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Mismatch repair pathway major steps with genes associated. Genes in red are the one usually screened for mutations in a clinical setting. MLH1, PMS2, MSH2, and MSH6 are all involved in the recognition of DNA damage. PMS2 has an endonuclease function in nicking around the damaged region. EXO1 will then remove the DNA strand containing the error and RPA (Replication Protein A) will protect the remaining single strand of DNA. The DNA polymerase Polδ resynthesises the new DNA strand which is then ligated with a ligase (based on Hsieh & Yamane, 2008)
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Background:
Lynch-like syndrome (LLS) represents around 50% of the patients fulfilling the Amsterdam Criteria II/revised Bethesda Guidelines, characterized by a strong family history of Lynch Syndrome (LS) associated cancer, where a causative variant was not identified during genetic testing for LS.
Methods:
Using data extracted from a larger ge...
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Background
Glioblastoma (GBM) is the most common and malignant gliomas of adults and recur, resulting in death, despite surgery, radiotherapy, and temozolomide-based chemotherapy. There are a few reports on immunotherapy for the mismatch repair (MMR)-deficient GBMs with high tumor mutational burden (TMB). However, the clinicopathological and geneti...
Background:
Immunohistochemical (IHC) staining for mismatch repair (MMR) proteins is useful for gastric cancer treatment and prognosis. Different IHC staining patterns reflect the complex biological phenomena underlying MMR deficiency. We herein report a rare IHC staining pattern of four MMR-related proteins in gastric cancer.
Case summary:
A "n...
Citations
... The MUTYH-associated polyposis can overlap with the LS phenotype, by somatic inactivation of MMR genes [34]. LLS patients carrying POLE and POLD1 germline variants have also been identified [36,37]. Whole exome sequencing identified germline pathogenic/likely pathogenic variants in DNA repair genes, such as MCM8, MCM9, WRN, MCPH1, BARD1, REV3L, EXO1, POLD1, RFC1, RPA1, ATM, and MLH3. ...
... Whole exome sequencing identified germline pathogenic/likely pathogenic variants in DNA repair genes, such as MCM8, MCM9, WRN, MCPH1, BARD1, REV3L, EXO1, POLD1, RFC1, RPA1, ATM, and MLH3. In addition, other cancerrelated genes, such as PPARG , CTC1, DCC and ALPK, were identified as candidate genes for LLS [13,[37][38][39]. ...
Background
Based on molecular characteristics, deficient DNA mismatch repair (dMMR) solid tumors are largely divided into three categories: somatically MLH1 -hypermethylated tumors, Lynch syndrome (LS)-associated tumors, and Lynch-like syndrome (LLS)-associated tumors. The incidence of each of these conditions and the corresponding pathogenic genes related to LLS remain elusive.
Methods
We identified dMMR tumors in 3609 tumors from 9 different solid organs, including colorectal cancer, gastric cancer, small-bowel cancer, endometrial cancer, ovarian cancer, upper urinary tract cancer, urinary bladder cancer, prostate cancer, and sebaceous tumor, and comprehensively summarized the characterization of dMMR tumors. Characterization of dMMR tumors were performed as loss of at least one of MMR proteins (MLH1, MSH2, MSH6, and PMS2), by immunohistochemistry, followed by MLH1 promotor methylation analysis and genetic testing for MMR genes where appropriate. Somatic variant analysis of MMR genes and whole exome sequencing (WES) were performed in patients with LLS.
Results
In total, the incidence of dMMR tumors was 5.9% (24/3609). The incidence of dMMR tumors and the proportion of the three categorized dMMR tumors varied considerably with different tumor types. One to three likely pathogenic/pathogenic somatic MMR gene variants were detected in 15 out of the 16 available LLS tumors. One patient each from 12 patients who gave consent to WES demonstrated non- MMR germline variants affect function ( POLQ or BRCA1 ).
Conclusions
Our data regarding the LS to LLS ratio would be useful for genetic counseling in patients who are suspected to have LS, though the genetic backgrounds for the pathogenesis of LLS need further investigation.
