0%) were MSI-low. Penetrance at 70 years was 30.6% for AMS1 cancers (colorectal cancers), 42.8% for AMS2 cancers, 47.2% for Bethesda cancers, 55.6% for MSI-high and MSI-low cancers and 52.2% for MSI-high cancers. The mutation met class 5 criteria for pathogenicity. IHC was insensitive in detecting tumours caused by the mutation. Penetrance of cancers that displayed MSI was 56% at 70 years. Besides colorectal cancers, the most frequent expressions were carcinoma of the endometrium and breast in females and stomach and prostate in males.
    Hereditary Cancer in Clinical Practice 04/2014; 12(1):12. DOI:10.1186/1897-4287-12-12 · 1.47 Impact Factor
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    • "Current methods seek to enhance the detection of the real PMS2 gene and reduce the selection of the pseudogenes by targeting the few differences in nucleotide sequence between them (Vaughn et al. 2010, 2011). Phenotypic testing for signs of mismatch repair deficiency of bowel and endometrial tumours is useful in identifying patients with PMS2 mutations, as PMS2 mutations are associated with high microsatellite instability and loss of PMS2 expression as detected by immunohistochemistry (Hendriks et al. 2006). There is some evidence that the cancer risks for PMS2 Lynch syndrome are lower than for the other three genes, with colorectal cancer lifetime risk to age 70 years estimated at 15–20 %, and at 15 % for endometrial cancer (Senter et al. 2008). "
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    ABSTRACT: We present a case where an apparently straightforward Lynch syndrome predictive genetic test of DNA from a blood sample from a woman yielded an unexpected result of X/Y chromosome imbalance. Furthermore, it demonstrates the complexities of genetic testing in people who have had bone marrow transplants. This highlights the potential for multiple ethical and counselling challenges, including the inadvertent testing of the donor. Good communication between clinics and laboratories is essential to overcome such challenges and to minimise the provision of false results.
    Journal of Genetic Counseling 08/2013; 23(1). DOI:10.1007/s10897-013-9643-x · 2.24 Impact Factor
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    • "Thus the expression status of PMS-2 should correspond to that of MLH-1, and the inclusion of PMS-2 in the IHC panel should increase the sensitivity of MSI detection by identifying those additional cases with MLH-1 mutations which, for a number of reasons, may show false positive staining for MLH-1 but are negative for PMS-2.57 However, the concept of a substantial role of PMS-2 in the pathogenesis and detection of HNPCC and sporadic MSI tumours appears to be still evolving.58 "
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    ABSTRACT: Preoperative radiotherapy may improve the resectability and subsequent local control of rectal cancers. However, the extent of radiation induced regression in these tumours varies widely between individuals. To date no reliable predictive marker of radiation sensitivity in rectal cancer has been identified. At the cellular level, radiation injury initiates a complex molecular network of DNA damage response (DDR) pathways that leads to cell cycle arrest, attempts at re-constituting the damaged DNA and should this fail, then apoptosis. This review presents the details which suggest the roles of DNA mismatch repair proteins, the lack of which define a distinct subset of colorectal cancers with microsatellite instability (MSI), in the DDR pathways. Hence routine assessment of the MSI status in rectal cancers may potentially serve as a predictor of radiotherapy response, thereby improving patient stratification in the administration of this otherwise toxic treatment.
    The Korean Journal of Pathology 02/2013; 47(1):1-8. DOI:10.4132/KoreanJPathol.2013.47.1.1 · 0.17 Impact Factor
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