Prevalence mutací genu ATM je v naší populaci nízká. Zatímco jeho vliv na zvýšení incidence nádorů je znám, výběr jednotlivých léčebných modalit u pozitivně testovaných pacientek není většinou jednoznačný. Uvádíme přehled studií a kazuistik u pacientek s časným karcinomem prsu s mutacemi v proteinu ATM a jejich vliv na rozhodování v klinické praxi. Mutace v genu ATM riziko vzniku kontralaterálního tumoru prsu zvyšuje v případě jakékoli vzácné missense varianty ATM; nositelky této mutace, které obdržely radiační terapii pro svůj první karcinom prsu, měly významně zvýšené riziko rozvoje kontralaterálního karcinomu prsu ve srovnání s neexponovanými ženami (2,8-3,3*), pro jiné varianty to však není potvrzeno. Údaje o toxicitě radioterapie jsou rozporuplné, jasnou kontraindikací zůstávají jen mutace v genu TP53, jinak není jednoznačná kontraindikace ani pro mutaci skupiny genů BRCA. U missence variant ATM lze riziko toxicity předpokládat a prokázáno je i zvýšené riziko pozdní poradiační fibrózy. Další data jsou o riziku podávání antracyklinů jednak pro nižší účinek u některých variant a jednak pro vyšší toxicitu. V systémové protinádorové léčbě jsou preferovanou variantou taxany. Naplánování protinádorové léčby u pacientek s časným karcinomem prsu s mutací v genu ATM je záležitostí multidisciplinárního týmu, kde je klíčové vyjádření genetika. Adjuvantní radioterapii a adjuvantní léčbu antracykliny je vždy nutno indikovat uvážlivě s ohledem na poměr rizik.

The prevalence of ATM mutations in our population is low, while the importance of increasing the incirdence of tumors is known, the individual treatment modalities and their choice in a positively tested patient is mostly not clear. We present reviews of studies and case reports in patients with mutations in the ATM protein and their influence on decision-making in clinical practice in patients with early breast cancer. A mutation in the ATM gene increases the risk of developing a contralateral breast tumor in carriers of any rare ATM missense variant who received radiation therapy for a first breast cancer had an optimal risk of developing a contralateral breast cancer compared to unexposed women by 2.8-33*, for other variants it however, it is not confirmed. The data on the toxicity of radiotherapy are full, the only clear contraindications to the contradiction remain are mutations in the TP53 gene, otherwise there is no clear contraindication even for the BRCA group mutation, although the risk of toxicity can be assumed for the ATM missense variant mutation and the risk of late consultation fibrosis can also be proven. Other data are about the risk of administering anthracyclines, both because of a lower effect in some variants and because of higher toxicity. In systemic antitumor treatment, taxanes are the preferred variant. Planning antitumor treatment in patients with early breast cancer and with a mutation in the ATM gene is a matter of a multidisciplinary team, where the expression of genetics is key. Adjuvant radiotherapy and adjuvant anthracycline treatment must always be indicated judiciously with regard to the risk ratio.

• MeSH
• Radiotherapy, Adjuvant adverse effects   MeSH
• Anthracyclines adverse effects   therapeutic use   MeSH
• Ataxia Telangiectasia Mutated Proteins * analysis   radiation effects   MeSH
• Early Detection of Cancer MeSH
• Humans MeSH
• Breast Neoplasms * diagnosis   drug therapy   genetics   radiotherapy   MeSH
• Antineoplastic Protocols MeSH
• Radiation Tolerance MeSH
• Patient Care Team MeSH
• Check Tag
• Humans MeSH
• Female MeSH

Allosteric changes imposed by post-translational modifications regulate and differentiate the functions of proteins with intrinsic disorder regions. HDM2 is a hub protein with a large interactome and with different cellular functions. It is best known for its regulation of the p53 tumour suppressor. Under normal cellular conditions, HDM2 ubiquitinates and degrades p53 by the 26S proteasome but after DNA damage, HDM2 switches from a negative to a positive regulator of p53 by binding to p53 mRNA to promote translation of the p53 mRNA. This change in activity is governed by the ataxia telangiectasia mutated kinase via phosphorylation on serine 395 and is mimicked by the S395D phosphomimetic mutant. Here we have used different approaches to show that this event is accompanied by a specific change in the HDM2 structure that affects the HDM2 interactome, such as the N-termini HDM2-p53 protein-protein interaction. These data will give a better understanding of how HDM2 switches from a negative to a positive regulator of p53 and gain new insights into the control of the HDM2 structure and its interactome under different cellular conditions and help identify interphases as potential targets for new drug developments.

