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MMR Genes (mmr + gene)
Terms modified by MMR Genes Selected AbstractsMolecular characterization of the spectrum of genomic deletions in the mismatch repair genes MSH2, MLH1, MSH6, and PMS2 responsible for hereditary nonpolyposis colorectal cancer (HNPCC)GENES, CHROMOSOMES AND CANCER, Issue 2 2005Heleen van der Klift A systematic search by Southern blot analysis in a cohort of 439 hereditary nonpolyposis colorectal cancer (HNPCC) families for genomic rearrangements in the main mismatch repair (MMR) genes, namely, MSH2, MLH1, MSH6, and PMS2, identified 48 genomic rearrangements causative of this inherited predisposition to colorectal cancer in 68 unrelated kindreds. Twenty-nine of the 48 rearrangements were found in MSH2, 13 in MLH1, 2 in MSH6, and 4 in PMS2. The vast majority were deletions, although one previously described large inversion, an intronic insertion, and a more complex rearrangement also were found. Twenty-four deletion breakpoints have been identified and sequenced in order to determine the underlying recombination mechanisms. Most fall within repetitive sequences, mainly Alu repeats, in agreement with the differential distribution of deletions between the MSH2 and MLH1 genes: the higher number and density of Alu repeats in MSH2 corresponded with a higher incidence of genomic rearrangement at this disease locus when compared with other MMR genes. Long interspersed nuclear element (LINE) repeats, relatively abundant in, for example, MLH1, did not seem to contribute to the genesis of the deletions, presumably because of their older evolutionary age and divergence among individual repeat units when compared with short interspersed nuclear element (SINE) repeats, including Alu repeats. Moreover, Southern blot analysis of the introns and the genomic regions flanking the MMR genes allowed us to detect 6 novel genomic rearrangements that left the coding region of the disease-causing gene intact. These rearrangements comprised 4 deletions upstream of the coding region of MSH2 (3 cases) and MSH6 (1 case), a 2-kb insertion in intron 7 of PMS2, and a small (459-bp) deletion in intron 13 of MLH1. The characterization of these genomic rearrangements underlines the importance of genomic deletions in the etiology of HNPCC and will facilitate the development of PCR-based tests for their detection in diagnostic laboratories. © 2005 Wiley-Liss, Inc. [source] Beta2-microglobulin mutations in microsatellite unstable colorectal tumorsINTERNATIONAL JOURNAL OF CANCER, Issue 2 2007Matthias Kloor Abstract Defects of DNA mismatch repair (MMR) cause the high level microsatellite instability (MSI-H) phenotype. MSI-H cancers may develop either sporadically or in the context of the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome that is caused by germline mutations of MMR genes. In colorectal cancer (CRC), MSI-H is characterized by a dense lymphocytic infiltration, reflecting a high immunogenicity of these cancers. As a consequence of immunoselection, MSI-H CRCs frequently display a loss of human leukocyte antigen (HLA) class I antigen presentation caused by mutations of the ,2 -microglobulin (,2m) gene. To examine the implications of ,2m mutations during MSI-H colorectal tumor development, we analyzed the prevalence of ,2m mutations in MSI-H colorectal adenomas (n = 38) and carcinomas (n = 104) of different stages. Mutations were observed in 6/38 (15.8%) MSI-H adenomas and 29/104 (27.9%) MSI-H CRCs. A higher frequency of ,2m mutations was observed in MSI-H CRC patients with germline mutations of MMR genes MLH1 or MSH2 (36.4%) compared with patients without germline mutations (15.4%). The high frequency of ,2m mutations in HNPCC-associated MSI-H CRCs is in line with the hypothesis that immunoselection may be particularly pronounced in HNPCC patients with inherited predisposition to develop MSI-H cancers. ,2m mutations were positively related to stage in tumors without distant metastases (UICC I-III), suggesting that loss of ,2m expression may promote local progression of colorectal MSI-H tumors. However, no ,2m mutations were observed