Gene Summary

Gene:PMS1; PMS1 homolog 1, mismatch repair system component
Aliases: MLH2, PMSL1, hPMS1, HNPCC3
Summary:This gene encodes a protein belonging to the DNA mismatch repair mutL/hexB family. This protein is thought to be involved in the repair of DNA mismatches, and it can form heterodimers with MLH1, a known DNA mismatch repair protein. Mutations in this gene cause hereditary nonpolyposis colorectal cancer type 3 (HNPCC3) either alone or in combination with mutations in other genes involved in the HNPCC phenotype, which is also known as Lynch syndrome. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:PMS1 protein homolog 1
Source:NCBIAccessed: 17 August, 2015


What does this gene/protein do?
Show (12)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 17 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Species Specificity
  • Genetic Predisposition
  • Nuclear Proteins
  • Research Design
  • Proto-Oncogene Proteins
  • Genetic Testing
  • MutS Homolog 2 Protein
  • Urinary System Cancers
  • Transcription Factors
  • Base Pair Mismatch
  • Research
  • Fungal Proteins
  • DNA Repair
  • Sex Factors
  • Colorectal Cancer
  • Mutation
  • Skin Cancer
  • Hereditary Nonpolyposis Colorectal Cancer (HNPCC)
  • DNA-Binding Proteins
  • Chromosome 2
  • Molecular Sequence Data
  • Polymerase Chain Reaction
  • Proteins
  • Risk Factors
  • DNA Mutational Analysis
  • Adenosine Triphosphatases
  • DNA Repair Enzymes
  • Saccharomyces cerevisiae Proteins
  • Carrier Proteins
  • Microsatellite Repeats
  • Spain
  • Base Sequence
  • Transforming Growth Factor beta Receptors
  • Neoplasm Proteins
  • Recombinant Fusion Proteins
  • Tumor Markers
  • Signal Transducing Adaptor Proteins
  • beta Catenin
  • Germ-Line Mutation
Tag cloud generated 17 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: PMS1 (cancer-related)

Belloni E, Veronesi G, Rotta L, et al.
Whole exome sequencing identifies driver mutations in asymptomatic computed tomography-detected lung cancers with normal karyotype.
Cancer Genet. 2015; 208(4):152-5 [PubMed] Related Publications
The efficacy of curative surgery for lung cancer could be largely improved by non-invasive screening programs, which can detect the disease at early stages. We previously showed that 18% of screening-identified lung cancers demonstrate a normal karyotype and, following high-density genome scanning, can be subdivided into samples with 1) numerous; 2) none; and 3) few copy number alterations. Whole exome sequencing was applied to the two normal karyotype, screening-detected lung cancers, constituting group 2, as well as normal controls. We identified mutations in both tumors, including KEAP1 (commonly mutated in lung cancers) in one, and TP53, PMS1, and MSH3 (well-characterized DNA-repair genes) in the other. The two normal karyotype screening-detected lung tumors displayed a typical lung cancer mutational profile that only next generation sequencing could reveal, which offered an additional contribution to the over-diagnosis bias concept hypothesized within lung cancer screening programs.

Svec J, Schwarzová L, Janošíková B, et al.
Synchronous gastric and sebaceous cancers, a rare manifestation of MLH1-related Muir-Torre syndrome.
Int J Clin Exp Pathol. 2014; 7(8):5196-202 [PubMed] Free Access to Full Article Related Publications
Muir-Torre syndrome (MTS), a rare variant of the hereditary non polyposis colorectal cancer syndrome, is an autosomal dominant genodermatosis characterised by coincidence of sebaceous gland neoplasms (sebaceous adenoma, epithelioma, or carcinoma) and at least one internal malignancy. The underlying cause of MTS is a germline mutation in DNA mismatch repair genes MSH2, MLH1 and MSH6. We report the case of a 52-year-old caucasian woman with the development of metachronous colon cancer at the age of 38 years, uterine cancer at the age of 43 years, and unique occurrence of synchronous gastric and sebaceous carcinomas related to germline point mutation c. 2194A>T in the last exon of MLH1 gene, resulting in truncated protein in C-terminal region p. Lys732X due to premature stop codon. This mutation, not previously reported in MTS, disrupts the function of MutL complexes presumably by preventing the interaction with PMS1/PMS2 and impairing the endonuclease active site. This case points out the importance of sebaceous neoplasia, especially sebaceous adenocarcinoma, as cutaneous markers of MTS for timely implementation of cancer screening programs.

Alvarado-Bachmann R, Smith A, Gundara JS, et al.
The incidence of mismatch repair gene defects in colorectal liver metastases.
Mol Med Rep. 2014; 10(2):1003-6 [PubMed] Related Publications
Knowledge of the molecular biology of primary colorectal cancer (CRC) has improved in recent years, and one reason for this is the identification of microsatellite instability (MSI), which occurs in up to 15% of sporadic CRC. However, less is known regarding the processes involved in colorectal liver metastases (CRLM). Increasing numbers of patients with CRLM are suitable for curative resection, so the identification of molecular markers may improve patient selection. The aim of the present study was to characterise the incidence of MSI in resected CRLM. Fifty‑one sequentially resected CRLM specimens were selected. Clinicopathologic data was collated and immunohistochemistry for MLH1 and MSH2 was performed on paraffin sections of the CRLM specimens. The association between abnormal staining and the clinicopathological data was examined. The median age of the subjects in the current study was 65 years, the average number of CRLM was 2 and the median overall survival time was 42.1 months post liver resection. None of the 50 resected specimens demonstrated abnormal staining for MLH1 or MSH2. Compared with the previously reported incidence of MSI in primary CRC, the low incidence of MSI in the current cohort of CRLM precludes its use as a marker for use in making clinical decisions regarding this condition.

