DNA mismatch repair

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Accuracy of four mononucleotide repeat markers for the identification of DNA mismatch repair deficiency in solid tumors

Accuracy of four mononucleotide repeat markers for the identification of DNA mismatch repair deficiency in solid tumors

Microsatellite instability (MSI) is characterized by the accumulation of insertion-deletion mutations at microsatellite-repeat sequences and represents a hall- mark feature of cancer cells with DNA mismatch-repair deficiency (dMMR) [1, 2]. Inactivation of any one or a combination of MMR genes, including MutL homolog (MLH)1, MutS protein homolog (MSH)2, MSH6, and PMS2, can result in MSI. Originally, MSI was discov- ered to correlate with germline defects in MMR genes in patients with Lynch syndrome, where > 90% of colorec- tal cancer (CRC) patients exhibit this phenotype [3, 4]. It was later recognized that MSI also occurs in ~ 12 to ~ 15% of sporadic CRCs that lack germline MMR muta- tions; however, in these patients, MSI manifests due to methylation-induced silencing of the MLH1 promoter [5, 6]. Determination of MMR deficiency by MSI status or immunohistochemical staining for MMR proteins in CRC patients has clinical significance due to its prog- nostic and therapeutic implications [7]. Patients with MSI CRCs typically have better prognosis, although these cancers are less responsive to 5FU-based adjuvant chemotherapy [8]. Recently, clinical trials demonstrated the utility of MSI status in predicting response to PD-1 blockade in advanced unresectable solid tumor patients [9–11]. Additionally, MSI status was a significant predic- tor of the immune-related objective response rate [40% in dMMR CRC, 71% in dMMR non-CRC, 0% in MMR-pro- ficient (pMMR) CRC] and immune-related progression- free survival rates (78, 67, and 11%, respectively) [9].
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Maternal Effect for DNA Mismatch Repair in the Mouse

Maternal Effect for DNA Mismatch Repair in the Mouse

DNA mismatch repair (DMR) functions to maintain genome stability. Prokaryotic and eukaryotic cells deficient in DMR show a microsatellite instability (MSI) phenotype characterized by repeat length alter- ations at microsatellite sequences. Mice deficient in Pms2, a mammalian homolog of bacterial mutL, develop cancer and display MSI in all tissues examined, including the male germ line where a frequency of ⵑ10% was observed. To determine the consequences of maternal DMR deficiency on genetic stability, we analyzed F 1 progeny from Pms2 ⫺ / ⫺ female mice mated with wild-type males. Our analysis indicates that MSI in the
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Dual daughter strand incision is processive and increases the efficiency of DNA mismatch repair

Dual daughter strand incision is processive and increases the efficiency of DNA mismatch repair

DNA mismatch repair (MMR) is crucial for the mainte- nance of genomic stability. Malfunction of MMR results in a 100 to 1000-fold increase in spontaneous mutation rates and is associated with Lynch syndrome in humans (1,2). MMR has many functions that involve the recognition of mispaired bases, most notably the strand-specific correction of mismatches and small insertion/deletion loops remain- ing after replication (1). The MMR pathway of Escherichia coli was the first to be reconstituted in vitro from purified components (3). The three proteins MutS, MutL and MutH are sufficient for mismatch recognition and endonucleolytic incision of the newly-synthesized DNA strand (4). Subse- quently, DNA helicase II (UvrD) is loaded onto the DNA by MutL and unwinds the incised strand from the nick to- ward the mismatch in a 3 to 5 direction (5). The exonu- cleases RecJ, ExoI, ExoVII and ExoX then degrade the dis- placed strand containing the replication error, the resulting single-stranded gap is filled-in by repair synthesis and the remaining nick is sealed by a DNA ligase (6). In eukary- otes, several homologues of MutS and MutL are present (2). The two MutS homologues that play a role in MMR are MutS ␣ (a heterodimer of MSH2 and MSH6) and MutS ␤ (a heterodimer of MSH2 and MSH3). The functional ho- mologue of MutL is MutL ␣ (a heterodimer of MLH1 and PMS2). Following recognition of the mismatch and the strand discrimination signal, daughter strand removal is ac- complished either via Exonuclease I (7,8) or via strand dis- placement by DNA polymerase ␦ (9), after which resynthe- sis and ligation take place.
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Saturation of DNA Mismatch Repair and Error Catastrophe by a Base Analogue in Escherichia coli