• MeSH
• Allosteric Regulation MeSH
• Amino Acid Motifs MeSH
• Ataxia Telangiectasia Mutated Proteins genetics   metabolism   MeSH
• Phosphorylation MeSH
• Humans MeSH
• Mutation, Missense * MeSH
• Tumor Suppressor Protein p53 genetics   metabolism   MeSH
• Proto-Oncogene Proteins c-mdm2 chemistry   genetics   metabolism   MeSH
• Protein Binding MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Doporučené postupy klinické péče o nosiče patogenních variant v klinicky relevantních nádorových predispozičních genech definují kroky primární a sekundární prevence, která by měla být těmto osobám ve vysokém riziku vzniku dědičných nádorů v ČR poskytnuta. Tvorba doporučení byla organizována pracovní skupinou onkogenetiky Společnosti lékařské genetiky a genomiky (SLG ČLS JEP) ve spolupráci se zástupci onkologie a onkogynekologie. Doporučené postupy vycházejí z aktuálních doporučení National Comprehensive Cancer Network (NCCN), European Society of Medical Oncology (ESMO) a zohledňují kapacitní možnosti našeho zdravotnictví.

The Guidelines for Clinical Practice for carriers of pathogenic variants in clinically relevant cancer predisposition genes define the steps of primary and secondary prevention that should be provided to these individuals at high risk of developing hereditary cancer in the Czech Republic. The drafting of the guidelines was organized by the Oncogenetics Working Group of the Society for Medical Genetics and Genomics of J. E. Purkyně Czech Medical Society (SLG ČLS JEP) in cooperation with the representatives of oncology and oncogynecology. The guidelines are based on the current recommendations of the National Comprehensive Cancer Network (NCCN), European Society of Medical Oncology (ESMO) and take into account the capacity of the Czech healthcare system.

• MeSH
• Ataxia Telangiectasia Mutated Proteins genetics   MeSH
• Checkpoint Kinase 2 genetics   MeSH
• Genetic Predisposition to Disease * MeSH
• Genes, BRCA1 MeSH
• Genes, BRCA2 MeSH
• Prostatic Neoplasms diagnosis   genetics   prevention & control   MeSH
• Breast Neoplasms diagnosis   genetics   prevention & control   MeSH
• Pancreatic Neoplasms diagnosis   genetics   prevention & control   MeSH
• Ovarian Neoplasms diagnosis   genetics   prevention & control   MeSH
• Primary Prevention methods   MeSH
• Fanconi Anemia Complementation Group N Protein genetics   MeSH
• Secondary Prevention methods   MeSH
• Practice Guidelines as Topic MeSH
• Germ-Line Mutation MeSH

ATM abnormalities are frequent in chronic lymphocytic leukemia and represent an important prognostic factor. Sole 11q deletion does not result in ATM inactivation by contrast to biallelic defects involving mutations. Therefore, the analysis of ATM mutations and their functional impact is crucial. In this study, we analyzed ATM mutations in predominantly high-risk patients using: i) resequencing microarray and direct sequencing; ii) Western blot for total ATM level; iii) functional test based on p21 gene induction after parallel treatment of leukemic cells with fludarabine and doxorubicin. ATM dysfunction leads to impaired p21 induction after doxorubicin exposure. We detected ATM mutation in 16% (22 of 140) of patients, and all mutated samples manifested demonstrable ATM defect (impaired p21 upregulation after doxorubicin and/or null protein level). Loss of ATM function in mutated samples was also evidenced through defective p53 pathway activation after ionizing radiation exposure. ATM mutation frequency was 34% in patients with 11q deletion, 4% in the TP53-defected group, and 8% in wild-type patients. Our functional test, convenient for routine use, showed high sensitivity (80%) and specificity (97%) for ATM mutations prediction. Only cells with ATM mutation, but not those with sole 11q deletion, were resistant to doxorubicin. As far as fludarabine is concerned, this difference was not observed. Interestingly, patients from both these groups experienced nearly identical time to first treatment. In conclusion, ATM mutations either alone or in combination with 11q deletion uniformly led to demonstrable ATM dysfunction in patients with chronic lymphocytic leukemia and mutation presence can be predicted by the functional test using doxorubicin.

