Patient with ataxia telangiectasia undergoing elective staging laparoscopy: a case report and literature review

Ataxia telangiectasia is a rare autosomal recessive condition which develops due to a mutation in the ataxia telangiectasia mutated gene (ATM gene). As a result of this mutation, the ability of the DNA to undergo repair is undermined. The resulting cellular demise is responsible for the diverse presentation of the clinical condition. Neurological symptoms such as cerebellar ataxia, abnormal eye movements and malignancies occur commonly. Immunodeficiency predisposes these patients to recurrent infections. Perioperative management of patients with this rare condition can be associated with increased morbidity. Therefore, it is recommended that patients with ataxia telangiectasia should be managed in a multidisciplinary center, under the supervision of senior clinicians who have the insight into the clinical needs of such patients. We report herein, the perioperative management of a patient with Ataxia telangiectasia undergoing laparoscopic procedure. Continuous....

A rare case of hairy cell leukemia variant with ATM nonsense mutation and ATM deletion, resulting in complete loss of function

Introduction/Objective Hairy cell leukemia variant (HCL-v) is a rare B cell lymphoproliferative disorder. Although HCL- v shares some overlapping features with classic HCL, it lacks the characteristic immune-morphology and pathogenic BRAF V600E mutation seen in classic HCL and recognized as a distinct entity in the 2017 WHO classification. Approximately half of HCL-v harbors MAPK2 mutation and one third has TP53 mutation. Cytogenetic abnormalities include gain of chromosome 5, loss of chromosome 7q, and deletion of 17p13/TP53 and 11q/22 ATM gene Methods/Case Report We report a case of HCL-v with total loss of ATM gene function. A 71-year-old male with splenomegaly presented with an outside diagnosis of splenic marginal zone lymphoma and underwent splenectomy. Flow cytometry on spleen demonstrated mature clonal B lymphoid cells and was positive for CD11c and CD103. However, unlike classical HCL, it was CD25 negative, which supports the diagnosis of HCL-v. Sections of spleen revealed most of the red pulp replaced by hairy cell leukemic infiltrate with minimal preservation of the normal lymphoid stroma. Peripheral blood smear showed atypical lymphocytosis with prominent nucleoli but most lacking circumferential shaggy contours, seen in classic HCL. Cytogenetic analysis identified a deletion in chromosome 11(q13q23), which deletes the ATM gene. NGS analysis demonstrated a nonsense variant in ATM (p. E888*). No significant sequence variants were identified in BRAF, MAP2K1 or TP53. This is the first case report of HCL-v with a deletion as well as a non-sense mutation in the ATM gene. ATM gene belongs to the PI3/PI4-kinase family, and is an important cell cycle checkpoint kinase that phosphorylates downstream proteins, including TP53, BRCA1 etc. Although detection of the ATM has therapeutic application for prostate cancer patient for poly [ADP]-ribose polymerase inhibitor treatment, the significance of loss of ATM function in hairy cell leukemia variant is unknown. Results (if a Case Study enter NA) N/A Conclusion In conclusion, our case demonstrates that molecular test in hairy cell leukemia variant can be helpful for confirming the diagnosis as well as providing predictive information for potential target therapy. In our case, lack of MAP2K1 mutation precludes the patient for targeted therapy. In addition, the finding of novel mutation might help to understand the molecular pathogenesis in this rare entity.

The prevalence of ataxia telangiectasia mutated (ATM) variants in patients with breast cancer patients: a systematic review and meta-analysis

Breast cancer is the most common cancer in women, and its high mortality has become one of the biggest health problems globally. Several studies have reported an association between breast cancer and ATM gene variants. This study aimed to demonstrate and analyze the relationship between ATM gene polymorphisms and breast cancer prevalence rate. A systematic literature review was undertaken using the following databases: Medline (PubMed), Web of sciences, Scopus, EMBASE, Cochrane, Ovid, and CINHAL to retrieve all cross-sectional studies between January 1990 and January 2020, which had reported the frequency of ATM variants in patients with breast cancer. A random-effects model was applied to calculate the pooled prevalence with a 95% confidence interval. The pooled prevalence of ATM variants in patients with breast cancer was 7% (95% CI: 5−8%). Also, the pooled estimate based on type of variants was 6% (95% CI: 4−8%; I square: 94%; P: 0.00) for total variants¸ 0% (95% CI: 0−1%; I square: 0%; P: 0.59) for deletion variants, 12% (95% CI: 7−18%; I square: 99%; P: 0.00) for substitution variants, and 2% (95% CI: 4−9%; I square: 67%; P: 0.08) for insertion variants. This meta-analysis showed that there is a significant relationship between ATM variants in breast cancer patients. Further studies are required to determine which of the variants of the ATM gene are associated with BRCA mutations.

