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PubMed1996

Genetic counseling in a Navajo hereditary nonpolyposis colorectal cancer kindred.

BACKGROUND: Cross-cultural genetic counseling was provided to an extended Navajo Indian family in which the MLH1 gene mutation for hereditary nonpolyposis colorectal cancer (HNPCC) had been identified. The family had been observed by the authors since 1983 and over the years had been provided with intensive education regarding the natural history of HNPCC as well as recommendations for cancer surveillance and management that was responsive to this natural history. METHODS: Following identification of the MLH1 mutation, DNA from family members was evaluated by a reference laboratory (OncorMed, Gaithersburg, MD), where sequences were checked in both the forward and reverse directions against the published sequence for MLH1. The 4bp deletion beginning at the first nucleotide of codon 727 was easily visualized in the heterozygous condition in both affected and predispositional individuals. The family was reeducated as a group and then provided further education individually during genetic counseling sessions, at which time they were appraised of potential penalties, such as insurance and employer discrimination, and psychological sequelae that could result from knowledge of the MLH1 mutation. Strict confidentiality of this information was assured. RESULTS: DNA testing was performed on 51 family members. Twenty-three individuals were counseled, seven of whom were positive for MHL1. Reactions ranged from full acceptance of the genetic implications to traditional Navajo reasoning such as the family had been cursed. CONCLUSIONS: DNA-based genetic counseling requires comparison and empathy, coupled with intensive preeducation regarding potential penalties and advantages that might emanate from this knowledge. Special care must be given to patients' culture, beliefs, and traditions.

Adult↗
PubMed1999

Gene-environment interaction in hereditary nonpolyposis colorectal cancer with implications for diagnosis and genetic testing.

Hereditary nonpolyposis colorectal cancer (Lynch syndrome) is an autosomal dominant disease caused by mutations in the mismatch repair genes in particular in MLH1, MSH2 and MSH6. The disease is characterized by the development of colorectal, endometrial cancer and several other cancers. There is evidence that the clinical expression of the disease varies from one country to another. This variation might affect not only the application of criteria proposed to identify families but also clinical risk factors reported to predict the outcome of genetic testing. Data on site of the cancer, age at diagnosis and pathology were collected from 155 families with suspected HNPCC known at the Korean and Dutch HNPCC registries. DGGE, SSCP and DNA-sequencing were performed to identify MSH2, MLH1 and MSH6 mutations. A total of 33 Korean and 42 Dutch families met the clinical criteria for HNPCC. Germline mutations in the MMR-genes were found in 23 Korean and 24 Dutch families. In families that met the Amsterdam criteria, and also in those associated with MLH1 mutations, more cancers of the stomach and pancreas were observed in the Korean families than in the Dutch HNPCC families; in relative terms, the incidence of cancers of the endometrium in the Korean families was lower. Multivariate analysis showed that an early age at diagnosis, and the occurrence of pancreatic cancer were independent predictive factors of germline mutations in MLH1, MSH2 and MSH6 in the Korean subset of families.

Adult↗
PubMed2000

Prediction of a mismatch repair gene defect by microsatellite instability and immunohistochemical analysis in endometrial tumours from HNPCC patients.