Saturation of DNA Mismatch Repair and Error Catastrophe by a Base Analogue in Escherichia coli

for kanamycin resistance followed by testing for mutator phe- ties associated with the recA, umuDC, or uvrA genes. notype. The recA56 allele was introduced by P1 transduction However, the mutH, -L, -S DNA mismatch-repair system using linkage with srl360::Tn10. The ⌬(umuDC595::cat) was found to strongly protect cells against dP mutagene- marker was transferred by P1 transduction from strain RW82 (Woodgate 1992) selecting for chloramphenicol resistance. sis, particularly at low dP dose levels. At high doses, dP

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Role of DNA Mismatch Repair and Double-Strand Break Repair in Genome Stability and Antifungal Drug Resistance in Candida albicans

Role of DNA Mismatch Repair and Double-Strand Break Repair in Genome Stability and Antifungal Drug Resistance in Candida albicans

In many organisms, cells deficient in DNA mismatch repair (MMR) exhibit a mutator phenotype in which the rate of spontaneous mutation is greatly elevated (6, 10). The MMR pathway acts to remove bases that are mispaired as a result of a failure during replication, illustrated by the functional inter- action of the MMR proteins with the DNA replication factor PCNA (5, 8). The MMR pathway also plays a role in main- taining the stability of certain types of repetitive DNA tracts (28). This pathway was first described in Escherichia coli, where MutS and MutL bind to the mismatch, activating the MutH endonuclease. Multiple MutS and MutL homologues have been characterized in Saccharomyces cerevisiae (13, 24). Null mutations in MSH2 (MutS homolog) or PMS1 (MutL ho- molog) cause an increase in base substitutions and insertion/ deletion in simple sequence repeats in S. cerevisiae (23, 32).
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Dynamics of DNA Mismatch Repair Initiation Complexes Revealed by Single Molecule Fluorescence.

Dynamics of DNA Mismatch Repair Initiation Complexes Revealed by Single Molecule Fluorescence.

In this thesis, we have examined structural dynamics of the DNA mismatch repair protein MutS that control its roles in MMR pathways. MutS is a homodimer in prokaryotes and heterodimer in eukaryotes, containing five well folded domains in each subunit. The DNA binding domain I of MutS undergoes substantial conformational changes during mismatch recognition and signaling repair. In chapter III, we used smFRET to extensively characterize the nucleotide binding and DNA binding effects on conformation of MutS. By labeling the domain I of each subunit with a donor and an acceptor respectively, we were able to report its conformation by measuring the distance between them. We found that domain I of MutS was mobile without binding to DNA or nucleotides, yielding a broad FRET distribution. Binding to ADP or ATP stabilized MutS in two conformations, one with high FRET and another with low FRET. When MutS was bound to homoduplex DNA, it also adopted a high FRET and a low FRET state. The low FRET state was less stable on a DNA with an unblocked end but the high FRET state was unaffected by free end blocking, suggesting that the low FRET conformation could diffuse on DNA while the high FRET conformation was immobile. When recognizing a mismatch on DNA, MutS converted into a single high FRET state, consistent with the conformation reported in crystal structures where the domains I were close to each other. The recognition of a mismatch by MutS is the starting point of the MMR cascade.
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Functional role of DNA mismatch repair gene PMS2 in prostate cancer cells

Functional role of DNA mismatch repair gene PMS2 in prostate cancer cells

DNA mismatch repair (MMR) enzymes act as proofreading complexes that maintains genomic integrity and MMR-deficient cells show an increased mutation rate. MMR has also been shown to influence cell signaling and the regulation of tumor development. MMR consists of various genes and includes post-meiotic segregation (PMS) 2 which is a vital component of mutL-alpha. In prostate, the functional role of this gene has never been reported and in this study, our aim was to investigate the effect of PMS2 on growth properties of prostate cancer (PCa) cells. Previous studies have shown PMS2 to be deficient in DU145 cells and this lack of expression was confirmed by Western blotting whereas normal prostatic PWR-1E and RWPE-1 cells expressed this gene. PMS2 effects on various growth properties of DU145 were then determined by creating stable gene transfectants. Interestingly, PMS2 caused decreased cell proliferation, migration, invasion, and in vivo growth; and increased apoptosis as compared to vector control. We further analyzed genes affected by PMS2 expression and observe the apoptosis-related TMS1 gene to be significantly upregulated whereas anti-apoptotic BCL2A1 was downregulated. These results demonstrate a functional role for PMS2 to protect against PCa progression by enhancing apoptosis of PCa cells.
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PMS2 gene mutation results in DNA mismatch repair system failure in a case of adult granulosa cell tumor

