The MRE11, RAD50, and NBN genes encode for the nuclear MRN protein complex, which senses the DNA double strand breaks and initiates the DNA repair. The MRN complex also participates in the activation of ATM kinase, which coordinates DNA repair with the p53-dependent cell cycle checkpoint arrest. Carriers of homozygous germline pathogenic variants in the MRN complex genes or compound heterozygotes develop phenotypically distinct rare autosomal recessive syndromes characterized by chromosomal instability and neurological symptoms. Heterozygous germline alterations in the MRN complex genes have been associated with a poorly-specified predisposition to various cancer types. Somatic alterations in the MRN complex genes may represent valuable predictive and prognostic biomarkers in cancer patients. MRN complex genes have been targeted in several next-generation sequencing panels for cancer and neurological disorders, but interpretation of the identified alterations is challenging due to the complexity of MRN complex function in the DNA damage response. In this review, we outline the structural characteristics of the MRE11, RAD50 and NBN proteins, the assembly and functions of the MRN complex from the perspective of clinical interpretation of germline and somatic alterations in the MRE11, RAD50 and NBN genes.

• Klíčová slova
• ATLD, DNA repair, MRE11, NBN, NBS, NBSLD, NGS, RAD50, TP53, hereditary cancer syndromes, variant interpretation,
• MeSH
• ATM protein genetika   metabolismus   MeSH
• DNA vazebné proteiny genetika   metabolismus   MeSH
• enzymy opravy DNA genetika   metabolismus   MeSH
• homologní protein MRE11 genetika   metabolismus   MeSH
• hydrolasy působící na anhydridy kyselin genetika   metabolismus   MeSH
• jaderné proteiny genetika   metabolismus   MeSH
• lidé MeSH
• nádorové supresorové proteiny * genetika   MeSH
• oprava DNA genetika   MeSH
• proteiny buněčného cyklu * metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• ATM protein MeSH
• DNA vazebné proteiny MeSH
• enzymy opravy DNA MeSH
• homologní protein MRE11 MeSH
• hydrolasy působící na anhydridy kyselin MeSH
• jaderné proteiny MeSH
• nádorové supresorové proteiny * MeSH
• NBN protein, human MeSH Prohlížeč
• proteiny buněčného cyklu * MeSH
• RAD50 protein, human MeSH Prohlížeč

BACKGROUND: Nijmegen breakage syndrome (NBS) is an autosomal-recessive chromosome instability disorder characterized by, among others, hypersensitivity to X-irradiation and an exceptionally high risk for lymphoid malignancy. The vast majority of NBS patients is homozygous for a common Slavic founder mutation, c.657del5, of the NBN gene, which is involved in the repair of DNA double-strand breaks (DSBs). The founder mutation also predisposes heterozygous carriers to cancer, apparently however, with a higher risk in the Czech Republic/Slovakia (CS) than in Poland. AIM: To examine whether the age of cancer manifestation and cancer death of NBN homozygotes is different between probands from CS and Poland. METHODS: The study is restricted to probands born until 1989, before replacement of the communist regime by a democratic system in CS and Poland, and a substantial transition of the health care systems. Moreover, all patients were recruited without knowledge of their genetic status since the NBN gene was not identified until 1998. RESULTS: Here, we show that cancer manifestation of NBN homozygotes is at a significantly earlier age in probands from CS than from Poland. This is explained by the difference in natural and medical radiation exposure, though within the permissible dosage. CONCLUSION: It is reasonable to assume that this finding also sheds light on the higher cancer risk of NBN heterozygotes in CS than in Poland. This has implications for genetic counseling and individualized medicine also of probands with other DNA repair defects.

• Klíčová slova
• NBS, age of cancer manifestation, cancer risk of heterozygotes, environmental and medical exposure to ionizing radiation,
• MeSH
• heterozygot MeSH
• jaderné proteiny genetika   MeSH
• lidé MeSH
• mutace MeSH
• nádory * MeSH
• proteiny buněčného cyklu genetika   MeSH
• syndrom Nijmegen breakage * genetika   patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• jaderné proteiny MeSH
• NBN protein, human MeSH Prohlížeč
• proteiny buněčného cyklu MeSH

Hepatocellular carcinoma (HCC) mainly stems from liver cirrhosis and its genetic predisposition is believed to be rare. However, two recent studies describe pathogenic/likely pathogenic germline variants (PV) in cancer-predisposition genes (CPG). As the risk of de novo tumors might be increased in PV carriers, especially in immunosuppressed patients after a liver transplantation, we analyzed the prevalence of germline CPG variants in HCC patients considered for liver transplantation. Using the panel NGS targeting 226 CPGs, we analyzed germline DNA from 334 Czech HCC patients and 1662 population-matched controls. We identified 48 PVs in 35 genes in 47/334 patients (14.1%). However, only 7/334 (2.1%) patients carried a PV in an established CPG (PMS2, 4×NBN, FH or RET). Only the PV carriers in two MRN complex genes (NBN and RAD50) were significantly more frequent among patients over controls. We found no differences in clinicopathological characteristics between carriers and non-carriers. Our study indicated that the genetic component of HCC is rare. The HCC diagnosis itself does not meet criteria for routine germline CPG genetic testing. However, a low proportion of PV carriers may benefit from a tailored follow-up or targeted therapy and germline testing could be considered in liver transplant recipients.