... Deregulation of MutSα/MutSβ ratio results in microsatellite instability (MSI) and/or Elevated Microsatellite Alterations at Selected Tetranucleotide repeats (EMAST) genotypes [14]. Several lines of evidence have well-documented the role of MMR genes (MSH2, MSH6, MLH1, PMS2) and to some extent MSH3 in CRC pathogenesis [11,[15][16][17]. ...
The maintenance of DNA sequence integrity is critical to avoid accumulation of cancer-causing mutations. Inactivation of DNA Mismatch Repair (MMR) genes (e.g., MLH1 and MSH2) is common among many cancers, including colorectal cancer (CRC) and is the driver of classic microsatellite instability (MSI) in tumors. Somatic MSH3 alterations have been linked to a specific form of MSI called elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) that is associated with patient poor prognosis and elevated among African American (AA) rectal cancer patients. Genetic variants of MSH3 and their pathogenicity vary among different populations, such as among AA, which are not well-represented in publicly available databases. Targeted exome sequencing of MSH3 among AA CRC samples followed by computational bioinformatic pipeline and molecular dynamic simulation analysis approach confirmed six identified MSH3 variants (c.G1237A, c.C2759T, c.G1397A, c.G2926A, c.C3028T, c.G3241A) that corresponded to MSH3 amino-acid changes (p.E413K; p.S466N; p.S920F; p.E976K; p.H1010Y; p.E1081K). All identified MSH3 variants were non-synonymous, novel, pathogenic, and show loss or gain of hydrogen bonding, ionic bonding, hydrophobic bonding, and disulfide bonding and have a deleterious effect on the structure of MSH3 protein. Some variants were located within the ATPase site of MSH3, affecting ATP hydrolysis that is critical for MSH3′s function. Other variants were in the MSH3-MSH2 interacting domain, important for MSH3’s binding to MSH2. Overall, our data suggest that these variants among AA CRC patients affect the function of MSH3 making them pathogenic and likely contributing to the development or advancement of CRC among AA. Further clarifying functional studies will be necessary to fully understand the impact of these variants on MSH3 function and CRC development in AA patients.
... The most prevalent cancers in LS cases are colorectal and endometrial cancer (EC) [3]. One of the first steps to reach the diagnosis is the application of the Amsterdam II and revised Bethesda clinical criteria, which allow for selecting patients with a high risk of having LS, and who therefore must undergo further tests [11], such as immunohistochemical assays, MSI tests, and finally germline DNA analysis, to confirm the presence of pathogenic variants [12]. However, many of the affected individuals do not meet such criteria and are excluded from these analyses. ...
Background
Lynch Syndrome (LS) is an autosomal dominant inheritance disorder characterized by genetic predisposition to develop cancer, caused by pathogenic variants in the genes of the mismatch repair system. Cases are detected by implementing the Amsterdam II and the revised Bethesda criteria, which are based on family history.
Main body
Patients who meet the criteria undergo posterior tests, such as germline DNA sequencing, to confirm the diagnosis. However, these criteria have poor sensitivity, as more than one-quarter of patients with LS do not meet the criteria. It is very likely that the lack of sensitivity of the criteria is due to the incomplete penetrance of this syndrome. The penetrance and risk of developing a particular type of cancer are highly dependent on the affected gene and probably of the variant. Patients with variants in low-penetrance genes have a lower risk of developing a cancer associated with LS, leading to families with unaffected generations and showing fewer clear patterns. This study focuses on describing genetic aspects of LS cases that underlie the lack of sensitivity of the clinical criteria used for its diagnosis.
Conclusion
Universal screening could be an option to address the problem of underdiagnosis.
... Research set for open exome analysis was constructed by searching at various databases or literature reviews: (i) genes, previously described as infertility causing in model organisms (Mouse Genome Database [27], Flybase [28], and high expression in testis [29,30]) (Supplementary 3) and (ii) genes, involved in genome instability and DNA reparation errors [31][32][33][34][35][36][37][38][39][40][41] (Supplementary 4). Finally, an additional gene set with a prognostic value for pretesticular sperm extraction (TESE) prediction was investigated. ...
