scholarly journals Epimutation in DNA Mismatch Repair (MMR) Genes

10.5772/53812 ◽  
2013 ◽  
Author(s):  
Kouji Banno ◽  
Iori Kisu ◽  
Megumi Yanokura ◽  
Yuya Nogami ◽  
Kiyoko Umene ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Dna Mismatch ◽  
Mmr Genes

scholarly journals Examination of gene loss in the DNA mismatch repair pathway and its mutational consequences in a fungal phylum

2021 ◽  
Author(s):  
Megan A Phillips ◽  
Jacob L Steenwyk ◽  
Xing-Xing Shen ◽  
Antonis Rokas
Keyword(s):  
Powdery Mildew ◽  
Mismatch Repair ◽  
Gene Loss ◽  
Dna Mismatch Repair ◽  
Gc Content ◽  
Mutational Bias ◽  
Sequence Evolution ◽  
Loss Of Function ◽  
Dna Mismatch ◽  
Mmr Genes

AbstractThe DNA mismatch repair (MMR) pathway corrects mismatched bases produced during DNA replication and is highly conserved across the tree of life, reflecting its fundamental importance for genome integrity. Loss of function in one or a few MMR genes can lead to increased mutation rates and microsatellite instability, as seen in some human cancers. While loss of MMR genes has been documented in the context of human disease and in hypermutant strains of pathogens, examples of entire species and species lineages that have experienced substantial MMR gene loss are lacking. We examined the genomes of 1,107 species in the fungal phylum Ascomycota for the presence of 52 genes known to be involved in the MMR pathway of fungi. We found that the median ascomycete genome contained 49 / 52 MMR genes. In contrast, four closely related species of obligate plant parasites from the powdery mildew genera Erysiphe and Blumeria, have lost between 6 and 22 MMR genes, including MLH3, EXO1, and DPB11. The lost genes span MMR functions, include genes that are conserved in all other ascomycetes, and loss of function of any of these genes alone has been previously linked to increased mutation rate. Consistent with the hypothesis that loss of these genes impairs MMR pathway function, we found that powdery mildew genomes with high levels of MMR gene loss exhibit increased numbers of monomer repeats, longer microsatellites, accelerated sequence evolution, elevated mutational bias in the A|T direction, and decreased GC content. These results identify a striking example of macroevolutionary loss of multiple MMR pathway genes in a eukaryotic lineage, even though the mutational outcomes of these losses appear to resemble those associated with detrimental MMR dysfunction in other organisms.

Impact of DNA mismatch repair deficiency on relapse rate in early-stage, sporadic colorectal cancer.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 415-415
Author(s):  
Veronika Buxhofer-Ausch ◽  
Heike Bauer ◽  
Marina Mollik ◽  
Angelika Reiner-Concin ◽  
Guenther Nirnberger ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Relapse Rate ◽  
Dna Mismatch Repair ◽  
Early Stage ◽  
Sporadic Colorectal Cancer ◽  
Uicc Stage ◽  
Dna Mismatch ◽  
Mmr Genes ◽  
Significant Difference ◽  
Deficient Group