Instability of microsatellite repeat sequences has been observed in colorectal carcinomas and in extracolonic malignancies, predominantly endometrial tumours, occurring in the context of hereditary non-polyposis colorectal cancer (HNPCC). Microsatellite instability (MSI) as a feature of human DNA mismatch repair (MMR)-driven tumourigenesis of the uterine mucosa has been studied primarily in sporadic tumours showing predominantly somatic hypermethylation of MLH1. The present study shows that all endometrial carcinomas (n=12) from carriers of MLH1 and MSH2 germline mutations demonstrate an MSI-high phenotype involving all types of repeat markers, while in endometrial carcinomas from MSH6 mutation carriers, only 36% (4 out of 11) demonstrate an MSI-high phenotype. Interestingly, an MSI-high phenotype was found in endometrial hyperplasias from MSH2 mutation carriers, in contrast to hyperplasias from MLH1 mutation carriers, which exhibited an MSI-stable phenotype. Instability of only mononucleotide repeat markers was found in both endometrial carcinomas and hyperplasias from MSH6 mutation carriers. In 29 out of 31 (94%) endometrial tumour foci, combined MSI and immunohistochemical analysis of MLH1, MSH2, and MSH6 could predict the identified germline mutation. The observation of MSI in endometrial hyperplasia and of altered protein staining for the MMR genes supports the idea that inactivation of MMR genes is an early event in endometrial tumourigenesis. A correlation was found between the variation in the extent and level of MSI and the age of onset of carcinoma, suggesting differences in the rate of tumour progression. A high frequency of MSI in hyperplasias, found only in MSH2 mutation carriers, might indicate a more rapid tumour progression, correlating with an earlier age of onset of carcinoma. The present study indicates that assessment of altered protein staining combined with MSI analysis of endometrial tumours might direct the mutational analysis of MMR genes.

Adult↗
PubMed2006

Pathologic features of endometrial carcinoma associated with HNPCC: a comparison with sporadic endometrial carcinoma.

BACKGROUND: Endometrial carcinoma is a common malignancy in hereditary nonpolyposis colorectal carcinoma (HNPCC). Like colon carcinoma, endometrial carcinoma is diagnosed at an earlier age in women with HNPCC. In contrast to colon carcinoma, the pathologic features of endometrial carcinoma in HNPCC have not been studied in detail. It was the purpose of this study to pathologically characterize a series of HNPCC associated endometrial carcinomas. METHODS: Fifty women with HNPCC and endometrial carcinoma were analyzed from four different hereditary cancer registries. H&E stained slides and pathology reports were reviewed for clinically important pathologic features of endometrial carcinoma. These results were compared with those for two different groups of sporadic endometrial carcinoma--women younger than age 50 years (n = 42) and women of all ages with tumors demonstrating microsatellite instability (MSI-high) secondary to methylation of MLH1 (n = 26). RESULTS: Nearly one-fourth of HNPCC patients in this study had endometrial tumors with pathologic features that would require adjuvant therapy after hysterectomy. There was a trend toward the HNPCC patients having more nonendometrioid tumors; all of these patients were carriers of MSH2 mutations. Such nonendometrioid tumors were extremely rare in the MLH1 methylated group. A subset of MLH1 methylated sporadic tumors demonstrated a unique, 'undifferentiated' histology that was not observed in HNPCC or the young group. CONCLUSION: Data suggest a genotype-phenotype relation in which microsatellite instability resulting from MLH1 methylation is almost exclusively associated with classical or 'undifferentiated' endometrioid tumors, whereas microsatellite instability secondary to MSH2 mutation can result in a more variable histologic spectrum of endometrial carcinoma.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Germline mutations and polymorphic variants in MMR, E-cadherin and MYH genes associated with familial gastric cancer in Jiangsu of China.

Germline mutations in MSH2, MLH1, E-cadherin and MutY (MYH) genes have been implicated in the occurrence of gastric cancer (GC). Epidemiological investigation was performed by recruiting patients with GC onset during 2002 in Jiangsu province, China. We identified suspected hereditary GC patients based on either the GC family history or GC onset at early ages. We have screened germline variations in 101 suspected hereditary GC patients at the coding sequences of MSH2, MLH1, E-cadherin and MYH genes with polymerase chain reaction-denaturing high-performance liquid chromatography (PCR-DHPLC) analysis and DNA sequencing. The result showed that about 40% of patients carried germline variations, predominantly with missense mutations. Of the variations detected are 2 base pair substitutions, c.53C > T and c.74G > A, which is predicted to generate missense mutations of p.Pro18Leu and p.Gly25Asp, respectively, and occurred at the same allele of MYH gene. The frequency of variant haplotype T/A in patients was higher than that in the control group (p = 0.021, odds ratio [OR] = 4.43, 95% confidence interval [95% CI] = 1.33-14.72). Difference in the frequency of the silent mutation p.Asn751Asn in E-cadherin gene was also found between patients and controls (p = 0.009, OR = 2.54, 95% CI = 1.30-4.95). Moreover, 6 types of variations were detected in MSH2 and MLH1 genes in 14 of 101 patients. Most of them occurred at exon7 of MSH2, frequently c.1168C > T, resulting in mutation of p.Leu390Phe. In summary, germline mutation at MSH2, MLH1, E-cadherin and MYH genes is a frequent event in the familial GC. They may form a genetic basis for the familial GC susceptibility in Chinese population.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Expression of DNA mismatch repair proteins in acute lymphoblastic leukaemia and normal bone marrow.