PMS2 gene mutation results in DNA mismatch repair system failure in a case of adult granulosa cell tumor

create a mutator phenotype which predisposes to add- itional mutations involved in cancer development. The PMS2 N775L mutation was identified in both lympho- cyte and tumor in this study. The FOXL2 402C > G mu- tation was observed in granulosa cell tumor, but not in the blood or normal tissue [9]. Therefore, the tumor ex- hibited both PMS2 and FOXL2 mutations, and PMS2 mutation occurred before FOXl2 mutation. The results of this study indicated that the amino acid changing mu- tation, N775L, in PMS2 gene may be the driver mutation which induces DNA mismatch repair system failure. Our hypothesis is that DNA mismatch repair system failure induces FOXL2 402C > G mutation, leading to granulosa cell tumor development [9]. The DNA mis- match repair system failure randomly causes further mutations of tumor suppressor genes or oncogenes, resulting in late recurrence and unpredictable malignant behavior of granulosa cell tumor [9].
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A Role for DNA Mismatch Repair Protein Msh2 in Error-Prone Double-Strand-Break Repair in Mammalian Chromosomes

A Role for DNA Mismatch Repair Protein Msh2 in Error-Prone Double-Strand-Break Repair in Mammalian Chromosomes

ity of NHEJ events for MT⫹ and clone B cells involved one or several bases of microhomology at the site where consistent difference between MT⫹ cell lines vs. clone B DNA termini were joined. However, we noted that when cell lines regarding the types of repair events recovered, all NHEJ junctions are considered, 16 of 49 junctions although we noted that one cell line, CB6, produced recovered from clone B cells displayed no terminal bases 25 NHEJ with duplication events of 44 events recovered of microhomology, while only 5 of 51 junctions recov- from this line (Table 2, and data not shown). ered from MT⫹ cells involved no microhomology. This Analysis of nucleotide sequences across NHEJ repair difference in the number of clones recovered that dis- junctions: PCR products generated from 45 NHEJ played no microhomology at NHEJ junctions is highly events recovered from MT⫹ cell lines and from 45 NHEJ statistically significant (p ⫽ 0.0050 by a chi-square test). events recovered from clone B cell lines were se- If we discount the data from cell line CB6, which yields quenced. The clones that were sequenced were ran- a low frequency of DSB-induced G418 R colonies (Table
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Escherichia coli mutator mutD5 is defective in the mutHLS pathway of DNA mismatch repair.

Escherichia coli mutator mutD5 is defective in the mutHLS pathway of DNA mismatch repair.

Competent cells derived from the mutD5 strain are severely affected in their ability to perform mismatch repair, yielding a percentage of mixed bursts close to that of the mu[r]

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Ensemble and single-molecule fluorescence studies of DNA mismatch repair initiation by MutS

Ensemble and single-molecule fluorescence studies of DNA mismatch repair initiation by MutS

Fluorescence anisotropy is sensitive to the rotational diffusion of the fluorescent molecule in solution, where freely tumbling molecules exhibit a lower net anisotropy value than molecules interacting with larger binding molecules (ie. DNA bound by MutS). However, if the small fluorescent molecule exhibits dynamic segmental motions (such as DNA bending), the net anisotropy would reflect those motions and be reduced (Lakowicz 1999). As a result, dynamic DNA bending in mismatched DNA bound by MutS would contribute to a reduced net change in anisotropy as was observed for mismatched DNA- E339A complexes. Additionally, single-molecule FRET measurements on the homologous mutation in Taq MutS reveal substantially more DNA bending dynamics relative to the wild- type protein on the same mismatched DNA substrates, further supporting the idea that elimination of the interaction between Glu and the mismatch increases dynamics of DNA bending in mismatch-MutS() complexes. The relative difference between the saturation anisotropy for E339A-T and E339A-GT (50% E339A-T vs. 70% for E330A-GT relative to wild-type) further reveals that, in comparison, E339A-GT exhibits less DNA bending dynamics or segmental motions than E339A-T complexes.
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DNA mismatch repair gene MSH6 implicated in determining age at natural menopause

DNA mismatch repair gene MSH6 implicated in determining age at natural menopause

involved in DNA repair were identified in the recent GWAS for age at menopause, including EXO1, UIMC1, MCM8 and POLG(3). EXO1 has 5 ′ – 3 ′ exonuclease activity and interacts with several of the MMR proteins, including MSH2, MLH1, MSH3, PCNA and WRN for its role in MMR and recombination (24). UIMC1 recruits BRCA1 to DNA damage sites and initiates G2/M checkpoint control (25). MCM8 is a member of a family of DNA replication complex proteins and is thought to have a role in meiotic double-strand break repair (26). Finally, POLG is re- sponsible for the replication and repair of the mitochondrial genome (27). Thus, variation in DNA repair processes, including single nucleotide, double-strand and mitochondrial DNA repair, appear to play a crucial role in determining age at natural meno- pause. A recent paper showed accumulation of double-strand DNA breaks in human follicles with age, with concomitant downregulation of key DNA repair genes BRCA1, MRE11, Rad51 and ATM, providing evidence that these processes play a functional role in ovarian ageing (28). It has also been reported that carriers of germline mutations in MMR genes, namely BRCA1 and BRCA2 are at increased risk of early menopause (29 –32). We demonstrated that rs1800932 is an expression quantitative trait locus for MSH6, with the rarer allele being asso- ciated with increased levels of mRNA. Thus, the lower expres- sion of MSH6 is associated with earlier menopause, consistent with the work of Titus et al. (28), where downregulation of DNA repair genes was associated with ovarian ageing. The effect of the MSH6 variant on menopause age is relatively small and only explains a small proportion of the variance in menopause age. There are thus likely to be many more undiscov- ered genetic variants responsible for determining age at natural menopause.
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DNA Mismatch Repair Proteins Are Required for Efficient Herpes Simplex Virus 1 Replication

DNA Mismatch Repair Proteins Are Required for Efficient Herpes Simplex Virus 1 Replication

To further test whether MLH1 is indeed an ND10 compo- nent, we chose to silence PML and monitor the localization of MLH1. PML is the central organizer of ND10, and many ND10 components become nuclear diffuse or have altered localization in the absence of PML (16). Figure 5 demonstrates that PML was successfully silenced in shPML cells, as no PML protein was detectable by IF (Fig. 5A, middle) or Western blotting (Fig. 5B). TO-PRO-3 dye was used to detect cellular DNA and mark the boundary of the nucleus. In control shGFP cells, MLH1 and PML colocalized; however, in cells expressing shPML, MLH1 was observed in a nuclear diffuse staining pat- tern (Fig. 5A, middle). Although MLH1 staining in shPML cells appeared less intense than that in uninfected cells (Fig. 5A, middle), this was likely due to the diffuse localization and not a result of degradation, as no decrease was observed in the total amount of MLH1 in shPML cells by Western blotting (Fig. 5B). Figure 5B indicates that in shMLH1 cells, MLH1 has been silenced efficiently. PML levels were also decreased in FIG. 5. Punctate MLH1 localization requires intact ND10. HFF-1 cells were infected with lentiviruses expressing the indicated shRNA and selected with puromycin. (A, B) Localization of MLH1 and PML was determined by immunofluorescence analysis (A), and knockdown was determined by Western blotting (B). (C) HFF-1 cells were either mock infected or infected with d106, which is deleted for all IE genes except ICP0, at an MOI of 10 PFU/cell, fixed at 6 h postinfection, and stained for ICP0, MLH1, and PML. (D) HFF-1 cells were either mock infected or infected with HSV-1 (KOS), the ICP0-null virus 0 ␤ , or d106 at an MOI of 10 PFU/cell. Cells were harvested at 6 h postinfection for Western blot analysis as indicated. For the triple-label experiments shown in panel C, all antibodies were directly conjugated to fluorophores, as described in Materials and Methods, to allow for the simultaneous use of the monoclonal mouse antibodies for MLH1 and ICP0. All immunofluorescence samples were prepared using Fix/Perm type 1, and TO-PRO-3 was used as a nuclear counterstain in panel A.
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The Role of DNA Mismatch Repair and Recombination in the Processing of DNA Alkylating Damage in Living Yeast Cells

The Role of DNA Mismatch Repair and Recombination in the Processing of DNA Alkylating Damage in Living Yeast Cells