415 Background: 15-20% of sporadic colorectal cancers (CRC) are characterized by DNA mismatch repair (MMR) deficiency resulting in the phenomenon of microsatellite instability (MSI). There is evidence that CRC with MSI have a significant better prognosis compared to those with intact MMR. We investigated MMR gene expression in patients (pat.) with CRC and correlated it with early relapse rate. Methods: The study relates to 146 pat. with primary CRC UICC stage 0-II who underwent surgical resection at the Donauspital in Vienna and had a complete follow up of at least 60 months. Expression of the MMR genes MLH1, PMS2, MSH2, MSH6 was detected by immunohistochemical staining. Expression of MMR genes was correlated with pat. and disease characteristics as well as relapse frequency within the first 5 years after diagnosis. Chi-squared test was used to compare the distribution of the given variables between MMR gene proficient and deficient pat. Results: Mean age of the total group was 66.14 years, 45.2% were females and 54.8 males. Localization of the tumor was the colon in 69.2% and the rectum in 30.8% of pat., respectively. 33.6% of diseases were classified as UICC stage 0-I, and 66.4% as UICC stage II. 37/ 146 pat. experienced relapse, mean duration to relapse was 2.17 years. 13.7% of all pat. displayed a MMR deficient state. All MMR deficiencies occurred in the colon, none in rectum tumors. MLH1 was always associated with PMS2 deficiency and occurred in 9.6% of pat. There was a significant difference in sex distribution between the proficient and deficient group with 71.4% females with MLH1/PMS2 deficiency (p= 0.038). MSH2 deficiency was detected in 1 pat. only. MSH6 deficiency occurred in 5.5% of pat., none of the variables was significantly different distributed between the proficient and deficient group. None of the MMR deficiencies correlated with relapse rate. Conclusions: Our data suggest that the supposed better prognosis of MMR deficient compared to proficient pat. might not be explained by a different relapse rate within 5 years from diagnosis. Larger and prospective trials are warranted to elucidate plausible explanations for the proposed survival benefit of a MMR deficient state.

Variable DNA mismatch repair-associated gene profiles in colorectal versus uterine cancers.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11610-11610
Author(s):  
Tabari Baker ◽  
Safoora Deihimi ◽  
Lainie P. Martin ◽  
Michael J. Hall ◽  
Heather Hampel ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mismatch Repair ◽  
Immune Checkpoint ◽  
Dna Mismatch Repair ◽  
Uterine Cancer ◽  
Study Cohort ◽  
Specific Mutation ◽  
Dna Mismatch ◽  
Mmr Genes ◽  
Uterine Cancers

11610 Background: DNA mismatch repair (MMR) plays an important role in maintaining DNA synthesis fidelity in the genome. Mutation in MMR genes occurs in colorectal and uterine cancers and leads to increased mutation burden that is associated with response to immune checkpoint inhibitors. It is unknown if there is an MMR gene-specific mutation signature in MMR-deficient tumors, or whether mutations in MMR genes drive specific mutation patterns. Methods: The study cohort consisted of 1060 uterine cancer (UtCa), and 797 colorectal cancer (CRC) cases consecutively submitted to Caris Life Science for molecular profiling using multiple technologies, including next generation sequencing (NGS), immunohistochemistry (IHC), and in situ hybridization (ISH). Mutation, IHC-positive, and ISH-positive frequencies were compared using Fisher’s exact test (p-value < 0.05 considered significant). Results: In total, 1,857 tumors were examined. Of the 797 CRC cases, 115 (14.4%) had at least one mutation in MLH1, MSH2, or MSH6. Nineteen (19; 2.3%) of the CRC cases had mutations in multiple MMR related genes. Of the 1060 UtCa cases, 52 (4.9%) had at least one mutation in MLH1, MSH2, or MSH6. Twenty-two (22; 2.1%) of the UtCa cases had mutations in multiple MMR related genes. Colorectal cancers that were MLH1, MSH2, and MSH6 mutated enriched for rare, lineage specific co-mutations, including KRAS A146T (4/32 MLH1-mutated cases; 12.5%). Uterine cancers that were MLH1, MSH2, and MSH6 mutated also enriched for several co-mutations, including ARID1A (8/9 MLH1-mutated cases; 88.9%), a SWI-SNF chromatin remodeling complex family member. Further analyses revealed differences in PD-L1 positivity between MMR mutated CRCs versus UtCa (8/131; 6.1% versus 8/51; 15.7%). Tumor mutational load (defined as the total number of non-synonymous mutations per Mb sequenced) was 35 mutations per Mb in CRC and 51 mutations per Mb in UtCa. Conclusions: There are differences in mutation signatures between uterine and colorectal cancer, and possible additional molecular targets for combination with immune checkpoint therapies. Further analysis of MMR gene-specific differences in molecular profiles is ongoing and will be discussed.