Adamkov M, Furjelová M, Horáček J, et al.
Relationship of mismatch repair proteins and survivin in colon polyps and carcinomas.
Acta Histochem. 2014; 116(6):1007-14 [PubMed] Related Publications
Mismatch repair genes (MMR) play an essential role in DNA repair. MMR mutations predominantly in MLH1, MSH2, MSH6, PMS2, and rarely in PMS1, may cause the production of abnormally short or inactivated proteins. The antiapoptotic protein survivin functions in the inhibition of apoptosis, regulation of cell division and also enhances angiogenesis. Both MMRP and survivin are considered to be powerful prognostic parameters. This study was designed to determine the relationship between MMRP and survivin in colon lesions. The study included 113 cases of colon carcinoma and 51 cases of colon polyps. Survivin expression and MMRP status were assessed by immunohistochemistry. In each section, expression, intensity of immunostaining and percentage of labeled cells were analyzed. In carcinomas, immunoreaction was detected in 100/113 cases for MLH1 (88.5%), 112/113 cases for MSH2 (99.1%), 110/113 cases for MSH6 (97.3%), and 103/113 cases for PMS2 (91.2%). Survivin was shown in 47/113 cases (41.6%). The statistical analysis confirmed a significant correlation between the expression of MMRP and survivin in the assessed parameters. All 51 polyp samples were positive for MLH1, MSH2, MSH6 and PMS2. Only 8 of those (15.7%) were positive for survivin. Statistically significant differences were observed between the expression of MMRP and survivin. In conclusion, this study revealed that MMRP may suppress the antiapoptotic function of survivin through p53 inactivation of its promoter in grade 1 and grade 2 colon carcinomas.

Lazarev I, Leibovitch L, Czeiger D, et al.
Cell-free DNA blood levels in colorectal cancer patients do not correlate with mismatch repair-proficiency.
In Vivo. 2014 May-Jun; 28(3):349-54 [PubMed] Related Publications
UNLABELLED: While sporadic cases of colorectal cancer (CRC) most commonly arise via the well-characterized chromosomal instability pathway (CIN), most other cases develop via a serrated neoplasia pathway (CIMP), in which methylation of CpG islands results in silencing of DNA nucleotide mismatch repair (MMR)-related genes, and a high level of microsatellite instability (MSI). MSI-high tumors typically show proximal location, mucinous histology, poor differentiation, and lymphocytic infiltration. Cell-free circulating DNA (CFD) may become elevated in CRC patients compared to healthy individuals. Because of these biological differences, we hypothesized that compared to MMR-proficient tumors MMR-deficient CRCs may produce higher CFD blood levels.
PATIENTS AND METHODS: Forty-one patients with newly-diagnosed CRC from all stages were studied for MMR-proficiency status, and CFD and carcinoembryonic antigen (CEA) blood levels. MMR proficiency was evaluated in formalin-fixed, paraffin-embedded tissues by immunohistochemistry (IHC) for MLH1/MSH2. CFD plasma levels were measured with SYBR gold nucleic acid gel staining on fluorometry. MMR-proficiency status was studied by clinicopathological parameters, CFD and CEA blood levels.
RESULTS: Tumors were MMR-proficient, and -deficient in 16 patients (39%), and 25 patients (61%), respectively. The mean age of MMR-deficient patients was approximately 10 years higher than that of MMR-proficient patients (61.2±8.4 years versus 71.9±9.7 years, p=0.07). MMR-deficient tumors were more often proximally-located, (p=0.018). The mean CFD plasma levels in MMR-proficient, and MMR-deficient patients were 795±431 ng/ml, and 906±494 ng/ml, respectively (p=0.68). The mean CEA serum levels in MMR-proficient and MMR-deficient patients were 10.4±17.6 μg/l, and 15±48 μg/l, respectively (p=0.46).
CONCLUSION: Compared to MMR-proficient CRCs, MMR-deficient tumors occurred in older patients, and were more commonly proximally-located. Despite the presence of distinct biological and histopathological characteristics, both tumor types produced similar CFD blood levels.

Sameer AS, Nissar S, Fatima K
Mismatch repair pathway: molecules, functions, and role in colorectal carcinogenesis.
Eur J Cancer Prev. 2014; 23(4):246-57 [PubMed] Related Publications
The microsatellite instability (MSI) pathway is one of the important mutational pathways that play a critical role in colorectal carcinogenesis. About 15% of colorectal cancers (CRCs) are characterized by MSI. MSI tumors usually arise because of a genetic defect in mismatch repair (MMR) genes, one of the main DNA-repairing systems. MMR is a highly conserved biological pathway that plays a key role in maintaining genomic stability by correcting the base-base mismatches and insertion/deletion mispairs generated during DNA replication and recombination. Escherichia coli MutS and MutL and their eukaryotic homologs, MutSα and MutLα, respectively, are key players in MMR-associated genome maintenance. Mutations in at least five pivotal genes of MMR, namely, in those encoding mutS homolog 2 (MSH2), mutL homolog 1 (MLH1), mutS homolog 6 (MSH6), postmeiotic segregation increased 1 (PMS1), and postmeiotic segregation, increased 2 (PMS2) have been found in CRC, highlighting the importance of understanding the basic structure and functions of the essential molecules that make up the MMR system. In this review, we have attempted to focus on this aspect, that is, the role that MMR molecules play in CRC carcinogenesis.

Castéra L, Krieger S, Rousselin A, et al.
Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes.
Eur J Hum Genet. 2014; 22(11):1305-13 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
To optimize the molecular diagnosis of hereditary breast and ovarian cancer (HBOC), we developed a next-generation sequencing (NGS)-based screening based on the capture of a panel of genes involved, or suspected to be involved in HBOC, on pooling of indexed DNA and on paired-end sequencing in an Illumina GAIIx platform, followed by confirmation by Sanger sequencing or MLPA/QMPSF. The bioinformatic pipeline included CASAVA, NextGENe, CNVseq and Alamut-HT. We validated this procedure by the analysis of 59 patients' DNAs harbouring SNVs, indels or large genomic rearrangements of BRCA1 or BRCA2. We also conducted a blind study in 168 patients comparing NGS versus Sanger sequencing or MLPA analyses of BRCA1 and BRCA2. All mutations detected by conventional procedures were detected by NGS. We then screened, using three different versions of the capture set, a large series of 708 consecutive patients. We detected in these patients 69 germline deleterious alterations within BRCA1 and BRCA2, and 4 TP53 mutations in 468 patients also tested for this gene. We also found 36 variations inducing either a premature codon stop or a splicing defect among other genes: 5/708 in CHEK2, 3/708 in RAD51C, 1/708 in RAD50, 7/708 in PALB2, 3/708 in MRE11A, 5/708 in ATM, 3/708 in NBS1, 1/708 in CDH1, 3/468 in MSH2, 2/468 in PMS2, 1/708 in BARD1, 1/468 in PMS1 and 1/468 in MLH3. These results demonstrate the efficiency of NGS in performing molecular diagnosis of HBOC. Detection of mutations within other genes than BRCA1 and BRCA2 highlights the genetic heterogeneity of HBOC.