BCL-2, CDKN1A and ATM gene methylation in chronically exposed individuals

DNA methylation is the most common epigenetic modification, caused by ionizing radiation. There may be both hypermethylation, which suppresses transcription of gene promoter regions, and hypomethylation, resulting in gene activation. Both mechanisms may be involved in carcinogenesis. The study was aimed to assess methylation status of CpG islands in the protective system BCL-2, CDKN1A and ATM gene promoters in the peripheral blood cells of the chronically exposed individuals, living in the villages, located along the Techa River, over a long-term period. Methylation of BCL-2, CDKN1A and ATM gene promoter regions in 68 residents of the villages, located along the Techa River (Chelyabinsk region), was assessed by the real-time methylation-specific PCR. The group of exposed individuals included 54 people with accumulated dose to red bone marrow within the range of 0.09–3.51 Gy. The comparison group included 14 people, living in similar economic and social environment, with the dose to red bone marrow, accumulated during the whole life, not exceeding 70 mGy. The pilot study of exposed individuals over a long period of time after chronic low-dose radiation exposure revealed no significant changes in methylation levels of CpG islands in the CDKN1A, BCL-2, ATM gene promoter regions compared to the comparison group. None were revealed in the dose subgroups “87–994 mGy” and “over 1000 mGy”.

Cisplatin Resistance in Epstein–Barr-Virus-Associated Gastric Carcinoma Acquired through ATM Methylation

Epstein–Barr-virus-associated gastric carcinoma (EBVaGC), first reported in 1992, currently accounts for 10% of all gastric carcinoma worldwide. EBVaGC has unique DNA hypermethylation phenotypes that allow for higher proportions of DNA methylation than any other gastric cancer. CpG islands in the gene promoter region are one of the major regions in which DNA methylation controls gene transcription. Despite cisplatin-based chemotherapy being one of the standard treatment regimens for advanced gastric cancer, including EBVaGC, cisplatin alone or in combination with 5-fluorouracil has been limited by its less potent anticancer activity and the occurrence of cisplatin resistance. Accordingly, the current study evaluated the anticancer activities of a combination of cisplatin and 5-Azacytidine (5-AZA) against EBVaGC. Our findings showed that cisplatin upregulated the DNMT3A gene, whereas shRNA-targeted removal of DNMT3A mRNA contributed to cisplatin-mediated EBV lytic reactivation. Moreover, the removal of DNMT3A mRNA upregulated the ATM gene through DNA demethylation on the ATM promoter. Furthermore, CRISPR/Cas9-targeted removal of the ATM gene resulted in significantly reduced cell susceptibility and EBV lytic reactivation by a combination of cisplatin and DNMT3A inhibitor 5-AZA. Finally, 5-AZA exhibited a synergistic effect with cisplatin in anti-EBV and anti-EBVaGC activities by increasing drug susceptibility and EBV lytic reactivation. The aforementioned results suggest that cisplatin combined with DNA methylation inhibitors could be a novel therapeutic approach for EBVaGC.

Germline Mutations Including the Rare Pathogenic Variant c.3206delC in the ATM Gene Cause Ataxia Teleangiectasia-Associated Primary Central Nervous System Lymphoma

We here report the case of a 2-year-old patient with a primary central nervous system lymphoma of B-cell origin. Due to their past medical history of repeated respiratory tract infections and the marked chemotherapy-associated toxicity and infectious comorbidity, we suspected that the patient also suffered from an inherited immune deficiency disorder. Despite the lack of classical pathognomonic symptoms for ataxia teleangiectasia and missing evidence for a cancer predisposition syndrome in the family, genetic testing identified biallelic germline mutations, including the rare pathogenic variant c.3206delC (p.Pro1069Leufs*2), in the ataxia telangiectasia-mutated (ATM) gene. The case highlights the importance of searching for immune deficiency disorders associated with primary central nervous system lymphoma before treatment initiation and the urgent need to develop novel treatment strategies for cancer patients with underlying immunodeficiency syndromes.

The ATM Gene in Breast Cancer: Its Relevance in Clinical Practice

Molecular alterations of the Ataxia-telangiectasia (AT) gene are frequently detected in breast cancer (BC), with an incidence ranging up to 40%. The mutated form, the Ataxia-telangiectasia mutated (ATM) gene, is involved in cell cycle control, apoptosis, oxidative stress, and telomere maintenance, and its role as a risk factor for cancer development is well established. Recent studies have confirmed that some variants of ATM are associated with an increased risk of BC development and a worse prognosis. Thus, many patients harboring ATM mutations develop intermediate- and high-grade disease, and there is a higher rate of lymph node metastatic involvement. The evidence concerning a correlation of ATM gene mutations and the efficacy of therapeutic strategies in BC management are controversial. In fact, ATM mutations may sensitize cancer cells to platinum-derived drugs, as BRCA1/2 mutations do, whereas their implications in objective responses to hormonal therapy or target-based agents are not well defined. Herein, we conducted a review of the role of ATM gene mutations in BC development, prognosis, and different treatment strategies.