• Klíčová slova
• MRN complex, genetic predisposition, germline mutation, hepatocellular carcinoma, liver cirrhosis, liver transplantation, panel sequencing,
• Publikační typ
• časopisecké články MeSH

Patients with double stranded DNA repair disorders (DNARDs) (Ataxia Telangiectasia (AT) and Nijmegen Breakage syndrome (NBS)) are at a very high risk for developing hematological malignancies in the first two decades of life. The most common neoplasms are T-cell lymphoblastic malignancies (T-cell ALL and T-cell LBL) and diffuse large B cell lymphoma (DLBCL). Treatment of these patients is challenging due to severe complications of the repair disorder itself (e.g., congenital defects, progressive movement disorders, immunological disturbances and progressive lung disease) and excessive toxicity resulting from chemotherapeutic treatment. Frequent complications during treatment for malignancies are deterioration of pre-existing lung disease, neurological complications, severe mucositis, life threating infections and feeding difficulties leading to significant malnutrition. These complications make modifications to commonly used treatment protocols necessary in almost all patients. Considering the rarity of DNARDs it is difficult for individual physicians to obtain sufficient experience in treating these vulnerable patients. Therefore, a team of experts assembled all available knowledge and translated this information into best available evidence-based treatment recommendations.

• Klíčová slova
• Ataxia Telangiectasia, DNA repair disorder, Nijmegen breakage syndrome, clinical management, leukemia, lymphoma,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The vast majority of patients with Nijmegen Breakage Syndrome (NBS) are of Slavic origin and carry a deleterious deletion (c.657del5; rs587776650) in the NBN gene on chromosome 8q21. This mutation is essentially confined to Slavic populations and may thus be considered a Slavic founder mutation. Notably, not a single parenthood of a homozygous c.657del5 carrier has been reported to date, while heterozygous carriers do reproduce but have an increased cancer risk. These observations seem to conflict with the considerable carrier frequency of c.657del5 of 0.5% to 1% as observed in different Slavic populations because deleterious mutations would be eliminated quite rapidly by purifying selection. Therefore, we propose that heterozygous c.657del5 carriers have increased reproductive success, i.e., that the mutation confers heterozygote advantage. In fact, in our cohort study of the reproductive history of 24 NBS pedigrees from the Czech Republic, we observed that female carriers gave birth to more children on average than female non-carriers, while no such reproductive differences were observed for males. We also estimate that c.657del5 likely occurred less than 300 generations ago, thus supporting the view that the original mutation predated the historic split and subsequent spread of the 'Slavic people'. We surmise that the higher fertility of female c.657del5 carriers reflects a lower miscarriage rate in these women, thereby reflecting the role of the NBN gene product, nibrin, in the repair of DNA double strand breaks and their processing in immune gene rearrangements, telomere maintenance, and meiotic recombination, akin to the previously described role of the DNA repair genes BRCA1 and BRCA2.

• MeSH
• detekce genetických nosičů MeSH
• dospělí MeSH
• efekt zakladatele * MeSH
• haplotypy MeSH
• jaderné proteiny genetika   MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace * MeSH
• oprava DNA MeSH
• poškození DNA MeSH
• proteiny buněčného cyklu genetika   MeSH
• rozmnožování genetika   MeSH
• syndrom Nijmegen breakage etnologie   genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH
• Slovenská republika MeSH
• Názvy látek
• jaderné proteiny MeSH
• NBN protein, human MeSH Prohlížeč
• proteiny buněčného cyklu MeSH

BACKGROUND: Nijmegen breakage syndrome (NBS) is an autosomal recessive chromosomal instability disorder with hypersensitivity to ionising radiation. The clinical phenotype is characterised by congenital microcephaly, mild dysmorphic facial appearance, growth retardation, immunodeficiency, and greatly increased risk for lymphoreticular malignancy. Most NBS patients are of Slavic origin and homozygous for the founder mutation 657del5. The frequency of 657del5 heterozygotes in the Czech population is 1:150. Recently, another NBS1 mutation, 643C>T(R215W), with uncertain pathogenicity was found to have higher frequency among tumour patients of Slavic origin than in controls. This alteration results in the substitution of the basic amino acid arginine with the non-polar tryptophan and thus could potentially interfere with the function of the NBS1 protein, nibrin. METHODS AND RESULTS: Children with congenital microcephaly are routinely tested for the 657del5 mutation in the Czech and Slovak Republics. Here, we describe for the first time a severe form of NBS without chromosomal instability in monozygotic twin brothers with profound congenital microcephaly and developmental delay who are compound heterozygotes for the 657del5 and 643C>T(R215W) NBS1 mutations. Both children showed reduced expression of full length nibrin when compared with a control and a heterozygote for the 657del5 mutation. Radiation response processes such as phosphorylation of ATM and phosphorylation/stabilisation of p53, which are promoted by NBS1, are strongly reduced in cells from these patients. CONCLUSIONS: Interestingly, the patients are more severely affected than classical NBS patients. Consequently, we postulate that homozygosity for the 643C>T(R215W) mutation will also lead to a, possibly very, severe disease phenotype.

• MeSH
• chromozomální nestabilita MeSH
• fosforylace MeSH
• geny recesivní MeSH
• jaderné proteiny genetika   metabolismus   MeSH
• lidé MeSH
• mapování chromozomů * MeSH
• mikrocefalie genetika   MeSH
• mutace * MeSH
• nemoci u dvojčat MeSH
• polymerázová řetězová reakce MeSH
• proteiny buněčného cyklu genetika   metabolismus   MeSH
• substituce aminokyselin MeSH
• syndrom Nijmegen breakage genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• jaderné proteiny MeSH
• NBN protein, human MeSH Prohlížeč
• proteiny buněčného cyklu MeSH