Li H, Wawrose JS, Gooding WE, et al.
Genomic analysis of head and neck squamous cell carcinoma cell lines and human tumors: a rational approach to preclinical model selection.
Mol Cancer Res. 2014; 12(4):571-82 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
UNLABELLED: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common type of cancer worldwide. The increasing amount of genomic information on human tumors and cell lines provides more biologic data to design preclinical studies. We and others previously reported whole-exome sequencing data of 106 HNSCC primary tumors. In 2012, high-throughput genomic data and pharmacologic profiling of anticancer drugs of hundreds of cancer cell lines were reported. Here, we compared the genomic data of 39 HNSCC cell lines with the genomic findings in 106 HNSCC tumors. Amplification of eight genes (PIK3CA, EGFR, CCND2, KDM5A, ERBB2, PMS1, FGFR1, and WHSCIL1) and deletion of five genes (CDKN2A, SMAD4, NOTCH2, NRAS, and TRIM33) were found in both HNSCC cell lines and tumors. Seventeen genes were only mutated in HNSCC cell lines (>10%), suggesting that these mutations may arise through immortalization in tissue culture. Conversely, 11 genes were only mutated in >10% of human HNSCC tumors. Several mutant genes in the EGF receptor (EGFR) pathway are shared both in cell lines and in tumors. Pharmacologic profiling of eight anticancer agents in six HNSCC cell lines suggested that PIK3CA mutation may serve as a predictive biomarker for the drugs targeting the EGFR/PI3K pathway. These findings suggest that a correlation of gene mutations between HNSCC cell lines and human tumors may be used to guide the selection of preclinical models for translational research.
IMPLICATIONS: These findings suggest that a correlation of gene mutations between HNSCC cell lines and human tumors may be used to guide the selection of preclinical models for translational research.

Xiao X, Melton DW, Gourley C
Mismatch repair deficiency in ovarian cancer -- molecular characteristics and clinical implications.
Gynecol Oncol. 2014; 132(2):506-12 [PubMed] Related Publications
DNA mismatch repair (MMR) deficiency is associated with increased risk of developing several types of cancer and is the most common cause of hereditary ovarian cancer after BRCA1 and BRCA2 mutations. While there has been extensive investigation of MMR deficiency in colorectal cancer, MMR in ovarian cancer is relatively under-investigated. This review summarizes the mechanism of MMR, the ways in which MMR deficiency can promote carcinogenesis in general and then assesses the available studies regarding MMR deficiency in ovarian cancers with specific emphasis on implications for disease incidence and therapy. The incidence of germline MMR gene mutations in ovarian cancer is only 2% but other mechanisms of gene inactivation mean that loss of expression of one of the seven main genes (MSH2, MSH3, MSH6, MLH1, MLH3, PMS1 and PMS2) occurs in up to 29% of cases. Both mutational and expression data suggest that MMR deficiency is more common in non-serous ovarian cancer. Some studies suggest an improved survival for patients with MMR deficiency compared to historical controls but these do not account for the preponderance of non-serous tumors. A number of in vitro studies have suggested that MMR deficiency is a cause of platinum resistance. To date this has not been categorically demonstrated in the clinic. Larger studies that account for stage of presentation and immunohistochemical subtype are required to assess the effect of MMR deficiency on survival and chemosensitivity. Investigation of MMR related synthetic lethality in colorectal cancer has identified dihydrofolate reductase, DNA polymerase β and DNA polymerase γ and PTEN-induced putative kinase 1 as synthetic lethal to certain MMR defects by causing accumulation of oxidative DNA damage. These synthetic lethal targets require tested and others should be sought within the context of MMR deficient ovarian cancer in an attempt to provide novel therapeutic strategies for these patients.

Chong IY, Cunningham D, Barber LJ, et al.
The genomic landscape of oesophagogastric junctional adenocarcinoma.
J Pathol. 2013; 231(3):301-10 [PubMed] Related Publications
The incidence of oesophagogastric junctional (OGJ) adenocarcinoma is rising rapidly in western countries, in contrast to the declining frequency of distal gastric carcinoma. Treatment options for adenocarcinomas involving the oesophagogastric junction are limited and the overall prognosis is extremely poor. To determine the genomic landscape of OGJ adenocarcinoma, exomes of eight tumours and matched germline DNA were subjected to massively parallel DNA sequencing. Microsatellite instability was observed in three tumours which coincided with an elevated number of somatic mutations. In total, 117 genes were identified that had predicted coding alterations in more than one tumour. Potentially actionable coding mutations were identified in 67 of these genes, including those in CR2, HGF , FGFR4, and ESRRB. Twenty-nine genes harbouring somatic coding mutations and copy number changes in the MSS OGJ dataset are also known to be altered with similar predicted functional consequence in other tumour types. Compared with the published mutational profile of gastric cancers, 49% (57/117) of recurrently mutated genes were unique to OGJ tumours. TP53, SYNE1, and ARID1A were amongst the most frequently mutated genes in a larger OGJ cohort. Our study provides an insight into the mutational landscape of OGJ adenocarcinomas and confirms that this is a highly mutated and heterogeneous disease. Furthermore, we have uncovered somatic mutations in therapeutically relevant genes which may represent candidate drug targets.

Smith CE, Mendillo ML, Bowen N, et al.
Dominant mutations in S. cerevisiae PMS1 identify the Mlh1-Pms1 endonuclease active site and an exonuclease 1-independent mismatch repair pathway.
PLoS Genet. 2013; 9(10):e1003869 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Lynch syndrome (hereditary nonpolypsis colorectal cancer or HNPCC) is a common cancer predisposition syndrome. Predisposition to cancer in this syndrome results from increased accumulation of mutations due to defective mismatch repair (MMR) caused by a mutation in one of the mismatch repair genes MLH1, MSH2, MSH6 or PMS2/scPMS1. To better understand the function of Mlh1-Pms1 in MMR, we used Saccharomyces cerevisiae to identify six pms1 mutations (pms1-G683E, pms1-C817R, pms1-C848S, pms1-H850R, pms1-H703A and pms1-E707A) that were weakly dominant in wild-type cells, which surprisingly caused a strong MMR defect when present on low copy plasmids in an exo1Δ mutant. Molecular modeling showed these mutations caused amino acid substitutions in the metal coordination pocket of the Pms1 endonuclease active site and biochemical studies showed that they inactivated the endonuclease activity. This model of Mlh1-Pms1 suggested that the Mlh1-FERC motif contributes to the endonuclease active site. Consistent with this, the mlh1-E767stp mutation caused both MMR and endonuclease defects similar to those caused by the dominant pms1 mutations whereas mutations affecting the predicted metal coordinating residue Mlh1-C769 had no effect. These studies establish that the Mlh1-Pms1 endonuclease is required for MMR in a previously uncharacterized Exo1-independent MMR pathway.