Errors during normal DNA synthesis may produce mismatched base pairs. 6-Mercaptopurine (6MP), given during continuing therapy in acute lymphoblastic leukaemia (ALL), undergoes intracellular activation to give cytotoxic thioguanine nucleotides which are then incorporated into the DNA of dividing cells in place of guanine. Cell death is thought to result from futile attempts at mismatch repair. Previous work has shown that cell lines with a defect in this pathway develop tolerance to incorporated 6-thioguanine bases. In order to investigate the possible relevance of mismatch repair to the chemosensitivty of blasts to 6MP, relative to normal tissues, we have measured the expression of the mismatch repair proteins MLH1, MSH2, PMS2 and MSH6 in blasts from children and adults with ALL and in normal bone marrows, using western blotting. Fifty cases of childhood ALL, 22 cases of adult ALL and 7 normal marrows have been studied. Expression of MSH2, and of MLH1 in all but three cases, was detectable in all the blasts studied. Noticeably, expression of MLH1 was not detected in any of the normal marrow samples. MSH2 was detected in 4 of the normal marrows. Expression of PMS2 was not detected in 29 cases of ALL and, like MLH1, was absent from each of the normal marrow samples. In contrast, MSH6 was detected in all of the normal marrows and all but 16 of the cases of ALL. There was no difference in expression between adults and children. These results may help to explain the relative sensitivity of leukaemic blasts to thiopurines at presentation as compared to normal bone marrow.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Single-nucleotide polymorphisms of mismatch repair genes in healthy Chinese individuals and sporadic colorectal cancer patients.

Mismatch repair (MMR) genes are among of the most important genes associated with colorectal cancer (CRC). Single-nucleotide polymorphisms (SNPs) are generally thought to provide important information across a wide spectrum of life sciences; however, no study of association between SNPs of MMR genes and Chinese sporadic colorectal cancer (SCRC) is available. We chose 29 reported single-nucleotide variants that have rarely been verified in a population-based study. We identified SNPs and the genotype-phenotype association in Chinese populations of 150 healthy individuals and 160 SCRC patients. We extracted the genomic DNA from the blood of these individuals and used sequencing to determine these SNPs. Three SNPs (MLH1 394G-->C, 655A-->G, 1151T-->A) occurred with a frequency of 8.8-11.2% in the Chinese population. These SNPs formed a series with combined effects. The haplotype of concurrent MLH1 655 and 1151 SNPs and the haplotype combinations of MLH1 1151, MLH1 394 occurred exclusively in SCRC. None of the other 26 variants were detected in the Chinese population.

Adaptor Proteins, Signal Transducing↗
PubMed2005

N-acetyltransferase (NAT) 2 acetylator status and age of onset in patients with hereditary nonpolyposis colorectal cancer (HNPCC).

N-acetyltransferase (NAT) 2 is an essential polymorphic enzyme involved in the metabolism of various xenobiotics, including potential carcinogens. The individual differences in the NAT2 metabolic capacity are caused by allelic variants of the NAT2 gene which are determined by a pattern of single nucleotide polymorphisms (SNPs) resulting in slow (SA), intermediate (IA) or rapid acetylator (RA) phenotypes. Highly penetrant germline mutations in mismatch repair (MMR) genes are the cause of the disease in hereditary nonpolyposis colorectal cancer (HNPCC). There is no strict correlation between the type of germline mutation in MMR genes and the HNPCC phenotype, but age of tumor onset (AO) in HNPCC has been associated at least in part with different variants in apoptosis-related genes. To clarify the potential modifying role of the NAT2 acetylator status in HNPCC, we performed a multicenter study in 226 individuals with colorectal cancer carrying exclusively pathogenic germline mutations in MSH2 or MLH1. We did not observe any significant difference in the NAT2 acetylator status frequency between HNPCC patients and 107 healthy controls (P=0.156), and between MLH1 and MSH2 mutation carriers (P=0.198). Multivariate Cox regression analysis revealed that male patients had a significantly increased risk to develop CRC compared to females during any interval (P=0.043), while the NAT2 acetylator status (P=0.447) and the mutated gene (MLH1 or MSH2) (P=0.236) were not risk factors for AO. The median AO in HNPCC patients was 39 years in patients with RA as well as with SA status (P=0.347). In MLH1 mutation carriers, the median AO was 38 years in RA and 36 years in SA status patients (P=0.901), whereas in MSH2 mutation carriers, the median AO was 39 years in RA and 42 years in SA status patients (P=0.163). Log-rank test revealed a significantly lower age of CRC onset in male compared to female HNPCC patients (P=0.0442). These data do not support the hypothesis that the NAT2 acetylatorship acts as a modifying factor on AO in HNPCC-associated CRC.

Acetylation↗
PubMed2004

Application of in situ hybridization probes for MLH-1 and MSH-2 in tissue microarrays of paraffin-embedded malignant melanomas: correlation with immunohistochemistry and tumor stage.

Defects in DNA mismatch-repair genes MLH1 and MSH2 reported primarily in hereditary nonpolyposis colorectal carcinoma are present in many sporadic tumors, including malignant melanomas. The main aim of this study was to investigate the expression of these genes in malignant melanomas in relation to tumor stage. An experiment was performed on paraffin-embedded tissue microarrays of malignant melanomas applying in situ hybridization with probes produced by our research group and immunohistochemical techniques. In situ hybridization demonstrated MLH1 expression in 45 of 59 melanomas and MSH2 expression in 51 of 59 melanomas. Immunohistochemistry detected MLH1 expression in 46 of 59 melanomas and MSH2 expression in 50 of 59 melanomas. Down-regulation of expression of both DNA mismatch repair genes in malignant melanomas was observed. The findings obtained by in situ hybridization and immunohistochemistry correlated significantly. Our study demonstrates the suitability of in situ hybridization with MLH1 and MSH2 probes for paraffin-embedded tissue. Tissue microarrays can be used successfully in both in situ hybridization and immunohistochemistry to analyze the expression of DNA mismatch-repair genes.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Role of the mitogen-activated protein kinase and phosphoinositide 3-kinase/AKT pathways downstream molecules, phosphorylated extracellular signal-regulated kinase, and phosphorylated AKT in colorectal cancer-a tissue microarray-based approach.

Tumor budding is defined as dedifferentiated cancer cells at the invasive margin of colorectal cancer (CRC) and correlates with a worse prognosis. The invasive margin and tumor budding are normally not present in a superficial diagnostic biopsy specimen. The aim of this study was to investigate the expression/overexpression of 2 downstream molecules of the mitogen-activated protein kinase and phosphoinositide 3-kinase/AKT pathways, phosphorylated AKT (pAKT) and phosphorylated extracellular signal-regulated kinase (pERK), in areas of CRC away from the invasive margin and determining if these variables were predictive of tumor budding or prognosis. A series of 1420 unselected, nonconsecutive CRC resections were subdivided into 3 groups: (1) DNA mismatch repair (MMR) proficient, (2) MLH1-negative, and (3) presumed HNPCC. Immunohistochemical analysis of pAKT and pERK expression (0% versus > 0%) and overexpression (increasing percentage of positivity) was performed using the tissue microarray technique. The results were correlated with clinicopathologic parameters. Fifty-seven samples of normal colon mucosa were included as a control group. Nuclear pERK expression (P = .008) was associated with presence of tumor budding in the MMR-proficient, but not in the MLH1-negative and presumed-HNPCC groups. In contrast, cytoplasmic pAKT overexpression was associated with early T stage (P = .04), early N stage (P = .02), and absence of tumor budding (P = .03) only in the MLH1-negative group. There was no association between pERK or pAKT and clinicopathologic parameters in the HNPCC group. Dysregulation of the mitogen-activated protein kinase pathway is likely to be implicated in the mechanism of tumor budding only in MMR-proficient CRC, whereas the phosphoinositide 3-kinase/AKT pathway is associated with early stage in MLH1-negative CRC.