To determine if the recruitment of homologous recombination is altered in a MMR defective background, we inactivated MMR genes in the strain containing the RAD52-GFP fusion. Spontaneous foci form at very low frequency in the absence of exposure to the DNA alkylating agent (less than 1 per 100 cells, Figure 3(a) top left panel) and is increased at least 15-fold after treatment (Figure 3(a) top right panel and Figure 3(a)). Inactiva- tion of MSH2 results in a considerable reduction of the RAD52 foci formed after exposure to MNNG (Figure 3(a)) to levels similar to those of unexposed cells (14-fold reduction, Figure 3(b)). Similarly, the inactivation of the MSH6 gene also reduces the accumulation of RAD52 foci (Figure 3(a)) by approximately 9-fold (Figure 3(b)). As expected, the inactivation of the MSH3 gene did not significantly reduced the formation of RAD52 fo- ci upon treatment with MNNG. As a control, exposure of the cells to ionizing radiation (+RAD) did not require a proficient MMR system since MMR mutants strains accumulate similar number of foci compared to the wild type strain (Figure 3(b)). In all cases that a RAD52 foci was observed, it was restricted to a specific damage area as indicated by histone γ -H2AX activation. Activation of γ -H2AX occurs predominantly after exposure to MNNG (Figure 3(a)). Interestingly, histone γ -H2AX still becomes activated in strains defective in MMR, which do not process the alkylation damage to DSB. This is consistent with observation that γ -H2AX activation is not restricted to DSBs but is a signal for DNA damage in general [31]. Consistent with the survival data (Figure 1(a)
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Dynamic Emergence of Mismatch Repair Deficiency Facilitates Rapid Evolution of Ceftazidime Avibactam Resistance in Pseudomonas aeruginosa Acute Infection

Dynamic Emergence of Mismatch Repair Deficiency Facilitates Rapid Evolution of Ceftazidime Avibactam Resistance in Pseudomonas aeruginosa Acute Infection

ABSTRACT Strains of Pseudomonas aeruginosa with deficiencies in DNA mismatch repair have been studied in the context of chronic infection, where elevated muta- tional rates (“hypermutation”) may facilitate the acquisition of antimicrobial resis- tance. Whether P. aeruginosa hypermutation can also play an adaptive role in the more dynamic context of acute infection remains unclear. In this work, we demon- strate that evolved mismatch repair deficiencies may be exploited by P. aeruginosa to facilitate rapid acquisition of antimicrobial resistance in acute infection, and we directly document rapid clonal succession by such a hypermutating lineage in a pa- tient. Whole-genome sequencing (WGS) was performed on nine serially cultured blood and respiratory isolates from a patient in whom ceftazidime-avibactam (CZA) resistance emerged in vivo over the course of days. The CZA-resistant clone was dif- ferentiated by 14 mutations, including a gain-of-function G183D substitution in the PDC-5 chromosomal AmpC cephalosporinase conferring CZA resistance. This lineage also contained a substitution (R656H) at a conserved position in the ATPase domain of the MutS mismatch repair (MMR) protein, and elevated mutational rates were confirmed by mutational accumulation experiments with WGS of evolved lineages in conjunction with rifampin resistance assays. To test whether MMR-deficient hyper- mutation could facilitate rapid acquisition of CZA resistance, in vitro adaptive evolu- tion experiments were performed with a mutS-deficient strain. These experiments demonstrated rapid hypermutation-facilitated acquisition of CZA resistance com- pared with the isogenic wild-type strain. Our results suggest a possibly underappre- ciated role for evolved MMR deficiency in facilitating rapid adaptive evolution of P. aeruginosa in the context of acute infection.
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Thyroid cancer in a patient with a germline MSH2 mutation. Case report and review of the Lynch syndrome expanding tumour spectrum

Thyroid cancer in a patient with a germline MSH2 mutation. Case report and review of the Lynch syndrome expanding tumour spectrum