Phenotype associated with recessively inherited mutations in DNA mismatch repair (MMR) genes

2005 ◽  
Vol 33 (4) ◽  
pp. 718-720 ◽  
Author(s):  
M. de Vos ◽  
B. Hayward ◽  
D.T. Bonthron ◽  
E. Sheridan
Keyword(s):  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Case Reports ◽  
Repair System ◽  
Cancer Predisposition Syndrome ◽  
Dna Mismatch ◽  
Mmr Genes ◽  
Dna Mismatch Repair System ◽  
Second Primaries ◽  
Biallelic Mutations

The MMR (DNA mismatch repair) system helps to maintain the integrity of the genome. This involves eliminating base–base mismatches and insertion/deletion loops, which can lead to microsatellite instability, as seen in tumour cells. Hereditary non-polyposis colon cancer is the result of dominant mutations in MMR genes, such as MLH1, MSH2 and MSH6. More recently there have been case reports of biallelic mutations in the MMR genes MLH1, MSH2 and PMS2. These result in a distinct autosomal recessive cancer predisposition syndrome. The syndrome is characterized by childhood haematological malignancies, brain tumours and the presence of café au lait patches. Second primaries occur frequently in this condition, and survival into adulthood is rare.

scholarly journals Oligonucleotide-directed mutagenesis screen to identify pathogenic Lynch syndrome-associated MSH2 DNA mismatch repair gene variants

2016 ◽  
Vol 113 (15) ◽  
pp. 4128-4133 ◽  
Author(s):  
Hellen Houlleberghs ◽  
Marleen Dekker ◽  
Hildo Lantermans ◽  
Roos Kleinendorst ◽  
Hendrikus Jan Dubbink ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Embryonic Stem ◽  
Mismatch Repair Gene ◽  
Missense Mutations ◽  
Repair Gene ◽  
Dna Mismatch ◽  
Mmr Genes ◽  
Pathogenic Variants

Single-stranded DNA oligonucleotides can achieve targeted base-pair substitution with modest efficiency but high precision. We show that “oligo targeting” can be used effectively to study missense mutations in DNA mismatch repair (MMR) genes. Inherited inactivating mutations in DNA MMR genes are causative for the cancer predisposition Lynch syndrome (LS). Although overtly deleterious mutations in MMR genes can clearly be ascribed as the cause of LS, the functional implications of missense mutations are often unclear. We developed a genetic screen to determine the pathogenicity of these variants of uncertain significance (VUS), focusing on mutator S homolog 2 (MSH2). VUS were introduced into the endogenous Msh2 gene of mouse embryonic stem cells by oligo targeting. Subsequent selection for MMR-deficient cells using the guanine analog 6-thioguanine allowed the detection of MMR-abrogating VUS. The screen was able to distinguish weak and strong pathogenic variants from polymorphisms and was used to investigate 59 Msh2 VUS. Nineteen of the 59 VUS were identified as pathogenic. Functional assays revealed that 14 of the 19 detected variants fully abrogated MMR activity and that five of the detected variants attenuated MMR activity. Implementation of the screen in clinical practice allows proper counseling of mutation carriers and treatment of their tumors.

scholarly journals High Prevalence of Alterations in DNA Mismatch Repair Genes of Lynch Syndrome in Pediatric Patients with Adrenocortical Tumors Carrying a Germline Mutation on TP53

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 621
Author(s):  
Vania Balderrama Brondani ◽  
Luciana Montenegro ◽  
Amanda Meneses Ferreira Lacombe ◽  
Breno Marchiori Magalhães ◽  
Mirian Yumie Nishi ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Germline Mutation ◽  
Pediatric Patients ◽  
Dna Mismatch Repair ◽  
Malignant Neoplasm ◽  
Adrenocortical Tumors ◽  
Dna Mismatch ◽  
Mmr Genes ◽  
Dismal Prognosis