in metastasized CRCs (UICC stage IV, p = 0.04). These results suggest that functional ,2m may be necessary for distant metastasis formation in CRC patients. © 2007 Wiley-Liss, Inc. [source] Diethylstilbestrol effects and lymphomagenesis in Mlh1 -deficient miceINTERNATIONAL JOURNAL OF CANCER, Issue 4 2005Omar Kabbarah Abstract Inherited defects in DNA mismatch repair (MMR) predispose to a variety of malignancies in humans and in mouse knockout models. In humans, hemizygosity for one of several DNA MMR genes greatly increases an individual's risk for colon and endometrial carcinoma. Hemizygous mice develop gastrointestinal tumors at a low to moderate frequency. Homozygous nulls have higher rates of gastrointestinal tumors and are particularly susceptible to lymphoma. In an effort to model endometrial carcinoma associated with mutation in MMR, we treated mice carrying knockout alleles for Mlh1 or Msh2 with the synthetic estrogen diethylstilbestrol (DES), a known promoter of uterine endometrial carcinoma. The C57BL/6 mice carrying DNA MMR mutations failed to develop endometrial carcinomas. However, the Mlh1 -deficient mice treated with DES tended to become moribund at an early age and had very early onset of lymphoma. Comparison of DES-treated and untreated Mlh1,/, animals suggests the combination of Mlh1 deficiency and DES exposure accelerates lymphomagenesis. © 2005 Wiley-Liss, Inc. [source] Infrequent microsatellite instability in liver fluke infection-associated intrahepatic cholangiocarcinomas from ThailandINTERNATIONAL JOURNAL OF CANCER, Issue 3 2003Upama Liengswangwong Abstract The liver fluke infection-associated intrahepatic cholangiocarcinoma (ICC) is a major liver cancer in Northeast Thailand. The molecular basis of this ICC is poorly understood. To address possible roles of the DNA mismatch repair (MMR) system in ICC carcinogenesis, a fluorescence-labeling PCR/laser scanning technique with high sensitivity was employed to analyze genomic instability in the nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) in 24 fresh and 13 formalin-fixed, paraffin-embedded tissues of ICC and their corresponding normal parts. Microsatellite instability (MSI) was assessed in nDNA, using 12 highly polymorphic loci including 5 Bethesda markers. These loci were mainly related to major MMR genes, hMSH2 and hMLH1. Also 3 (C)n and/or (C)n(A)n repeat instability at 1 noncoding region in the displacement-loop (D-loop) and 2 coding sequences in NADH dehydrogenase subunit 1 and subunit 5 gene in mtDNA were analyzed. MSI was only detected in 1 (2.7%), 6 (16.7%), 1 (2.9%), 1 (2.9%) or 2 (6.3%) out of 37, 36, 35, 35 or 32 cases at BAT-25, D2S123, D3S1611, D11S904 or D17S250, respectively. LOH was found at D3S1298, D3S1561, D5S346 and TP53 in 4 (18.2%) out of 22, 2 (18.2%) out of 11, 6 (33.3%) out of 18 and 3 (12.5%) out of 24 informative cases, respectively. In mtDNA, none except a single case out of the 37 (2.7%) exhibited repeat sequence instability in the D-loop. We conclude that the liver fluke infection-associated ICC in Thailand is classified as low frequency MSI or microsatellite stable type and that DNA MMR system, through hMSH2 and hMLH1 gene mutations, does not play a major role in its carcinogenesis. © 2003 Wiley-Liss, Inc. [source] Cutaneous sebaceous neoplasms as markers of Muir-Torre syndrome: a diagnostic algorithmJOURNAL OF CUTANEOUS PATHOLOGY, Issue 6 2009Ossama Abbas Sebaceous gland neoplasms such as adenoma, epithelioma, and carcinoma are uncommon cutaneous tumors. Although sporadic, their occurrence is clinically significant because of their association with Muir-Torre syndrome (MTS). MTS is a rare autosomal dominant genodermatosis characterized by the occurrence of sebaceous gland neoplasms and/or keratoacanthomas associated with visceral malignancies that include gastrointestinal and genitourinary cancers. MTS is usually the result of germline mutation in one or more of the DNA mismatch repair (MMR) genes. MMR genes commonly implicated include MSH -2 and MLH -1 and, more recently, MSH -6. Recent evidence suggests that immunohistochemistry is very sensitive and effective