• MeSH
• Ataxia Telangiectasia Mutated Proteins antagonists & inhibitors   genetics   physiology   MeSH
• Chromosome Deletion MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell diagnosis   genetics   pathology   MeSH
• Adult MeSH
• Doxorubicin pharmacology   MeSH
• Cohort Studies MeSH
• Leukocytes, Mononuclear drug effects   pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Chromosomes, Human, Pair 11 genetics   MeSH
• Mutation genetics   MeSH
• Retrospective Studies MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Cell Survival drug effects   physiology   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Ataxia-telangiectasia (A-T) is an autosomal-recessive disorder caused by pathogenic variants (PVs) of the ATM gene, predisposing children to hematological malignancies. We investigated their characteristics and outcomes to generate data-based treatment recommendations. In this multinational, observational study we report 202 patients aged ≤25 years with A-T and hematological malignancies from 25 countries. Ninety-one patients (45%) presented with mature B-cell lymphomas, 82 (41%) with acute lymphoblastic leukemia/lymphoma, 21 (10%) with Hodgkin lymphoma and 8 (4%) with other hematological malignancies. Four-year overall survival and event-free survival (EFS) were 50.8% (95% confidence interval [CI], 43.6-59.1) and 47.9% (95% CI 40.8-56.2), respectively. Cure rates have not significantly improved over the last four decades (P = .76). The major cause of treatment failure was treatment-related mortality (TRM) with a four-year cumulative incidence of 25.9% (95% CI, 19.5-32.4). Germ line ATM PVs were categorized as null or hypomorphic and patients with available genetic data (n = 110) were classified as having absent (n = 81) or residual (n = 29) ATM kinase activity. Four-year EFS was 39.4% (95% CI, 29-53.3) vs 78.7% (95% CI, 63.7-97.2), (P < .001), and TRM rates were 37.6% (95% CI, 26.4-48.7) vs 4.0% (95% CI, 0-11.8), (P = .017), for those with absent and residual ATM kinase activity, respectively. Absence of ATM kinase activity was independently associated with decreased EFS (HR = 0.362, 95% CI, 0.16-0.82; P = .009) and increased TRM (hazard ratio [HR] = 14.11, 95% CI, 1.36-146.31; P = .029). Patients with A-T and leukemia/lymphoma may benefit from deescalated therapy for patients with absent ATM kinase activity and near-standard therapy regimens for those with residual kinase activity.

• MeSH
• Ataxia Telangiectasia Mutated Proteins * genetics   MeSH
• Child MeSH
• Adult MeSH
• Hematologic Neoplasms * genetics   mortality   MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Child, Preschool MeSH
• Ataxia Telangiectasia * genetics   complications   mortality   MeSH
• Germ-Line Mutation * MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Observational Study MeSH

Mantle cell lymphoma (MCL) is characterized by the hallmark t(11;14)(q13;q32) translocation, leading to cyclin D1 over-expression. Additionally, disrupting the DNA damage response pathway through ATM or TP53 defects plays an important role in MCL pathogenesis. Using deep next-generation sequencing we analyzed the mutual composition of ATM and TP53 mutations in 72 MCL patients, and assessed their impact on progression-free survival (PFS) and overall survival (OS). Mutated ATM and TP53 alleles were found in 51% (37/72) and 22% (16/72) of the cases examined, respectively, with only three patients harboring mutations in both genes. Only a mutated TP53 gene was associated with the significantly reduced PFS and OS and the same output was observed when ATM and TP53 defective groups included also sole deletions 11q and 17p, respectively. Determining the exact ATM/p53 pathway dysfunction may influence the selection of MCL patients for innovative therapies based on the targeted inhibition of selected proteins.

