32 / Heritable RUNX1 and GATA2 mutation with a very rare gene variant associated with AML-MDS: a case report and review of literature (original) (raw)
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Heritable GATA2 mutations associated with familial AML-MDS: a case report and review of literature
Journal of Hematology & Oncology, 2014
A 50-year-old woman was diagnosed with acute myeloid leukemia (AML). She has history of thrombocytopenia for 25 years and a significant family history of thrombocytopenia, affecting her mother, siblings and their children, as well as her own children. Both her mother and maternal aunt died from myelodysplastic syndrome (MDS). Additional genetic analysis was performed and identified two heterozygous missence mutations in the second zinc finger domain of GATA2 gene (p.Thr358Lys, and p.Leu359Val), occurring in cis on the same allele. Given the patient's family history and clinical manifestation, this was interpreted as an acute myeloid leukemia with heritable GATA2 mutations associated with familial AML-MDS. Germline GATA2 mutations are involved in a group of complex syndromes with overlapping clinical features of immune deficiency, lymphedema and propensity to acute myeloid leukemia or myelodysplastic syndrome (AML-MDS).
The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants
Nature Communications
The inclusion of familial myeloid malignancies as a separate disease entity in the revised WHO classification has renewed efforts to improve the recognition and management of this group of at risk individuals. Here we report a cohort of 86 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) families with 49 harboring germline variants in 16 previously defined loci (57%). Whole exome sequencing in a further 37 uncharacterized families (43%) allowed us to rationalize 65 new candidate loci, including genes mutated in rare hematological syndromes (ADA, GP6, IL17RA, PRF1 and SEC23B), reported in prior MDS/AML or inherited bone marrow failure series (DNAH9, NAPRT1 and SH2B3) or variants at novel loci (DHX34) that appear specific to inherited forms of myeloid malignancies. Altogether, our series of MDS/AML families offer novel insights into the etiology of myeloid malignancies and provide a framework to prioritize variants for inclusion into routine diagnostics and patient mana...
Leukemia, 2012
SNP array, 4 in total 80 cases (Supplementary Table 1). Only patients that had been treated within the Nordic Society for Pediatric Hematology and Oncology ALL 1992/2000 protocols were included in the survival analyses, comprising 48 cases including cases 2-4, 7 and 9. The probabilities of 5 years eventfree survival (pEFS) and overall survival (pOS) were calculated using the Kaplan-Meier method; groups were compared with the log rank test. There were no differences in gender distribution (P ¼ 0.343; two-tailed Fisher exact probability test), white blood cell count (P ¼ 0.803; two-sided Mann-Whitney test), or pEFS (partial 17q gains: 0.60, SE 0.22; no partial 17q gains: 0.78, SE 0.07; P ¼ 0.292) but patients with partial 17q gain were significantly older, with a median age of 6.5 years (range 3-13 years) at diagnosis compared with 3 years (range 1-16 years) for those without partial 17q gain (P ¼ 0.0128; two-sided Mann-Whitney test), and had a lower pOS (partial 17q gains: 0.60, SE 0.22; no partial 17q gains: 0.93, SE 0.04; P ¼ 0.0200). Although based on a small number of cases, this suggests that partial 17q gain is a marker for poor prognosis, in line with some previous reportsalbeit debated-of a poor outcome in i(17q)-positive high hyperdiploid childhood ALL. 2,3,12 To ascertain whether partial 17q gains may be more common in relapsing high hyperdiploid ALL, we investigated published series of SNP array data, finding that 1/6 (17%) cases reported by Mullighan et al. 13 had partial 17q gain at diagnosis versus 2/6 (33%) at relapse, and 6/16 (38%) versus 8/16 (50%) cases reported by Inthal et al. 14 On the other hand, none of the 11 relapse cases investigated by us displayed partial 17q gains. 15 Taken together, however, there may be an increased frequency of partial 17q gain in relapsing high hyperdiploid ALL already at the time of diagnosis, becoming even more common at relapse. In summary, we have shown that partial gain of 17q, arising through different types of chromosomal rearrangements, is a recurrent aberration in high hyperdiploid childhood ALL. The most likely pathogenetic outcome is dosage effects of genes on 17q, possibly in addition to an as yet unidentified mutation in 17p. Furthermore, the aberration may be associated with a decreased pOS and relapsing ALL.
Implications of NRAS mutations in AML: a study of 2502 patients
Blood, 2006
: a study of 2502 patients http://bloodjournal.hematologylibrary.org/content/107/10/3847.full.html Updated information and services can be found at: (795 articles) Oncogenes and Tumor Suppressors (4217 articles) Neoplasia (3722 articles) Clinical Trials and Observations Articles on similar topics can be found in the following Blood collections http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#repub\_requests
Germline mutations among Polish patients with acute myeloid leukemia
Hereditary Cancer in Clinical Practice, 2021
Background: A small but important proportion of patients (4-10 %) with AML have germline mutations. They can cause the development of AML at an earlier age, confer a higher risk of relapse or predispose to secondary leukemias, including therapy-related leukemias. The analysis of germline mutations in a patient and his/her family is also critical for the selection of suitable family donors if the patient is a candidate for hematopoietic stem cell transplantation (HSCT). Methods: 103 unrelated consecutive patients with de novo AML were enrolled in the study. Control group consisted of 103 persons from the general population. We performed NGS sequencing of bone marrow cells and buccal swabs DNA of six genes: CEBPA, DDX41, ETV6, TERT, GATA2, and IDH2 to detect germline pathogenic mutations. Results: In the investigated group, 49 variants were detected in six genes. 26 of them were somatic and 23 germline. Germline variants were detected in all six tested genes. Eight pathogenic germline mutations were detected in 7 AML patients, in three genes: CEBPA, ETV6, and IDH2. One patient had two pathogenic germinal mutations, one in ETV6 and one in CEBPA gene. We identified one novel pathogenic germline mutation in CEBPA gene. The difference in frequency of all pathogenic germline mutations between the tested (7.77 %) and control groups (0.97 %) was statistically significant (p = 0.046). In the tested group, the median age at AML diagnosis was 11 years lower in patients with pathogenic germline mutations than in patients without them (p = 0.028). Conclusions: We showed higher frequency of CEBPA, ETV6, and IDH2 germline mutations in AML patients than in control group, which confirms the role of these mutations in the development of AML. We also showed that the median age at the onset of AML in patients with pathogenic germline mutations is significantly lower than in patients without them.
Differential Analysis of Genetic, Epigenetic, and Cytogenetic Abnormalities in AML
International journal of genomics, 2017
Acute myeloid leukemia (AML) is a haematological malignancy characterized by the excessive proliferation of immature myeloid cells coupled with impaired differentiation. Many AML cases have been reported without any known cytogenetic abnormalities and carry no mutation in known AML-associated driver genes. In this study, 200 AML cases were selected from a publicly available cohort and differentially analyzed for genetic, epigenetic, and cytogenetic abnormalities. Three genes (FLT3, DNMT3A, and NPMc) are found to be predominantly mutated. We identified several aberrations to be associated with genome-wide methylation changes. These include Del (5q), T (15; 17), and NPMc mutations. Four aberrations-Del (5q), T (15; 17), T (9; 22), and T (9; 11)-are significantly associated with patient survival. Del (5q)-positive patients have an average survival of less than 1 year, whereas T (15; 17)-positive patients have a significantly better prognosis. Combining the methylation and mutation data...
Klinická onkologie, 2015
Background: In this work, we evaluated the incidence and prognostic value of several genetic aberrations in patients with a dia gnosis of acute myeloid leukemia (AML). Patients and Methods: We analysed 90 patients: 42 males (mean age 54.5 years) and 48 females (mean age 59 years), with AML. The genetics of all leukemia samples was studied using conventional cytogenetics, the interphase fl uorescence in situ hybridisation as well as the standardized RT-PCR protocol. Results: In 34.4% of patients, we detected at least one of the analysed genetic aberrations, except the CBFB-MYH11, which we did not detect. Translocation t(8;21)/ AML1-ETO was found in 4.4% of patients with a mean age of 45.4 years, while none of these patients was older than 55 years. Translocation t(15;17)/ PML-RARA was found in 5.5% of patients with a mean age of 52.6 years and an almost equal distribution between younger and older patients. The MLL gene rearrangements were found in 6.6% of patients, the-5/ 5q-and/ or-7/ 7q-aberrations in 7.7% of patients, while the most frequent genetic abnormality in our study was trisomy 8 (10%). Moreover, we found a favorable clinical outcome in patients expressing fusion genes AML1-ETO or PML-RARA in contrast to an adverse clinical outcome with few remissions and death in AML patients with MLL,-5q/-5 and-7q/ 7-. Finally, an intermediate prognosis was found in patients with trisomy 8. Conclusion: In this study, we found a good congruence with published literature on the incidence and prognostic value of several well established AML-associated genetic aberrations. This simple genetic-based classifi cation system helps us to identify patients with a favorable, intermediate or unfavorable prognosis and to treat them with the best currently available therapy. However, analysis of new genetically defi ned abnormalities in AML is necessary for development of better therapeutic strategies and/ or dia gnostics.