Mahdi KM, Nassiri MR, Nasiri K
Hereditary genes and SNPs associated with breast cancer.
Asian Pac J Cancer Prev. 2013; 14(6):3403-9 [PubMed] Related Publications
Breast cancer is the most common cancer among women affecting up to one third of tehm during their lifespans. Increased expression of some genes due to polymorphisms increases the risk of breast cancer incidence. Since mutations that are recognized to increase breast cancer risk within families are quite rare, identification of these SNPs is very important. The most important loci which include mutations are; BRCA1, BRCA2, PTEN, ATM, TP53, CHEK2, PPM1D, CDH1, MLH1, MRE11, MSH2, MSH6, MUTYH, NBN, PMS1, PMS2, BRIP1, RAD50, RAD51C, STK11 and BARD1. Presence of SNPs in these genes increases the risk of breast cancer and associated diagnostic markers are among the most reliable for assessing prognosis of breast cancer. In this article we reviewed the hereditary genes of breast cancer and SNPs associated with increasing the risk of breast cancer that were recently were reported from candidate gene, meta-analysis and GWAS studies. SNPs of genes associated with breast cancer can be used as a potential tool for improving cancer diagnosis and treatment planning.

Kobayashi H, Ohno S, Sasaki Y, Matsuura M
Hereditary breast and ovarian cancer susceptibility genes (review).
Oncol Rep. 2013; 30(3):1019-29 [PubMed] Related Publications
Women with hereditary breast and ovarian cancer (HBOC) syndrome represent a unique group who are diagnosed at a younger age and result in an increased lifetime risk for developing breast, ovarian and other cancers. This review integrates recent progress and insights into the molecular basis that underlie the HBOC syndrome. A review of English language literature was performed by searching MEDLINE published between January 1994 and October 2012. Mutations and common sequence variants in the BRCA1 and BRCA2 (BRCA) genes are responsible for the majority of HBOC syndrome. Lifetime cancer risks in BRCA mutation carriers are 60-80% for breast cancer and 20-40% for ovarian cancer. Mutations in BRCA genes cannot account for all cases of HBOC, indicating that the remaining cases can be attributed to the involvement of constitutive epimutations or other cancer susceptibility genes, which include Fanconi anemia (FA) cluster (FANCD2, FANCA and FANCC), mismatch repair (MMR) cluster (MLH1, MSH2, PMS1, PMS2 and MSH6), DNA repair cluster (ATM, ATR and CHK1/2), and tumor suppressor cluster (TP53, SKT11 and PTEN). Sporadic breast cancers with TP53 mutations or epigenetic silencing (hypermethylation), ER- and PgR-negative status, an earlier age of onset and high tumor grade resemble phenotypically BRCA1 mutated cancers termed 'BRCAness', those with no BRCA mutations but with a dysfunction of the DNA repair system. In conclusion, genetic or epigenetic loss-of-function mutations of genes that are known to be involved in the repair of DNA damage may lead to increased risk of developing a broad spectrum of breast and ovarian cancers.

Wang Y, Zhou X, Song Y, et al.
The mismatch repair gene hPMS1 (human postmeiotic segregation1) is down regulated in oral squamous cell carcinoma.
Gene. 2013; 524(1):28-34 [PubMed] Related Publications
Genomic instability or microsatellite instability (MSI) was initially recognized in colonic carcinoma and subsequently in other tumors. MSI has been associated with mutations in genes that play a role in DNA replication and repair. In a previous study we detected MSI in 85% of young patients with OSCC and excluded the involvement of MMR genes hMLH1 and hMSH2. In the present study, we screened the mutation and expression status of the MMR genes hMSH3, hMSH6, hPMS1 and hPMS2 in OSCC and found expression of the hPMS1 protein to be down regulated. Genomic analysis of hPMS1 did not show any mutational changes in exonic or promoter regions. Expression of hPMS1 mRNA was not deregulated in either MSI positive or MSI negative tumor cell lines by Northern blot analysis. In contrast, analysis by Western blot showed that 100% of MSI positive tumor cell lines had decreased or no expression of hPMS1 while MSI negative cell lines had normal protein expression. Our data indicate that hPMS1 is most likely deregulated by post-transcriptional modification in OSCC while hMLH1 and hPMS2 has no detectable changes. Furthermore, our results are consistent with the hypothesis that hPMS1 is associated with MSI in OSCC.

Vergouwe F, Boutall A, Stupart D, et al.
Mismatch repair deficiency in colorectal cancer patients in a low-incidence area.
S Afr J Surg. 2013; 51(1):16-21 [PubMed] Related Publications
BACKGROUND: In a previous study we identified 206 patients with colorectal adenocarcinoma in the Northern Cape province of South Africa, diagnosed between January 2002 and February 2009. The age-standardised incidence was 4.2/100 000 per year world standard population. This is 10% of the rate reported in First-World countries. In high-incidence areas, the rate of abnormal mismatch repair gene expression in colorectal cancers is 2 - 7%.
OBJECTIVES: The aim of this study was to determine the prevalence of hMLH1- and hMSH2-deficient colorectal cancer in the Northern Cape.
METHODS: Formalin-fixed paraffin wax-embedded tissue blocks from 87 colorectal adenocarcinomas identified in the previous study were retrieved. Standard immunohistochemical staining methods were used to detect the expression of hMLH1 and hMSH2 (i.e. products of the hMLH1 and hMSH2 genes) in the tumours using heat-induced antigen retrieval and diaminobenzidene as a chromogen. Results. In 8 blocks there was insufficient tumour tissue and in 1 case the immunohistochemical staining failed, probably owing to poor fixation, leaving 78 cases for analysis. In 11 cases hMLH1 was deficient and in 6 cases hMSH2 was deficient. Overall, 21.8% of cancers were deficient for hMLH1 or hMSH2.
CONCLUSION: Presuming that 80% of all hMLH1 deficiencies are due to hypermethylation of the gene, we found 10.5% of colorectal cancers in an area with a low incidence of colorectal cancer to be deficient in the product of the mismatch repair gene/s. This is approximately three times the reported rate in high-incidence areas.

Bansal A, Soni A, Rao P, et al.
Implication of DNA repair genes in prostate tumourigenesis in Indian males.
Indian J Med Res. 2012; 136(4):622-32 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
BACKGROUND & OBJECTIVES: Prostate cancer (CaP) is the fifth most common cancer among Indian men. Tumour protein p53 (TP53) gene increases the fidelity of DNA replication and homologous recombination by transcriptional transactivation of mismatch repair (MMR) genes. DNA repair thus has a potential role in molecular carcinogenesis of CaP. The aim of the present study was to identify mutations, and polymorphisms in TP53 gene and MMR protein expression in CaP in Indian male population.
METHODS: TP53 codon 72 polymorphism was analysed in 105 CaP, 120 benign prostatic hyperplasia (BPH) cases and 106 normal controls. Mutational analysis of TP53 was done in DNA extracted from formalin fixed paraffin embedded tissue of 80 CaP and 24 BPH cases. Expression of MMR proteins viz. hMLH1, hMSH2, hPMS1 and hPMS2 was studied in 80 CaP, 15 prostatic intraepithelial neoplasia (PIN) and 15 BPH cases.
RESULTS: A somatic C/A variation at the intronic boundary of exon 7 in TP53 gene was observed in one each biopsy samples from CaP and BPH. A significant association of codon 72 TP53 Pro/Pro genotype was observed with the risk of CaP (OR, 2.59, P=0.02) and BPH (OR, 6.27, P<0.001). Immunohistochemical analysis of MMR proteins showed maximum loss of hPMS1 expression in cases of CaP and PIN while no loss in expression of MMR proteins was observed in BPH cases. The study also identified a significant loss of hPMS2 protein in poorly differentiated tumours (Gleason score >7) than in well differentiated tumours (Gleason score 3-6) (P<0.05).
INTERPRETATION & CONCLUSIONS: The results of the present study demonstrate that TP53 codon 72 polymorphism plays significant role in the pathogenesis and susceptibility to CaP and BPH. Also, an aberrant MMR protein expression could be involved in progression of prostate cancer through PIN, early CaP to aggressive CaP. The loss of hPMS2 protein expression may serve as a marker for progression of CaP.

Vogelsang M, Wang Y, Veber N, et al.
The cumulative effects of polymorphisms in the DNA mismatch repair genes and tobacco smoking in oesophageal cancer risk.
PLoS One. 2012; 7(5):e36962 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
The DNA mismatch repair (MMR) enzymes repair errors in DNA that occur during normal DNA metabolism or are induced by certain cancer-contributing exposures. We assessed the association between 10 single-nucleotide polymorphisms (SNPs) in 5 MMR genes and oesophageal cancer risk in South Africans. Prior to genotyping, SNPs were selected from the HapMap database, based on their significantly different genotypic distributions between European ancestry populations and four HapMap populations of African origin. In the Mixed Ancestry group, the MSH3 rs26279 G/G versus A/A or A/G genotype was positively associated with cancer (OR = 2.71; 95% CI: 1.34-5.50). Similar associations were observed for PMS1 rs5742938 (GG versus AA or AG: OR = 1.73; 95% CI: 1.07-2.79) and MLH3 rs28756991 (AA or GA versus GG: OR = 2.07; 95% IC: 1.04-4.12). In Black individuals, however, no association between MMR polymorhisms and cancer risk was observed in individual SNP analysis. The interactions between MMR genes were evaluated using the model-based multifactor-dimensionality reduction approach, which showed a significant genetic interaction between SNPs in MSH2, MSH3 and PMS1 genes in Black and Mixed Ancestry subjects, respectively. The data also implies that pathogenesis of common polymorphisms in MMR genes is influenced by exposure to tobacco smoke. In conclusion, our findings suggest that common polymorphisms in MMR genes and/or their combined effects might be involved in the aetiology of oesophageal cancer.

Okkels H, Lindorff-Larsen K, Thorlasius-Ussing O, et al.
MSH6 mutations are frequent in hereditary nonpolyposis colorectal cancer families with normal pMSH6 expression as detected by immunohistochemistry.
Appl Immunohistochem Mol Morphol. 2012; 20(5):470-7 [PubMed] Related Publications
INTRODUCTION: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant condition accounting for 2% to 4% of all colorectal cancer cases worldwide. Families with germ line mutations in 1 of 6 mismatch repair genes are known as Lynch syndrome families. The largest number of mutations has been detected in the mismatch repair genes MLH1 and MSH2, but several mutations in MSH6 have also been demonstrated.
AIM: : Whether HNPCC families are screened for mutations in mismatch repair genes often relies on their immunohistochemical profile. The aim of the present study was to evaluate this approach in Lynch families carrying mutations in MSH6.
MATERIALS AND METHODS: Results of the screening of the MSH6 gene in HNPCC families were compared with those obtained on immunohistochemical protein analysis.
RESULTS: In 56 (7%) of 815 families, at least 1 MSH6 mutation, 23 definitively pathogenic mutations and 38 missense mutations or unclassified variants, and several polymorphisms in the MSH6 gene were detected. In families carrying a pathogenic MSH6 mutation, 69.6% of 23 colon adenocarcinomas showed absence of pMSH6 in tumor tissue by immunohistochemical analysis. In 34.5%, all proteins could be detected, whereas in 34.5% pMSH6 was present and pMLH1/pPMS2 was absent.
CONCLUSIONS: If genetic screening of HNPCC families depended on immunohistochemical results, a substantial number of families harboring a pathogenic mutation in MSH6 and the vast majority of families harboring an MSH6 unclassified variant would not be detected.

Monteiro Santos EM, Valentin MD, Carneiro F, et al.
Predictive models for mutations in mismatch repair genes: implication for genetic counseling in developing countries.
BMC Cancer. 2012; 12:64 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
BACKGROUND: Lynch syndrome (LS) is the most common form of inherited predisposition to colorectal cancer (CRC), accounting for 2-5% of all CRC. LS is an autosomal dominant disease characterized by mutations in the mismatch repair genes mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), postmeiotic segregation increased 1 (PMS1), post-meiotic segregation increased 2 (PMS2) and mutS homolog 6 (MSH6). Mutation risk prediction models can be incorporated into clinical practice, facilitating the decision-making process and identifying individuals for molecular investigation. This is extremely important in countries with limited economic resources. This study aims to evaluate sensitivity and specificity of five predictive models for germline mutations in repair genes in a sample of individuals with suspected Lynch syndrome.
METHODS: Blood samples from 88 patients were analyzed through sequencing MLH1, MSH2 and MSH6 genes. The probability of detecting a mutation was calculated using the PREMM, Barnetson, MMRpro, Wijnen and Myriad models. To evaluate the sensitivity and specificity of the models, receiver operating characteristic curves were constructed.
RESULTS: Of the 88 patients included in this analysis, 31 mutations were identified: 16 were found in the MSH2 gene, 15 in the MLH1 gene and no pathogenic mutations were identified in the MSH6 gene. It was observed that the AUC for the PREMM (0.846), Barnetson (0.850), MMRpro (0.821) and Wijnen (0.807) models did not present significant statistical difference. The Myriad model presented lower AUC (0.704) than the four other models evaluated. Considering thresholds of ≥ 5%, the models sensitivity varied between 1 (Myriad) and 0.87 (Wijnen) and specificity ranged from 0 (Myriad) to 0.38 (Barnetson).
CONCLUSIONS: The Barnetson, PREMM, MMRpro and Wijnen models present similar AUC. The AUC of the Myriad model is statistically inferior to the four other models.

Dong J, Hu Z, Shu Y, et al.
Potentially functional polymorphisms in DNA repair genes and non-small-cell lung cancer survival: a pathway-based analysis.
Mol Carcinog. 2012; 51(7):546-52 [PubMed] Related Publications
To assess systematically whether potentially functional polymorphisms in DNA repair genes influence the clinical behavior of non-small-cell lung cancer (NSCLC), we examined the impact of a comprehensive panel of 218 signal nucleotide polymorphisms (SNP) in 50 candidate DNA repair genes on overall survival of NSCLC in a case-cohort of 568 lung cancer patients. SNPs associated with lung cancer prognosis primarily mapped to 14 genes in different repair pathways, and 6 SNPs were remained in the final model after multivariate stepwise Cox regression analysis: ATM rs189037; MRE11A rs11020802; ERCC2 rs1799793; MBD4 rs140693; XRCC1 rs25487, and PMS1 rs5742933. In the combined analysis of these 6 SNPs, an increasing number of unfavorable loci was associated with a poorer prognosis (P for trend: <0.0001) and patients having 2-4 unfavorable loci had a 1.99-fold elevated risk of death 95% confidence interval (CI) = 1.58-2.50, compared with those carrying 0-1 unfavorable loci, and this elevated risk was more evident among stages I-II patients (hazard ratio = 3.04, 95% CI = 1.86-4.98, P for heterogeneity: 0.07). Furthermore, a significant effect of SNPs in nucleotide excision repair pathway on lung cancer survival was observed among 185 stages III-IV patients treated with platinum-based chemotherapy without surgical operation: XPC rs2228000 (Ala499Val; P = 0.002) and ERCC1 rs11615 (Asn118Asn; P = 0.012). Our data indicate that potentially functional polymorphisms in DNA repair genes may serve as candidate prognostic markers of clinical outcome of NSCLC.

Wei W, Liu F, Liu L, et al.
Distinct mutations in MLH1 and MSH2 genes in hereditary non-polyposis colorectal cancer (HNPCC) families from China.
BMB Rep. 2011; 44(5):317-22 [PubMed] Related Publications
Hereditary non-polyposis Colorectal Cancer (HNPCC) is an autosomal dominant inheritance syndrome. HNPCC is the most common hereditary variant of colorectal cancer (CRC), which accounts for 2-5% CRCs, mainly due to hMLH1 and hMSH2 mutations that impair DNA repair functions. Our study aimed to identify the patterns of hMSH2 and hMLH1 mutations in Chinese HNPCC patients. Ninety-eight unrelated families from China meeting Amsterdam or Bethesda criteria were included in our study. Germline mutations in MLH1 and MSH2 genes, located in the exons and the splice-site junctions, were screened in the 98 probands by direct sequencing. Eleven mutations were found in ten patients (11%), with six in MLH1 (54.5%) and five in MSH2 (45.5%) genes. One patient had mutations in both MLH1 and MSH2 genes. Three novel mutations in MLH1 gene (c.157_160delGAGG, c.2157dupT and c.-64G>T) were found for the first time, and one suspected hotspot in MSH2 (c.1168C>T) was revealed.

Soni A, Bansal A, Singh LC, et al.
Gene expression profile and mutational analysis of DNA mismatch repair genes in carcinoma prostate in Indian population.
OMICS. 2011; 15(5):319-24 [PubMed] Related Publications
DNA mismatch repair (MMR) plays a role in promoting genetic stability by repairing DNA replication errors, inhibiting recombination between nonidentical DNA sequences, and participating in responses to DNA damage. Although the role of MMR in prostate carcinogenesis remains unclear, MMR deficiency in Carcinoma Prostate (Pca) could prove to be clinically significant. Thus, the present study investigated the gene expression profile of six major MMR genes, viz. hMLH1, hMSH2, hPMS1, hPMS2, hMSH3, and hMSH6, and polymorphism in hMLH1 and hMSH2 in Pca in Indian population. Further, correlation with clinicopathological parameters was evaluated to establish their role as a potential prognostic marker. A significant downregulation of hMLH1, hMSH2, and hPMS2 expression was observed in Pca compared to benign prostatic hyperplasia (BPH). A greater loss of hPMS2 protein in poorly differentiated tumors was demonstrated, which was in concordance with a significant inverse correlation of hPMS2 gene expression with the Gleason score indicating its significance as a marker for Pca progression. An important association of hMLH1-93G>A polymorphism with the risk of Pca was also identified. The results of the present study suggest that an altered MMR has important biological and clinical significance in Pca in Indian population.

Gong X, Schwartz PH, Linskey ME, Bota DA
Neural stem/progenitors and glioma stem-like cells have differential sensitivity to chemotherapy.
Neurology. 2011; 76(13):1126-34 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
OBJECTIVES: New data suggest that glioma stem-like cells (GSCs) and neural stem/progenitor cells (NSCs) may share common origins. GSCs drive tumor proliferation and appear to be resistant to classic chemotherapy, while the effects of chemotherapy on NSCs are not well studied. As the role of NSCs in learning and memory is increasingly recognized, we need to identify drugs that reduce neurotoxicity but are still effective against glial tumors.
METHODS: We treated 3 human NSC cultures and multiple low- and high-grade GSC cultures with the commonly used agents temozolomide (TMZ) and cisplatin (CIS), and with 2 newer, promising drugs: the proteasome inhibitor bortezomib (BTZ) and the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib (ERL). We measured cell survival, proliferation, cell death induction, and drug resistance markers.
RESULTS: TMZ decreased NSC viability, while minimally affecting GSCs. TMZ induced NSC death, which was partially compensated for by increased proliferation. CIS had similar effects. The NSC's sensitivity to TMZ and CIS correlated with low expression of the multidrug resistance gene ABCG2, but not of MGMT or MSH1/MLH2. BTZ caused an 80%decrease in GSCs, while minimally affecting NSCs. GSCs had lower proteasome levels and activity after BTZ treatment. ERL treatment also decreased GSC numbers, but not NSC viability, which correlated with low EGFR expression in NSCs compared to GSCs.
CONCLUSIONS: Newer chemotherapy agents ERL and BTZ are effective against GSCs yet produce minimal effects on NSCs, while the older drugs TMZ and CIS are more toxic for NSCs than for GSCs. The identification and testing of more selective drugs is clearly warranted.

Kim YM, Choe CG, Cho SK, et al.
Three novel germline mutations in MLH1 and MSH2 in families with Lynch syndrome living on Jeju island, Korea.
BMB Rep. 2010; 43(10):693-7 [PubMed] Related Publications
Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant syndrome characterized by predisposition to early-onset cancers. HNPCC is caused by heterozygous loss-of-function mutations within the mismatch repair genes MLH1, MSH2, MSH6, PMS1, and PMS2. We genotyped the MLH1 and MSH2 genes in patients suffering from Lynch syndrome and in 11 unrelated patients who were diagnosed with colorectal cancer and had subsequently undergone surgery. Five Lynch syndrome patients carried germline mutations in MLH1 or MSH2. Two of these were identified as known mutations in MLH1: deletion of exon 10 and a point mutation (V384D). The remaining three patients exhibited novel mutations: a duplication (937_942dupGAAGTT) in MLH1; deletion of exons 8, 9, and 10; and a point mutation in MLH1 (F396I) combined with multiple missense mutations in MSH2 (D295G, K808E, Q855P, and I884T). The findings underline the importance of efficient pre-screening of conspicuous cases.

Lim MC, Seo SS, Kang S, et al.
Hereditary non-polyposis colorectal cancer/Lynch syndrome in Korean patients with endometrial cancer.
Jpn J Clin Oncol. 2010; 40(12):1121-7 [PubMed] Related Publications
OBJECTIVE: We investigate the frequency of hereditary non-polyposis colorectal cancer among Korean endometrial cancer patients according to two clinical criteria and the uptake rate of a genetic test and genetic status of such patients in routine clinical practice.
METHODS: This was a retrospective study involving 161 consecutive endometrial cancer patients. Patients were classified into clinical and suspected hereditary non-polyposis colorectal cancer. Using direct sequencing, germline mutations were analyzed in the MLH1 and MSH2 genes.
RESULTS: There were four (2.5%) clinical hereditary non-polyposis colorectal cancer patients, three of whom underwent genetic testing, and a mutation (c.882delT) in the MSH2 gene was identified in one patient. There were also 14 (8.7%) suspected hereditary non-polyposis colorectal cancer patients, 6 of whom underwent genetic testing; 1 [1/6 (16.7%)] patient had a mutation (c.1757_1758insC) in the MLH1 gene and 1 patient had a sequence variant of unknown significance (c.1886A < G) in the MSH2 gene. Half of the patients (9 of 18) who met clinical or suspected hereditary non-polyposis colorectal cancer criteria declined genetic testing mainly for the reason of financial factor (8 of 9).
CONCLUSIONS: The proportion of hereditary non-polyposis colorectal cancer [11.2% (18 of 161)] was significant to offer genetic counseling and genetic testing in Korean endometrial cancer patients. Optimal financial support is crucial to increase the uptake rate of a genetic test.

Zhang H, Gao XS, Zhao J, et al.
Differential gene expression profiles of DNA repair genes in esophageal cancer cells after X-ray irradiation.
Chin J Cancer. 2010; 29(10):865-72 [PubMed] Related Publications
BACKGROUND AND OBJECTIVE: Various factors affect the radioresistance of tumor cells, with unknown molecular mechanism(s). Many genes have been found to associate with the radioresistance of tumor cells, however, the precise mechanism of these genes have not been elucidated. This paper was to analyze the differential expressions of DNA repair genes in esophageal carcinoma cells at different time after X-ray irradiation, and to investigate the role of these DNA repair genes in radiation resistance.
METHODS: Esophageal cancer parental cells Seg-1 were treated with continuous 2 Gy of fractionated irradiation until the total dose reached 60 Gy to establish the radioresistant cell line Seg-1R. Total RNA was extracted from each cell line at 0, 8, and 24 h after irradiation. Illumine Human-6 V3 microarray was used to identify differentially expressed genes between parental and radioresistant cells. Ten genes involved in DNA repair were obtained and their expressions at different time points after irradiation were analyzed by Gene Ontology analysis.
RESULTS: Ten DNA repair associated genes were found to be differentially expressed. Three of these genes, SLK, HMGB1, and PMS1, were not only differentially expressed between parental and radioresistant cell lines, but also expressed differently at different time points after irradiation in the same cell line.
CONCLUSIONS: PMS1 may be an important factor involved in the mechanism of radioresistance of esophageal carcinoma cells.

Rondeau G, Nolet S, Latour M, et al.
Clinical and biochemical features of seven adult adrenal ganglioneuromas.
J Clin Endocrinol Metab. 2010; 95(7):3118-25 [PubMed] Related Publications
BACKGROUND: Adrenal ganglioneuroma (GN) is seldom considered in the differential diagnosis of adrenal lesions, and its clinical presentation is not well known.
OBJECTIVE: Our aim was to describe the clinical, biochemical, and radiological features of adrenal GNs in adults.
METHODS: Seven adults underwent endocrine investigation for adrenal lesions that were confirmed to be adrenal GNs.
RESULTS: Mean age of the seven patients was 49 yr (range, 23 to 71 yr). Average tumor diameter was 5.0 cm (range, 1.5 to 10.4 cm). In five patients, the adrenal lesions were found incidentally. A 49-yr-old female carried a germline mutation in MSH2 gene. A 57-yr-old female presented with mild virilization and increased testosterone levels. Bilateral adrenal venous sampling revealed testosterone production from her right adrenal lesion. All tumors showed nonenhanced attenuation between 25 and 40 Hounsfield units on computed tomography scan. Magnetic resonance imaging revealed low- to iso-signal intensity on T1-weighted imaging and high-signal intensity on T2-weighted imaging. [(18)F]-2-Fluoro-deoxy-d-glucose-positron emission tomography scan (n = 5) disclosed a mean standard uptake value of 2.4. Three tumors were composite pheochromocytoma-GN. Microsatellite instability study and immunohistochemical analysis of MSH2 protein in a patient carrying a MSH2 mutation showed normal MSH2 protein expression and low microsatellite instability, indicating that the adrenal GN was not related to the patient's MSH2 germline defect.
CONCLUSIONS: We describe one of the largest series of adult adrenal GNs. Adrenal GNs may secrete testosterone or be part of a composite tumor with pheochromocytoma. The association of adrenal GN with MSH2 mutation seems to be a coincidental finding.

Pasche B, Yi N
Candidate gene association studies: successes and failures.
Curr Opin Genet Dev. 2010; 20(3):257-61 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Epidemiologic studies of twins indicate that 20-40% of common tumors such as breast, colorectal, and prostate cancers are inherited. However, the effect of high penetrance tumor susceptibility genes such as APC, BRCA1, BRAC2, MSH1, MLH2 and MSH6 only accounts for a small fraction of these cancers. Low to moderate penetrance tumor susceptibility genes likely account for the large remaining proportion of familial cancer risk. Candidate tumor susceptibility genes have been identified based on the discovery of tumor-specific mutations, in vitro experiments, as well as animal models of cancer. Translational studies based on in vitro and in vivo discoveries have led to the identification of novel phenotypes and genotypes associated with cancer in humans. Case-control studies followed by validation studies and meta-analyses have unveiled several novel tumor susceptibility genes, several of which belong to genes encoding metabolizing enzymes and genes from the TGF-beta signaling pathway. Together with genome-wide association studies, candidate gene approaches are likely to fill a large gap in our knowledge of the genetic basis of cancer within the next decade.

Conde J, Silva SN, Azevedo AP, et al.
Association of common variants in mismatch repair genes and breast cancer susceptibility: a multigene study.
BMC Cancer. 2009; 9:344 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
BACKGROUND: MMR is responsible for the repair of base-base mismatches and insertion/deletion loops. Besides this, MMR is also associated with an anti-recombination function, suppressing homologous recombination. Losses of heterozygosity and/or microsatellite instability have been detected in a large number of skin samples from breast cancer patients, suggesting a potential role of MMR in breast cancer susceptibility.
METHODS: We carried out a hospital-based case-control study in a Caucasian Portuguese population (287 cases and 547 controls) to estimate the susceptibility to non-familial breast cancer associated with some polymorphisms in mismatch repair genes (MSH3, MSH4, MSH6, MLH1, MLH3, PMS1 and MUTYH).
RESULTS: Using unconditional logistic regression we found that MLH3 (L844P, G>A) polymorphism GA (Leu/Pro) and AA (Pro/Pro) genotypes were associated with a decreased risk: OR = 0.65 (0.45-0.95) (p = 0.03) and OR = 0.62 (0.41-0.94) (p = 0.03), respectively.Analysis of two-way SNP interaction effects on breast cancer revealed two potential associations to breast cancer susceptibility: MSH3 Ala1045Thr/MSH6 Gly39Glu - AA/TC [OR = 0.43 (0.21-0.83), p = 0.01] associated with a decreased risk; and MSH4 Ala97Thr/MLH3 Leu844Pro - AG/AA [OR = 2.35 (1.23-4.49), p = 0.01], GG/AA [OR = 2.11 (1.12-3,98), p = 0.02], and GG/AG [adjusted OR = 1.88 (1.12-3.15), p = 0.02] all associated with an increased risk for breast cancer.
CONCLUSION: It is possible that some of these common variants in MMR genes contribute significantly to breast cancer susceptibility. However, further studies with a large sample size will be needed to support our results.

Marafie MJ, Al-Awadi S, Al-Mosawi F, et al.
Impact of 226C>T MSH2 gene mutation on cancer phenotypes in two HNPCC-associated highly-consanguineous families from Kuwait: emphasis on premarital genetic testing.
Fam Cancer. 2009; 8(4):289-98 [PubMed] Related Publications
Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) is one of the commonest cancer susceptibility syndromes. It is characterized by early onset colon cancer and a variety of extracolonic tumours. Germline mutations in the DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS1, and PMS2) are responsible for this disorder. Identifying an affected individual depends on the tumour histopathology, family history that fulfils the Amsterdam and/or Bethesda criteria, tumour immunohistochemistry, microsatellite instability, and finally molecular analysis of an affected member. It is a laborious, time consuming and expensive procedure, which needs the effort of a multi-disciplinary team. However, once the diagnosis is established and germline defect is identified, other high risk pre-symptomatic carriers could be offered intensive surveillance and management as a preventive measure against cancer development. Here, we present two large highly consanguineous HNPCC-families from Kuwait in whom a founder MSH2 mutation was identified. The relationship between this mutation and cancer expressivity in two large consanguineous families harbouring other genetic defects is discussed. Moreover, we shed light on the challenges pertaining to diagnosis, screening, premarital counselling of couples and prenatal diagnosis of offspring with biallelic MSH2 gene mutation.

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