• MeSH
• Ataxia Telangiectasia Mutated Proteins genetics   metabolism   MeSH
• Genetic Predisposition to Disease * MeSH
• Genetic Association Studies MeSH
• Humans MeSH
• Lymphoma, Mantle-Cell genetics   mortality   pathology   therapy   MeSH
• Mutation * MeSH
• Biomarkers, Tumor MeSH
• Tumor Suppressor Protein p53 genetics   metabolism   MeSH
• Prognosis MeSH
• Sequence Deletion MeSH
• SOXC Transcription Factors genetics   metabolism   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

PURPOSE: Germline missense variants of unknown significance in cancer-related genes are increasingly being identified with the expanding use of next-generation sequencing. The ataxia telangiectasia-mutated (ATM) gene on chromosome 11 has more than 1,000 germline missense variants of unknown significance and is a tumor suppressor. We aimed to determine if rare germline ATM variants are more frequent in chronic lymphocytic leukemia (CLL) compared with other hematologic malignancies and if they influence the clinical characteristics of CLL. METHODS: We identified 3,128 patients (including 825 patients with CLL) in our hematologic malignancy clinic who had received clinical-grade sequencing of the entire coding region of ATM. We ascertained the comparative frequencies of germline ATM variants in categories of hematologic neoplasms, and, in patients with CLL, we determined whether these variants affected CLL-associated characteristics such as somatic 11q deletion. RESULTS: Rare germline ATM variants are present in 24% of patients with CLL, significantly greater than that in patients with other lymphoid malignancies (16% prevalence), myeloid disease (15%), or no hematologic neoplasm (14%). Patients with CLL with germline ATM variants are younger at diagnosis and twice as likely to have 11q deletion. The ATM variant p.L2307F is present in 3% of patients with CLL, is associated with a three-fold increase in rates of somatic 11q deletion, and is a hypomorph in cell-based assays. CONCLUSION: Germline ATM variants cluster within CLL and affect the phenotype of CLL that develops, implying that some of these variants (such as ATM p.L2307F) have functional significance and should not be ignored. Further studies are needed to determine whether these variants affect the response to therapy or account for some of the inherited risk of CLL.

• MeSH
• Ataxia Telangiectasia Mutated Proteins * genetics   MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell * drug therapy   MeSH
• Humans MeSH
• Mutation MeSH
• Tumor Suppressor Proteins genetics   MeSH
• Protein Serine-Threonine Kinases genetics   therapeutic use   MeSH
• Cell Cycle Proteins genetics   MeSH
• Ataxia Telangiectasia MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

Germline pathogenic ATM (ataxia-telangiectasia mutated) variants are associated with the risk of multiple cancers; however, genetic testing reveals a large number of ATM variants of uncertain significance (VUS). Here, we studied germline ATM variants occurring in a real-world cohort of 336 patients with chronic lymphocytic leukaemia (CLL) and public cancer whole-exome/genome-sequencing datasets (445 CLL, 75 mantle cell lymphoma, 216 metastatic breast cancer, 140 lung cancer patients). We found that two-thirds of rare germline ATM variants are pathogenic (18%-50%) or VUS-predicted pathogenic (50%-82%), depending on cancer type and reaching a prevalence of up to 8%, and one-third are VUS-predicted benign. Patients with both pathogenic and VUS-predicted pathogenic variants, all heterozygous, mostly missense, are more predisposed to biallelic ATM inactivation by acquiring deletion (del)11q than patients without these variants, similar to patients with somatic ATM variants. A functional assay of ATM activity in primary CLL cells proved that VUS-predicted pathogenic ATM variants partially reduce ATM activity and concurrent del(11q) leads to complete loss of ATM activity. The rare germline variants were associated with reduced progression-free survival in CLL on novel agents, comparable to somatic ATM or TP53 disruptions. Our results highlight the need to determine the pathogenicity of VUS in clinically relevant genes such as ATM.