Adenocarcinoma↗
PubMed2005

Development of metastatic endometrial endometrioid adenocarcinoma while on progestin therapy for endometrial hyperplasia.

BACKGROUND: Conservative treatment with progestins is a reasonable treatment option for endometrial complex atypical hyperplasia and, in the experimental setting, for some women with grade 1 endometrial endometrioid adenocarcinoma. The risk of progression to a high-stage endometrial cancer is quite low, with only two previously reported cases in the English literature. CASE: A 40-year-old woman with endometrial complex atypical hyperplasia diagnosed by dilatation and curettage was managed conservatively with progestin therapy (initially, megesterol acetate; then, a combination oral contraceptive). More than 2 years after her original diagnosis, she developed endometrial endometrioid adenocarcinoma, FIGO grade 2, with lymph node metastasis. The tumor was microsatellite instability-high due to methylation of MLH1 and loss of MLH1 protein. CONCLUSION: Currently, there are no good criteria for predicting which patients with complex atypical hyperplasia/grade 1 endometrioid adenocarcinoma will optimally respond to progestin therapy. There is some evidence that endometrial complex hyperplasia demonstrating loss of MLH1 protein by immunohistochemistry is strongly related to subsequent or concurrent endometrial cancer, especially tumors of higher grade and stage. In a woman with a biopsy diagnosis of endometrial hyperplasia, evaluation of MLH1 protein status by immunohistochemistry may provide useful information when medical management is being considered.

Adult↗
PubMed2000

Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas: A newly described and characterized entity.

Medullary carcinomas of the pancreas are a recently described, histologically distinct subset of poorly differentiated adenocarcinomas that may have a unique pathogenesis and clinical course. To further evaluate these neoplasms, we studied genetic, pathological, and clinical features of 13 newly identified medullary carcinomas of the pancreas. Nine (69%) of these had wild-type K-ras genes, and one had microsatellite instability (MSI). This MSI medullary carcinoma, along with three previously reported MSI medullary carcinomas, were examined immunohistochemically for Mlh1 and Msh2 expression, and all four expressed Msh2 but did not express Mlh1. In contrast, all of the medullary carcinomas without MSI expressed both Msh2 and Mlh1. Remarkably, the MSI medullary carcinoma of the pancreas in the present series arose in a patient with a synchronous but histologically distinct cecal carcinoma that also had MSI and did not express Mlh1. The synchronous occurrence of two MSI carcinomas suggests an inherited basis for the development of these carcinomas. Indeed, the medullary phenotype, irrespective of MSI, was highly associated with a family history of cancer in first-degree relatives (P < 0.001). Finally, one medullary carcinoma with lymphoepithelioma-like features contained Epstein-Barr virus-encoded RNA-1 by in situ hybridization. Therefore, because of medullary carcinoma's special genetic, immunohistochemical, and clinical features, recognition of the medullary variant of pancreatic adenocarcinoma is important. Only by classifying medullary carcinoma as special subset of adenocarcinoma can we hope to further elucidate its unique pathogenesis.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Defective mismatch-repair in patients with multiple primary tumours including colorectal cancer.