The purpose of this study was to investigate the linkage of the association of azoospermia phenotype with genetic alterations, involved in genome instability. Male infertility is a multifactorial pathology, and genetic alterations might be the underlying factors in majority of cases of severe male infertility. The recent emergence of next-generation sequencing offers an opportunity to analyze many genes and their interactions at once, and whole-exome sequencing (WES) together with whole-genome sequencing (WGS) was recently suggested for implementation of diagnosis workup in severe infertility cases. However, the reports on WES in conjunction with burden tests and gene network analysis are scarce or lacking in cases of severe male infertility. WES was performed on 21 nonobstructive azoospermia patients. DNA samples were sequenced using the Twist Comprehensive Exome Panel. Genetic burden test was performed with Testing Rare vAriants using Public Data. Protein interactions were investigated with ConsensusPathDB and Cytoscape. For single nucleotide variants and copy number variations (CNV) analysis, samples were analyzed with the Illumina’s BaseSpace Variant Interpreter. Genetic variant burden was found elevated in 1,473 genes out of 30,000 known testis expressed genes. Three hundred and two genes with increased loss-of-function (LoF) variant set were present in more than one sample. Overrepresentation analysis with pathway-based set of genes with high variant burden demonstrated 26 pathways. Overrepresentation analysis with protein complex-based gene sets obtained 14 sets, showing the involvement in cell proliferation and DNA repair. Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) network analysis with Cytoscape identified two clusters: (1) genes, involved in DNA binding/condensation and repair processes and (2) genes with the role in ribosome biosynthesis and gene expression processes. Increased loss of function germline variant burden and sumoylation may have critical significance in spermatogenesis. These parameters may be used for focused diagnosis in nonobstructive azoospermia patients. This may have both general significance for the decreased organism functionality but in particular is critical in spermatogenesis.
... Interestingly, global changes in gene expression in DDR pathways were largely absent in our analysis of the pre-and post-PIKTOR tissues (Supplemental Table 4). Given the loss of MMR deficiency signatures in the 3 responders, we looked specifically at changes in gene expression of 22 MMR genes [44], but did not identify changes in expression that would account for the MMR deficiency signature loss, even when nonsignificant trends were considered. This further supports a shift in clonality of following PIKTOR treatment. ...
Background
A subset of triple-negative breast cancers (TNBCs) have homologous recombination deficiency with upregulation of compensatory DNA repair pathways. PIKTOR, a combination of TAK-228 (TORC1/2 inhibitor) and TAK-117 (PI3Kα inhibitor), is hypothesized to increase genomic instability and increase DNA damage repair (DDR) deficiency, leading to increased sensitivity to DNA-damaging chemotherapy and to immune checkpoint blockade inhibitors.
Methods
10 metastatic TNBC patients received 4 mg TAK-228 and 200 mg TAK-117 (PIKTOR) orally each day for 3 days followed by 4 days off, weekly, until disease progression (PD), followed by intravenous cisplatin 75 mg/m² plus nab paclitaxel 220 mg/m² every 3 weeks for up to 6 cycles. Patients received subsequent treatment with pembrolizumab and/or chemotherapy. Primary endpoints were objective response rate with cisplatin/nab paclitaxel and safety. Biopsies of a metastatic lesion were collected prior to and at PD on PIKTOR. Whole exome and RNA-sequencing and reverse phase protein arrays (RPPA) were used to phenotype tumors pre- and post-PIKTOR for alterations in DDR, proliferation, and immune response.
Results
With cisplatin/nab paclitaxel (cis/nab pac) therapy post PIKTOR, 3 patients had clinical benefit (1 partial response (PR) and 2 stable disease (SD) ≥ 6 months) and continued to have durable benefit in progression-free survival with pembrolizumab post-cis/nab pac for 1.2, 2, and 3.6 years. Their post-PIKTOR metastatic tissue displayed decreased mismatch repair (MMR), increased tumor mutation burden, and significantly lower levels of 53BP1, DAG Lipase β, GCN2, AKT Ser473, and PKCzeta Thr410/403 compared to pre-PIKTOR tumor tissue.
Conclusions
Priming patients’ chemotherapy-pretreated metastatic TNBC with PIKTOR led to very prolonged response/disease control with subsequent cis/nab pac, followed by pembrolizumab, in 3 of 10 treated patients. Our multi-omics approach revealed a higher number of genomic alterations, reductions in MMR, and alterations in immune and stress response pathways post-PIKTOR in patients who had durable responses.
Trial Registration
This clinical trial was registered on June 21, 2017, at ClinicalTrials.gov using identifier NCT03193853.
... The genetic basis of hereditary LLS is not yet fully understood. With the advent of next generation sequencing (NGS) and the ability to test many cancer-predisposing genes simultaneously, many have been shown to cause inherited cases of LLS -MUTYH [22], genes involved in cell activity regulation (EXO1, POLD1, RCF1, and RPA1) [23], BUB1 and BUB3 [24], SETD2 [24], WRN [25], BARD1 [25], and other genes that promote genomic integrity [25]. ...
Background
Synchronous endometrial and ovarian cancer (SEOC) accounts for 50–70% of all synchronous gynecology cancers in women. Approximately 14% of SEOC cases are caused by Lynch syndrome (LS). The widespread introduction of “universal screening” at LS (all cases with CRC and all EC cases diagnosed before age 60 should be tested for MMR deficiency) has led to an increasing number of suspected LS cases- MMR-deficient tumors without germline mutation in the MMR genes. These cases are attributed to the so-called Lynch-like syndrome (LLS).
Case presentation
We present a case of LLS with a detected germline, likely pathogenic variant in the WRN gene. The proband was a woman diagnosed with SEOC at the age of 51 years. Histology of both tumors (endometrium and ovary) was endometroid and showed loss of MLH1 and PMS protein expression. Genetic testing by next generation sequencing (NGS) detected a germline mutation (in the heterozygous state) in the WRN gene - c.4109del, p.(Asn1370ThrfsTer23) in the proband.
Conclusions
The presented case contributes to the etiology of LLS and confirms the need for specific genetic testing, together with genetic counseling, in hereditary cancer syndromes. The use of combined information from clinicians, pathologists, genetic counselors, and data from NGS testing for cancer predisposition, clinical surveillance, and follow-up management in women with gynecology cancers, especially SEOC, could be improved.
... The L474P mutation in POLD1 is associated with hereditary nonpolyposis colorectal cancer. Although Lynch syndrome (also known as hereditary nonpolyposis) has been primarily associated with mutations in several MMRrelated genes, mutations in POLD1, POLD2, POLD3 and POLD4 have more recently been identified as also being contributory [30]. These mutations in POLD1 may predispose to endometrial tumours and also breast and brain tumours [27,28,31]. ...
Replicative DNA polymerases, such as DNA polymerase α-primase, δ and ε, are multi-subunit complexes that are responsible for the bulk of nuclear DNA replication during the S phase. Over the last decade, extensive genome-wide association studies and expression profiling studies of the replicative DNA polymerase genes in human patients have revealed a link between the replicative DNA polymerase genes and various human diseases and disorders including cancer, intellectual disability, microcephalic primordial dwarfism and immunodeficiency. These studies suggest the importance of dissecting the mechanisms involved in the functioning of replicative DNA polymerases in understanding and treating a range of human diseases. Previous studies in Drosophila have established this organism as a useful model to understand a variety of human diseases. Here, we review the studies on Drosophila that explored the link between DNA polymerases and human disease. First, we summarize the recent studies linking replicative DNA polymerases to various human diseases and disorders. We then review studies on replicative DNA polymerases in Drosophila. Finally, we suggest the possible use of Drosophila models to study human diseases and disorders associated with replicative DNA polymerases.
... Outputs were recalibrated and intersect and union cohorts generated. A 22-gene extended MMR panel [33] was extracted, and variant mutations were inspected by type, frequency, ORF location, and SnpEff & VEP ontological mutation Impact annotations. Additional WES and MMR pathway capacity score information is provided in Supplementary Information Section 1.6. ...
Background:
Ovarian cancers are hallmarked by chromosomal instability. New therapies deliver improved patient outcomes in relevant phenotypes, however therapy resistance and poor long-term survival signal requirements for better patient preselection. An impaired DNA damage response (DDR) is a major chemosensitivity determinant. Comprising five pathways, DDR redundancy is complex and rarely studied alongside chemoresistance influence from mitochondrial dysfunction. We developed functional assays to monitor DDR and mitochondrial states and trialled this suite on patient explants.