• MeSH
• Ataxia Telangiectasia Mutated Proteins * genetics   MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell * genetics   MeSH
• Cohort Studies MeSH
• Humans MeSH
• Lymphoma, Mantle-Cell genetics   MeSH
• Breast Neoplasms * genetics   MeSH
• Germ-Line Mutation MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

BACKGROUND: Radiation-induced intestinal injury (RIII) interrupts the scheduled processes of abdominal and pelvic radiotherapy (RT) and compromises the quality of life of cancer survivors. However, the specific regulators and mechanisms underlying the effects of RIII remain unknown. The biological effects of RT are caused primarily by DNA damage, and ataxia telangiectasia mutated (ATM) is a core protein of the DNA damage response (DDR). However, whether ATM is regulated by deubiquitination signaling remains unclear. METHODS: We established animal and cellular models of RIII. The effects of ubiquitin-specific protease 15 (USP15) on DNA damage and radion-induced intestinal injury were evaluated. Mass spectrometry analysis, truncation tests, and immunoprecipitation were used to identify USP15 as a binding partner of ATM and to investigate the ubiquitination of ATM. Finally, the relationship between the USP15/ATM axes was further determined via subsequent experiments. RESULTS: In this study, we identified the deubiquitylating enzyme USP15 as a regulator of DNA damage and the pathological progression of RIII. Irradiation upregulates the expression of USP15, whereas pharmacological inhibition of USP15 exacerbates radiation-induced DNA damage and RIII both in vivo and in vitro. Mechanistically, USP15 interacts with, deubiquitinates, and stabilises ATM via K48-linked deubiquitination. Notably, ATM overexpression blocks the effect of USP15 genetic inhibition on DNA damage and RIII progression. CONCLUSIONS: These findings describe ATM as a novel deubiquitination target of USP15 upon radiation-induced DNA damage and intestinal injury, and provides experimental support for USP15/ATM axis as a potential target for developing strategies that mitigate RIII.

• MeSH
• Ataxia Telangiectasia Mutated Proteins * metabolism   genetics   MeSH
• Humans MeSH
• Disease Models, Animal MeSH
• Mice MeSH
• DNA Damage * MeSH
• Radiation Injuries metabolism   genetics   MeSH
• Ubiquitin-Specific Proteases * metabolism   genetics   MeSH
• Intestines radiation effects   pathology   MeSH
• Ubiquitination * MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

We performed comprehensive molecular analysis of five cases of metastasizing uveal malignant melanoma (UM) (fresh-frozen samples) with an NGS panel of 73 genes. A likely pathogenic germline TP53 mutation c.760A > G (p.I254V) was found in two tumor samples and matched nontumor tissue. In three cases, pathogenic BAP1 mutation was detected together with germline missense variants of uncertain significance in ATM. All cases carried recurrent activating GNAQ or GNA11 mutation. Moreover, we analyzed samples from another 16 patients with primary UM by direct Sanger sequencing focusing only on TP53 coding region. No other germline TP53 mutation was detected in these samples. Germline TP53 mutation, usually associated with Li-Fraumeni syndrome, is a rare event in UM. To the best of our knowledge, only one family with germline TP53 mutation has previously been described. In our study, we detected TP53 mutation in two patients without known family relationship. The identification of germline aberrations in TP53 or BAP1 is important to identify patients with Li-Fraumeni syndrome or BAP1 cancer syndrome, which is also crucial for proper genetic counseling.

• MeSH
• Ataxia Telangiectasia Mutated Proteins genetics   MeSH
• Adult MeSH
• Genetic Predisposition to Disease MeSH
• Middle Aged MeSH
• Humans MeSH
• Melanoma genetics   pathology   MeSH
• Survival Rate MeSH
• Young Adult MeSH
• DNA Mutational Analysis MeSH
• Tumor Suppressor Proteins genetics   MeSH
• Tumor Suppressor Protein p53 genetics   MeSH
• Liver Neoplasms genetics   secondary   MeSH
• Uveal Neoplasms genetics   pathology   MeSH
• Prognosis MeSH
• Aged MeSH
• Ubiquitin Thiolesterase genetics   MeSH
• Germ-Line Mutation * MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH