dna mismatch repair system
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lynch syndrome (LS) is an autosomal dominant genetic disorder with incomplete penetration caused by a germline mutation in one of the genes of the deoxyribonucleic acid (DNA) mismatch repair system (MMR) namely: mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MHS6), post-meiotic segregation increased 1 homolog 2 (PMS2) or the EpCAM (Epithelial CellAdhesionMolecule) gene, which causes the inactivation of MSH2. Patients with this syndrome have a high relative risk of developing cancers at a young age, led by colorectal cancer (CRC) and endometrial cancer in females. The diagnosis is suspected when the patient’s personal and family history meets the Amsterdam or Bethesda criteria. It is guided by immunohistochemistry (IHC) and/or molecular biology that show loss of expression of one or more proteins of the MMR system and microsatellite instability on tumor DNA. In case of positive IHC and/or molecular biology, the patient should be referred to an oncogenetic consultation for a definitive diagnosis. We present the case of a 49-year-old patient who presented an anaemic syndrome in metrorrhagia. After a clinical, imaging, biological and anatomopathological examination, the diagnosis of LS was made.

Breast cancer (BC) is not a typical manifestation of Lynch syndrome. The existence and extent of excessive breast cancer risk in carriers of pathogenic mutations in the Lynch syndrome-associated genes (MLH1, MSH2, MSH6, PMS2) remains an open question. In addition, it is known that some of the breast neoplasms in patients with this syndrome are causally linked to the hereditary mutation, and some arise completely independently of the hereditary defect in the gene of the DNA mismatch repair system. In the case of accidental detection of such germline mutations in breast cancer patients, a thorough differential diagnosis between these categories of tumors is required, and the result of it is actionable, requiring changes in the management. This is a report of a case of breast cancer that arose in a carrier of a pathogenic mutation in the PMS2 gene, which was an accidental finding. The description of molecular genetic diagnostics is given: the microsatellite markers assessment and the detection of «loss of heterozygosity» allowed to classify the neoplasm in a category of cases that developed without any causal link to the patient's Lynch syndrome.

Background. Microsatellites are short tandem nucleotide repeats, the change in length of which plays a key roles in the pathogenesis of various malignant neoplasms. This change is called microsatellite instability. It is caused by aberrations in the genes of DNA mismatch repair system. Tumors with microsatellite instability are a special subtype regardless of location and are characterized by high sensitivity to immune checkpoint inhibitors.Objective – determination of characteristic clinical and morphological patterns of tumors of various localizations with microsatellite instability.Materials and methods. The study included 512 patients with malignant tumors of different localizations. Of these, 359 patients were diagnosed with colorectal cancer, 57 with uterine body cancer, and 57 with stomach cancer. Determination of the status of microsatellite instability was performed by a PCR-based method using 5 mononucleotide markers: BAT-25, BAT-26, NR-21, NR-24, NR-27.Results. The prevalence of microsatellite instability in colorectal cancer, uterine neoplasm and gastric cancer was 6.4; 22.8 and 1.75 %, respectively. Patients with MSI-positive colorectal cancer are characterized by yonger age (p = 0.023), right-sided localization of the tumor (p <0.0001), presence of multiple primary tumors (p = 0.0299), poorly differentiation (p = 0.0025), mucinous component (p <0.0001), tumor-infiltrating lymphocytes (p <0.0001) and Crohn-like reaction (p = 0.0006). Patients with uterine neoplasms with microsatellite instability are characterized by the presence of endometrial adenocarcinoma (p = 0.047), as well as the presence of tumor-infiltrating lymphocytes (p = 0.0022) and cribriform growth (p = 0.0011).Conclusion. A common pattern for colorectal cancer and uterine neoplasms is the presence of tumor-infiltrating lymphocytes. Certain clinical and morphological features of tumors of these localizations will more accurately identify candidates for microsatellite instability status determination for further immunotherapy.

Introduction: Hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) is an autosomal dominant genetic disease. The disease is caused by a mutation in one of four genes of the DNA mismatch repair system and increases the risk for various cancers, especially the uterine and colon cancers. The prevalence of this disease in the general population is about 1 in 500 and it causes about 2-3% of colorectal cancers. Lynch syndrome is diagnosed in two stages: 1) the person is suspected of having the disease (because a patient is unusually diagnosed with cancer at a young age), and 2) evidence of incomplete repair defect is seen in the tumor tissue (microsatellite instability). The detection of a pathogenic mutation confirms the diagnosis in these patients and enables predictive testing for other family members. Diagnostic evaluation of Lynch syndrome should be performed with appropriate genetic counseling. Systemic colonoscopy surveillance could identify colon cancers at an earlier stage before patients present clinical symptoms. Conclusion: Although many studies have been done, but the benefits of an individualized, risk-adapted surveillance strategy are still unclear. Until this is identified, Lynch syndrome patients and healthy carriers with causative mutations should be monitored by annual colonoscopy and annual gynecological examination (for women).  