Methods:
We profiled DDR and mitochondrial signatures in cultures from 16 primary-setting ovarian cancer patients receiving platinum chemotherapy. Explant signature relationships to patient progression-free (PFS) and overall survival (OS) were assessed by multiple statistical and machine-learning methods.
Results:
DR dysregulation was wide-ranging. Defective HR (HRD) and NHEJ were near-mutually exclusive. HRD patients (44%) had increased SSB abrogation. HR competence was associated with perturbed mitochondria (78% vs 57% HRD) while every relapse patient harboured dysfunctional mitochondria. DDR signatures classified explant platinum cytotoxicity and mitochondrial dysregulation. Importantly, explant signatures classified patient PFS and OS.
Conclusions:
Whilst individual pathway scores are mechanistically insufficient to describe resistance, holistic DDR and mitochondrial states accurately predict patient survival. Our assay suite demonstrates promise for translational chemosensitivity prediction.
... The genetic basis of hereditary LLS is not yet fully understood. With the advent of next generation sequencing (NGS) and the ability to test many cancer-predisposing genes simultaneously, many have been shown to cause inherited cases of LLS -MUTYH [22], genes involved in cell activity regulation (EXO1, POLD1, RCF1, and RPA1) [23], BUB1 and BUB3 [24], SETD2 [24], WRN [25], BARD1 [25], and other genes that promote genomic integrity [25]. ...
Background: Synchronous endometrial and ovarian cancer (SEOC) accounts for 50-70% of all synchronous gynecology cancers in women. Approximately 14% of SEOC cases are caused by Lynch syndrome (LS). The widespread introduction of "universal screening" at LS (all cases with CRC and all EC cases diagnosed before age 60 should be tested for MMR deficiency) has led to an increasing number of suspected LS cases- MMR-deficient tumors without germline mutation in the MMR genes. These cases are attributed to the so-called Lynch-like syndrome (LLS).
Case presentation: We present a case of LLS with a detected germline, likely pathogenic variant in the WRN gene. The proband was a woman diagnosed with SEOC at the age of 51 years. Histology of both tumors (endometrium and ovary) was endometroid and showed loss of MLH1 and PMS protein expression. Genetic testing by next generation sequencing (NGS) detected a germline mutation (in the heterozygous state) in the WRN gene - c.4109del, p.(Asn1370ThrfsTer23) in the proband.
Conclusions: The presented case contributes to the etiology of LLS and confirms the need for specific genetic testing, together with genetic counseling, in hereditary cancer syndromes. The use of combined information from clinicians, pathologists, genetic counselors, and data from NGS testing for cancer predisposition, clinical surveillance, and follow-up management in women with gynecology cancers, especially SEOC, could be improved.
... The penetration of MMR gene mutations does not reach 100%. Additionally, a small number of offspring or lack of progeny, especially in highly developed countries, may contribute to the lack of the fulfilled Amsterdam II criteria [25][26][27]. ...
... Nonpolyposis colorectal cancer (CRC)[25][26][27]. Abbreviations are as follows: HNPCChereditary nonpolyposis colorectal cancer; IHC-immunohistochemistry; LLS-Lynch-like syndrome; LS-Lynch syndrome; MMR-mismatch repair; MSI-microsatellite instability. ...
Cancer is one of the most common causes of death worldwide. A strong predisposition to cancer is generally only observed in colorectal cancer (5% of cases) and breast cancer (2% of cases). Colorectal cancer is the most common cancer with a strong genetic predisposition, but it includes dozens of various syndromes. This group includes familial adenomatous polyposis, attenuated familial adenomatous polyposis, MUTYH-associated polyposis, NTHL1-associated polyposis, Peutz–Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, Lynch syndrome, and Muir–Torre syndrome. The common symptom of all these diseases is a very high risk of colorectal cancer, but depending on the condition, their course is different in terms of age and range of cancer occurrence. The rate of cancer development is determined by its conditioning genes, too. Hereditary predispositions to cancer of the intestine are a group of symptoms of heterogeneous diseases, and their proper diagnosis is crucial for the appropriate management of patients and their successful treatment. Mutations of specific genes cause strong colorectal cancer predispositions. Identifying mutations of predisposing genes will support proper diagnosis and application of appropriate screening programs to avoid malignant neoplasm.