in detecting these defects in cutaneous tumors in MTS. In addition, the genetic instability of cutaneous and visceral tumors in MTS caused by the defects in MMR genes can also be detected, using polymerase chain reaction (PCR)-based techniques, for microsatellite instability (MSI). Given that some sebaceous neoplasms represent cutaneous markers of MTS, what should we as dermatopathologists be advocating? Should we be looking for absence/loss of MMRs in all sebaceous neoplasms? When should we recommend assaying for MSI? This review attempts to address all of these issues with a view to streamlining the work-up of a patient presenting for the first time with a sebaceous neoplasm and no prior personal or family history of internal malignancies. [source] Malignant melanoma in patients with hereditary nonpolyposis colorectal cancerBRITISH JOURNAL OF DERMATOLOGY, Issue 1 2008G. Ponti Summary Background, Malignant melanoma (MM) is the most aggressive skin cancer. Most MMs are sporadic, and in this setting an association with mismatch repair (MMR) gene mutations, typical of hereditary nonpolyposis colorectal cancer (HNPCC) tumours, has been proposed. Objectives, To characterize clinically and/or by molecular biology the patients with MM belonging to a cohort of 60 kindreds with HNPCC. Methods, Patients with HNPCC with a diagnosis of MM were studied by immunohistochemistry (IHC) on tumour tissue using antibodies to MLH1, MSH2, p16, ,-catenin and E-cadherin, and by direct sequencing of MMR genes on germline DNA, and BRAF and NRAS on somatic DNA extracted from MM. Results, Nine cutaneous MMs were detected in the tumour spectrum of eight families with HNPCC. The median age at diagnosis was 46 years. In one HNPCC family the diagnosis of MM was made in two first-degree relatives fitting the clinical definition of familial melanoma. IHC and sequencing analysis showed an MSH2 mutation in one patient with MM. Conclusions, Dermatological surveillance should be recommended to families in which MM is diagnosed in at least one member, especially at a young age. The combination of MMR gene mutations and abnormalities of p16 or other molecular pathways is needed to induce melanocytic carcinogenesis in a familial setting as well as in sporadic MM. [source] Molecular epidemiological and mutational analysis of DNA mismatch repair (MMR) genes in endometrial cancer patients with HNPCC-associated familial predisposition to cancerCANCER SCIENCE, Issue 9 2008Y. Hirai Recently, a high rate of endometrial cancer has been reported in women with hereditary non-polyposis colorectal cancer (HNPCC), suggesting a relationship between familial endometrial cancers and HNPCC. Familial endometrial cancers constitute only about 0.5% of all endometrial carcinomas and it is essential to examine family histories in detail. A mutational analysis of three DNA mismatch repair (MMR) genes (hMLH1, hMSH2 and hMSH6) in patients with endometrial cancer who meet our criteria for familial predisposition to HNPCC-associated endometrial cancers was performed. Mutations were detected in 18 of the 120 patients (15.0%). Most HNPCC-related endometrial cancers do not meet the New Amsterdam Criteria for HNPCC. These clinical criteria may identify only some HNPCC-associated endometrial cancers. Establishing the correct family history for endometrial cancer patients is important for diagnosing familial endometrial carcinomas. An analysis of MMR genes may be useful for patients with endometrial cancer showing familial aggregation. In addition, gynecologists must be accurately informed, and it is important to perform large-scale, multicenter studies both nationwide and internationally. (Cancer Sci 2008; 99: 1715,1719) [source] Frequency of constitutional MSH6 mutations in a consecutive series of families with clinical suspicion of HNPCCCLINICAL GENETICS, Issue 3 2007B Roncari A large majority of constitutional mutations in hereditary non-polyposis colorectal cancer (HNPCC) are because of the MHL1 or MSH2 genes. In a lower fraction of cases, another gene of the mismatch repair (MMR) machinery, MSH6, may be responsible. Families with MSH6 