Microsatellite instability (MSI) is a tumor phenotype related to a deficient DNA mismatch repair system (dMMR). This phenotype, observed in 5% of metastatic mCRC but 10–18% of localized CRC, is associated with high tumor mutational burden with highly immunogenic neoantigens. It has emerged as a major predictive biomarker for the efficacy of ICIs. In this review, we will present a comprehensive overview of the literature concerning the efficacy of ICIs in MSI/dMMR mCRC, with a focus on new developments in first-line metastatic setting. Then, we will present current and future challenges of immuno-oncology for patients with MSI/dMMR metastatic CRC.

Cyclin-dependent kinases (CDKs) are crucial regulators of the eukaryotic cell cycle. The critical role of CDK2 in the progression of meiosis was demonstrated in a single mammalian species, the mouse. We used immunocytochemistry to study the localization of CDK2 during meiosis in seven rodent species that possess hetero- and homomorphic male sex chromosomes. To compare the distribution of CDK2 in XY and XX male sex chromosomes, we performed multi-round immunostaining of a number of marker proteins in meiotic chromosomes of the rat and subterranean mole voles. Antibodies to the following proteins were used: RAD51, a member of the double-stranded DNA break repair machinery; MLH1, a component of the DNA mismatch repair system; and SUN1, which is involved in the connection between the meiotic telomeres and nuclear envelope, alongside the synaptic protein SYCP3 and kinetochore marker CREST. Using an enhanced protocol, we were able to assess the distribution of as many as four separate proteins in the same meiotic cell. We showed that during prophase I, CDK2 localizes to telomeric and interstitial regions of autosomes in all species investigated (rat, vole, hamster, subterranean mole voles, and mole rats). In sex bivalents following synaptic specificity, the CDK2 signals were distributed in three different modes. In the XY bivalent in the rat and mole rat, we detected numerous CDK2 signals in asynaptic regions and a single CDK2 focus on synaptic segments, similar to the mouse sex chromosomes. In the mole voles, which have unique XX sex chromosomes in males, CDK2 signals were nevertheless distributed similarly to the rat XY sex chromosomes. In the vole, sex chromosomes did not synapse, but demonstrated CDK2 signals of varying intensity, similar to the rat X and Y chromosomes. In female mole voles, the XX bivalent had CDK2 pattern similar to autosomes of all species. In the hamster, CDK2 signals were revealed in telomeric regions in the short synaptic segment of the sex bivalent. We found that CDK2 signals colocalize with SUN1 and MLH1 signals in meiotic chromosomes in rats and mole voles, similar to the mouse. The difference in CDK2 manifestation at the prophase I sex chromosomes can be considered an example of the rapid chromosome evolution in mammals.

Uterine cancer is one of the few cancers with an increasing incidence and mortality rate in developed countries, which partly reflects the increasing prevalence of obesity and aging of the female population. Despite the fact that uterine cancer is usually diagnosed when lesions have affected only the uterine body, searching for new treatment regimens for advanced disease remains highly relevant due to unsatisfactory results of chemotherapy and high mortality among women with stage III–IV uterine cancer. In this article, we discuss the main aspects of using lenvatinib and pembrolizumab that have been approved by the US Food and Drug Administration (FDA), Australian Therapeutic Goods Administration (TGA), and Ministry of Health of Canada (HC). The lenvatinib + pembrolizumab scheme showed its efficacy (38.3 % objective responses) and safety (grade III and IV adverse events were reported in 83 (66.9%) of 124 patients) in 94 patients with advanced endometrial cancer whose tumors did not show signs of microsatellite instability (MSI) and defective DNA mismatch repair system. In 25 (69 %) patients who responded to treatment, the time to response was more than 6 months. In this article, we also report a case of progressive uterine cancer in a patient, who benefited from therapy with the combination of lenvatinib and pembrolizumab. We also describe adverse events of such therapy and ways of their management.

AbstractThe development of programmed cell death-1 inhibitor (PD-1) has shed light on the treatment of tumors with deficiencies in DNA mismatch repair system or microsatellite instability (dMMR/MSI). However, predicting the subset in this group that will benefit from PD-1 blockade remains a challenge. In this study, we aimed to investigate the relationship between the degree of microsatellite instability and the responses to anti-PD-1 immunotherapy. 33 patients with colorectal adenocarcinoma who had a known MSI status and received anti-PD-1 immunotherapy were included. PCR results for MSI of the whole cohort were collected and treatment response was evaluated. Our data indicated that objective response rate (ORR) in instability-high group (instability loci ≥ 3) was significantly higher than ORR in instability-intermediate group (13/16 versus 6/17, P = 0.008). Besides, patients in instability-high group had significant longer progression-free survival (log-rank test, P = 0.004), and a significant increase in T lymphocyte infiltration and cytolytic activity in tumors. Future study might implement the intensity of microsatellite instability for more delicate selection for anti-PD-1 therapy in patient with dMMR/MSI-H tumors.