Individuals with an inherited predisposition to cancer development are at an increased risk of developing multiple tumours. Hereditary non-polyposis colorectal cancer (HNPCC) is one of the most common hereditary cancer syndromes and is estimated to account for approximately 2% of colorectal cancers. However, HNPCC individuals are at an increased risk of developing other tumour types such as cancers of the endometrium, urothelium and small intestine. We have utilised a population-based regional cancer registry to identify all patients with double primary colorectal cancers and at least one additional malignancy and characterised the tumour spectrum in this patient group. We subsequently selected those 47 individuals who had developed at least four malignancies, including two colorectal cancers, for studies of the tumour characteristics associated with HNPCC. In total, these individuals developed 209 tumours, 156 of which were successfully retrieved. Microsatellite instability (MSI), a phenomenon caused by defective mismatch-repair (MMR), was identified in 63/154 (41%) evaluable tumours with a MSI-high pattern in 59 and a MSI-low pattern in four tumours. All tumours were immunohistochemically stained for the MMR proteins MLH1 and MSH2, with loss of expression in 55/63 (87%) MSI tumours and in 2/89 (2%) microsatellite stable (MSS) tumours. This loss affected MLH1 in 24 tumours and MSH2 in 33 tumours. A concordant loss of expression for the same MMR protein in several tumours from the same individual, a pattern that strongly suggests an underlying germline MMR gene mutation, was found in 17/45 (38%) patients and affected MLH1 in 8 patients and MSH2 in 9 patients. We conclude that the development of multiple primary tumours, including synchronous or metachronous colorectal cancers, is associated with an increased frequency of MSI and loss of immunohistochemical expression of MLH1 and MSH2.

Adult↗
PubMed1999

Dependence on RAD52 and RAD1 for anticancer drug resistance mediated by inactivation of mismatch repair genes.

Mismatch repair (MMR) proteins repair mispaired DNA bases and have an important role in maintaining the integrity of the genome [1]. Loss of MMR has been correlated with resistance to a variety of DNA-damaging agents, including many anticancer drugs [2]. How loss of MMR leads to resistance is not understood, but is proposed to be due to loss of futile MMR activity and/or replication stalling [3] [4]. We report that inactivation of MMR genes (MLH1, MLH2, MSH2, MSH3, MSH6, but not PMS1) in isogenic strains of Saccharomyces cerevisiae led to increased resistance to the anticancer drugs cisplatin, carboplatin and doxorubicin, but had no effect on sensitivity to ultraviolet C (UVC) radiation. Sensitivity to cisplatin and doxorubicin was increased in mlh1 mutant strains when the MLH1 gene was reintroduced, demonstrating a direct involvement of MMR proteins in sensitivity to these DNA-damaging agents. Inactivation of MLH1, MLH2 or MSH2 had no significant effect, however, on drug sensitivities in the rad52 or rad1 mutant strains that are defective in mitotic recombination and removing unpaired DNA single strands. We propose a model whereby MMR proteins - in addition to their role in DNA-damage recognition - decrease adduct tolerance during DNA replication by modulating the levels of recombination-dependent bypass. This hypothesis is supported by the finding that, in human ovarian tumour cells, loss of hMLH1 correlated with acquisition of cisplatin resistance and increased cisplatin-induced sister chromatid exchange, both of which were reversed by restoration of hMLH1 expression.

Antineoplastic Agents↗
PubMed2001

Prediction of the outcome of genetic testing in HNPCC kindreds using the revised Amsterdam criteria and immunohistochemistry.

BACKGROUND AND AIMS: Hereditary non-polyposis colorectal cancer (HNPCC) may be caused by mutations in the mismatch repair (MMR) genes MLH1, MSH2 or MSH6. Family history (Amsterdam criteria) has traditionally been used to select patients for mutation testing. It has been demonstrated that germline mutations in the MMR genes are associated with lack of the corresponding gene product as assessed with immunohistochemistry (IHC) in tumour specimens. The aim of the study was to assess the value of the Amsterdam criteria II and IHC in predicting germline mutations. METHODS: Fifty-six families that were previously tested for MLH1, MSH2 and MSH6 mutations were selected for this study. All pedigrees were extended and verified and the families were scored according to the original (I) and the revised Amsterdam criteria (II). The probabilities for MLH1 and MSH2 mutations were calculated by logistic regression. In addition, all available tumour material from indexed family members was examined by IHC for the presence of the three gene products. RESULTS: Three out of seven (39%) families where the mutation could be identified complied with the Amsterdam criteria I, while all seven (100%) met the Amsterdam criteria II. All families carrying a MLH1 or MSH2 mutation had > 15% calculated probability of finding a mutation. Tumours from all seven mutation carriers lacked the immunohistochemical expression of the corresponding MMR gene. CONCLUSION: The results indicate that the Amsterdam criteria II in combination with immunohistochemistry of the mismatch repair proteins in tumours may be a cost-effective approach to select families for mutation analysis.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Mismatch repair genes and mononucleotide tracts as mutation targets in colorectal tumors with different degrees of microsatellite instability.