Lynch syndrome (HNPCC) is a dominantly inherited disorder characterized by germline defects in DNA mismatch repair (MMR) genes and the development of a variety of cancers, predominantly colorectal and endometrial. We present a 44-year-old woman who was shown to carry the truncating MSH2 gene mutation that had previously been identified in her family. Recently, she had been diagnosed with an undifferentiated carcinoma of the thyroid and an adenoma of her coecum. Although the thyroid carcinoma was not MSI-high (1 out of 5 microsatellites instable), it did show complete loss of immunohistochemical expression for the MSH2 protein, suggesting that this tumour was not coincidental. Although the risks for some tumour types, including breast cancer, soft tissue sarcoma and prostate cancer, are not significantly increased in Lynch syndrome, MMR deficiency in the presence of a corresponding germline defect has been demonstrated in incidental cases of a growing range of tumour types, which is reviewed in this paper. Interestingly, the MSH2-associated tumour spectrum appears to be wider than that of MLH1 and generally the risk for most extra-colonic cancers appears to be higher for MSH2 than for MLH1 mutation carriers. Together with a previously reported case, our findings show that anaplastic thyroid carcinoma can develop in the setting of Lynch syndrome. Uncommon Lynch syndrome-associated tumour types might be useful in the genetic analysis of a Lynch syndrome suspected family if samples from typical Lynch syndrome tumours are unavailable.
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A gene expression assay for simultaneous measurement of microsatellite instability and anti-tumor immune activity

A gene expression assay for simultaneous measurement of microsatellite instability and anti-tumor immune activity

DNA mismatch repair deficiency (MMRd) has been observed in most cancer types in The Cancer Genome Atlas (TCGA), and occurs in more than 5% of adrenal, rectal, colon, stomach, and endometrial tumors [8]. Tu- mors with this phenotype develop both point and frame- shift mutations at an increased rate and are often described as “hypermutated”. The failure of mismatch repair (MMR) to correct replication errors at short re- peated DNA sequences can lead to the phenomenon of high-level MSI (MSI-H). MSI-H cancers have distinct clinical behavior, which has led to widespread MSI test- ing in cancers where MSI-H is common. In colorectal cancer, the MSI-H phenotype demonstrates association with proximal tumor localization, a dense local lympho- cyte infiltration, and a low frequency of distant organ metastasis [9]. Moreover, MSI-H colorectal cancers have a better prognosis than their microsatellite-stable (MSS) counterparts [10]. Despite this, diminished responsive- ness of MSI-H colorectal cancer patients towards chemotherapy has been shown in several studies, per- haps as a result of the elevated mutation rate more fre- quently giving rise to chemotherapy resistant clones [11]. In the era of immunotherapy, MMRd has gained greater relevance as a cause of hypermutation potentiat- ing anti-tumor immune responses which may be en- hanced by checkpoint inhibition [3]. Importantly, the frame-shift mutations that accrue in MMRd tumors can cause greater immunogenicity by leading to a shift in the protein coding sequence of the entire transcript down- stream of the mutation site, whereas point mutations only create a potential neoantigen at the site of the
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Molecular pathogenesis in granulosa cell tumor is not only due to somatic FOXL2 mutation

Molecular pathogenesis in granulosa cell tumor is not only due to somatic FOXL2 mutation

system failure appears likely in this patient. In such a case, early detection allows for treatment of benign tumor. Although this study could not elucidate the exact mechan- ism for the development of granulosa cell tumor, it does suggest the need to incorporate DNA mismatch repair system examination into the clinical management of pa- tients with granulosa cell tumor.

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Requirement of Mismatch Repair Genes MSH2 and MSH3 in the RAD1-RAD10 Pathway of Mitotic Recombination in Saccharomyces cerevisiae

Requirement of Mismatch Repair Genes MSH2 and MSH3 in the RAD1-RAD10 Pathway of Mitotic Recombination in Saccharomyces cerevisiae

The MSH2 and MSH3 genes participate in DNA mismatch repair; null mutations in these genes result in elevated rates of spontaneous mutations and in an increase in the [r]

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No Change in Frequency of Microsatellite Instability in Colorectal Cancers over a Period of 15 or More Years

No Change in Frequency of Microsatellite Instability in Colorectal Cancers over a Period of 15 or More Years

Microsatellite instability (MSI) is a molecular change resulting from inactiva- tion of DNA mismatch repair systems, occurring with a reported incidence between 15% - 20% of all sporadic colorectal cancers. Our aim was to deter- mine whether a change in the incidence of MSI in colorectal cancer had oc- curred at our institution over time. We assayed 106 cases from the mid-1990s and 69 cases from 15 or more years later for MSI. Those tumors with MSI were assayed for BRAF mutation and methylation. MSI was detected in 15 (14.2%) of the early cases and 11 (15.9%) of the later cases. For the two groups with MSI, a similar percentage was methylated and had a BRAF mutation. One tumor in each group was MSI, unmethylated, and BRAF wild type. Our data indicate consistency in the frequency of microsatellite unstable colorectal cancer across a time span of 15 or more years.
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