mutations are difficult to recognize, as microsatellite instability (MSI) may not be detectable and immunohistochemistry (IHC) may give ambiguous results. In the present study, we proposed (i) to determine the frequency of MSH6 mutations in a selected population of colorectal cancer patients obtained from a tumor registry, (ii) to assess whether IHC is a suitable tool for selecting and identifying MSH6 mutation carriers. One hundred neoplasms of the large bowel from suspected HNPCC families were analyzed for MSI (BAT25 and BAT26 markers) and immunohistochemical expression of the MSH6 protein. We found on 12 tumors (from different families) showing instability or lack of MSH6 expression. Among these, four potentially pathogenic MSH6 mutations were detected (del A at 2984; del TT at 3119; del AGG cod 385; and del CGT cod 1242) by direct gene sequencing. These represented 12.9% of all families with constitutional mutations of the DNA MMR genes. Thus, some 5% of all HNPCC families are featured by constitutional mutation of the MSH6 gene. This appears, however, as a minimum estimate; routine use of IHC and the study of large numbers of individuals and families with little or no evidence of Lynch syndrome might reveal that mutation of this gene account for a large fraction of HNPCC. [source] Constitutive deficiency in DNA mismatch repairCLINICAL GENETICS, Issue 6 2007KEA Felton Mutations in the DNA mismatch repair (MMR) genes are associated with the inheritance of hereditary non-polyposis colorectal cancer, also known as Lynch syndrome, a cancer syndrome with an average age at onset of 44. Individuals presenting with colorectal cancer are diagnosed with Lynch I, whereas individuals who present with extra-colonic tumors (such as endometrial, stomach, etc.) are identified as patients with Lynch syndrome II. Recently, 30 families have been reported with inheritance of biallelic mutations in the MMR genes. Here we summarize the phenotype of individuals with inheritance of homozygous or compound heterozygous mutations in the MMR genes that result in a complete lack of protein or greatly compromised protein function. In contrast to individuals with Lynch syndrome I and II, individuals with no MMR function present with childhood onset of hematological and brain malignancies, whereas residual MMR function can also result in gastrointestinal cancers and an age of onset in the second to fourth decade. Individuals with biallelic MMR mutations often present with café-au-lait spots, regardless of the level of MMR function remaining. Thus, the inheritance of two MMR gene mutations is a separate entity from Lynch I or II or the subtypes Turcot and Muir,Torre. [source] Constitutive deficiency in DNA mismatch repair: is it time for Lynch III?CLINICAL GENETICS, Issue 6 2007KEA Felton Hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch syndrome types I and II, and the related subtypes Turcot and Muir,Torre syndrome, have all been associated with inheritance of germ line mutations in the DNA mismatch repair (MMR) genes. Fifty individuals have recently been identified with an early onset of a different spectrum of cancers associated with inheritance of two MMR mutations , resulting either in a constitutive loss of MMR function, or greatly impaired MMR function. In contrast to Lynch I and II individuals, individuals with inheritance of homozygous or compound heterozygous mutations in the MMR genes that result in a complete lack of protein, present with hematological and brain malignancies in the first decade of life. Biallelic mutations with compromised but residual protein function present with a broader spectrum of cancers (brain, hematological or gastrointestinal) in the second to fourth decades of life. We propose that inheritance of two MMR mutations in an individual and the unique tumor spectrum that occurs with an early onset should be defined separately from Lynch syndrome I and II, or the subtypes Turcot and Muir,Torre. We suggest Lynch III as an appropriate name for identifying individuals with constitutively compromised MMR associated with biallelic mutations. [source] | ||||||||||||||||||||||