Adrenocortical cancer is a rare malignant neoplasm associated with a dismal prognosis. Identification of the molecular pathways involved in adrenal tumorigenesis is essential for a better understanding of the disease mechanism and improvement of its treatment. The aim of this study is to define the prevalence of alterations in DNA mismatch repair (MMR) genes in Lynch syndrome among pediatric patients with adrenocortical neoplasia from southern Brazil, where the prevalence of a specific TP53 germline mutation (p.Arg337His) is quite high. Thirty-six pediatric patients were retrospectively evaluated. Immunohistochemistry (IHC) for the MMR enzymes MLH1, MSH2, MSH6, and PMS2, as well as next-generation sequencing (NGS) were performed. For IHC, 36 pediatric tumors were tested. In all of them, the expression of all evaluated MMR proteins was well-preserved. For NGS, 35 patients with pediatric tumor were tested. Three patients (8.57%) with the TP53 p.Arg337His germline mutation presented pathogenic and likely pathogenic variants in the MMR genes (two in MLH1 and one in MSH6). The prevalence of altered MMR genes among pediatric patients was elevated (8.57%) and higher than in colorectal and endometrial cancer cohorts. Pediatric patients with adrenocortical tumors should, thus, be strongly considered as at genetic risk for Lynch syndrome.

scholarly journals Molecular epidemiological and mutational analysis of DNA mismatch repair (MMR) genes in endometrial cancer patients with HNPCC-associated familial predisposition to cancer

2008 ◽  
Vol 99 (9) ◽  
pp. 1715-1719 ◽  
Author(s):  
Y. Hirai ◽  
K. Banno ◽  
M. Suzuki ◽  
Y. Ichikawa ◽  
Y. Udagawa ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Cancer Patients ◽  
Mismatch Repair ◽  
Mutational Analysis ◽  
Dna Mismatch Repair ◽  
Familial Predisposition ◽  
Dna Mismatch ◽  
Mmr Genes

Prevalence and spectrum of DNA mismatch repair gene variation in the general Chinese population

2021 ◽  
pp. jmedgenet-2021-107886
Author(s):  
Li Zhang ◽  
Zixin Qin ◽  
Teng Huang ◽  
Benjamin Tam ◽  
Yongsen Ruan ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Chinese Population ◽  
Dna Mismatch Repair ◽  
Chinese Patients ◽  
Biological Study ◽  
Mismatch Repair Gene ◽  
Effective Prevention ◽  
Dna Mismatch ◽  
Mmr Genes ◽  
General Chinese Population

BackgroundIdentifying genetic disease-susceptible individuals through population screening is considered as a promising approach for disease prevention. DNA mismatch repair (MMR) genes including MLH1, MSH2, MSH6 and PMS2 play essential roles in maintaining microsatellite stability through DNA mismatch repair, and pathogenic variation in MMR genes causes microsatellite instability and is the genetic predisposition for cancer as represented by the Lynch syndrome. While the prevalence and spectrum of MMR variation has been extensively studied in cancer, it remains largely elusive in the general population. Lack of the knowledge prevents effective prevention for MMR variation–caused cancer. In the current study, we addressed the issue by using the Chinese population as a model.MethodsWe performed extensive data mining to collect MMR variant data from 18 844 ethnic Chinese individuals and comprehensive analyses for the collected MMR variants to determine its prevalence, spectrum and features of the MMR data in the Chinese population.ResultsWe identified 17 687 distinct MMR variants. We observed substantial differences of MMR variation between the general Chinese population and Chinese patients with cancer, identified highly Chinese-specific MMR variation through comparing MMR data between Chinese and non-Chinese populations, predicted the enrichment of deleterious variants in the unclassified Chinese-specific MMR variants, determined MMR pathogenic prevalence of 0.18% in the general Chinese population and determined that MMR variation in the general Chinese population is evolutionarily neutral.ConclusionOur study provides a comprehensive view of MMR variation in the general Chinese population, a resource for biological study of human MMR variation, and a reference for MMR-related cancer applications.

scholarly journals DNA Mismatch Repair (MMR) Genes and Endometrial Cancer

10.5772/23995 ◽  
2011 ◽  
Author(s):  
Kenta Masuda ◽  
Kouji Banno ◽  
Megumi Yanokura ◽  
Iori Kisu ◽  
Arisa Ueki ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Dna Mismatch ◽  
Mmr Genes

DNA Mismatch Repair Protein Mlh1

2020 ◽  
Author(s):  
Keyword(s):  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Dna Mismatch ◽  
Repair Protein ◽  
Mismatch Repair Protein
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