Microsatellite instability occurs in 15% of colorectal carcinomas and may be due to replication errors (RER). The pattern of instability--'severe' vs 'mild'--and the tumorigenic pathway, as reflected by the involvement of functionally important genes, may vary according to the underlying gene(s). We defined 'mild' RER as mono- or tetranucleotide repeat instability in the absence of widespread instability at dinucleotide repeats and studied 15 colorectal tumors with this phenotype for mutations in the DNA mismatch repair genes MSH2, MLH1, MSH3, and MSH6. No mutations were found, suggesting that these genes were not implicated. We then compared colorectal cancers with 'mild' RER (n = 15), and those with 'severe' RER without (n = 11) or with (n = 22) detectable mutations in MSH2 or MLH1 to assess the involvement of mononucleotide repeats contained in the coding regions of MSH3, MSH6, BAX, and TGFbeta RII. The combined mutation rates of the above mentioned loci varied significantly between the three groups of tumors, being 0%, 25% and 52%, respectively. Furthermore, the individual genes showed specific patterns of involvement; for example, among tumors with 'severe' RER, TGFbeta RII displayed uniformly high mutation rates while MSH3, MSH6, and BAX were more frequently altered in tumors that also showed MSH2 or MLH1 mutations. Our findings suggest that different subcategories exist among unstable tumors, defined by the RER pattern on the one hand and tumorigenic pathway on the other, and structural changes of MSH2 and MLH1 are likely to explain only a proportion of these cases.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Role of DNA mismatch repair genetic polymorphisms in the risk of childhood acute lymphoblastic leukaemia.

Acute lymphoblastic leukaemia (ALL) is the most common childhood cancer. Genetic variants in the coding regions of the mismatch repair genes MLH1 (Ile-219Val) and MSH3 (Arg-940Glu and Thr-1036Ala) could contribute to an individual's susceptibility as modifiers in leukaemogenesis. To investigate this possibility, we conducted a case-control study on 287 children with ALL and 320 healthy controls both of French-Canadian origin. MLH1 and MSH3 variants, when taken independently, seemed to play little or no role in the aetiology of childhood ALL. However, when the MLH1 genotypes were combined with genotypes previously shown to influence ALL susceptibility, we found that the MLH1 variant Val-219 further increases the risk of GSTM1 null and CYP1A1*2A genotypes [combined odds ratio (OR) = 6.0, P = 0.002] as well as that of CYP2E1*5 (OR = 15.8, P = 0.001). No association was found with MSH3 variants. This study suggests an association of leukaemogenesis in children with both xenobiotic metabolism and DNA repair, and thus points to the effect of environmental exposure.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Biochemical basis for dominant mutations in the Saccharomyces cerevisiae MSH6 gene.

Here, the ATP-binding, ATP hydrolysis, mispair-binding, sliding clamp formation, and Mlh1-Pms1 complex interaction properties of dominant mutant Msh2-Msh6 complexes have been characterized. The results demonstrate two mechanisms for dominance. In one, seen with the Msh6-S1036P and Msh6-G1067D mutant complexes, the mutant complex binds mispaired bases, is defective for ATP-induced sliding clamp formation and assembly of ternary complexes with Mlh1-Pms1, and occludes mispaired bases from other mismatch repair pathways. In the second, seen with the Msh6-G1142D complex, the mutant complex binds mispaired bases and is defective for ATP-induced sliding clamp formation but assembles ternary complexes with Mlh1-Pms1 that either occlude the mispaired base or prevent Mlh1-Pms1 from acting in alternate mismatch repair pathways.

Adaptor Proteins, Signal Transducing↗