Terezinha de Jesus Marques-Salles

Association between the MTHFR A1298C polymorphism and increased risk of acute myeloid leukemia in Brazilian children

Methylenetetrahydrofolate reductase (MTHFR) is an essential enzyme in the metabolism of folate. The presence of polymorphisms that reduce the activity of MTHFR has been linked to the multifactor process of development of acute leukemia. A case control study was conducted on Brazilian children in different regions of the country with the aim of investigating the role of MTHFR C677T and A1298C polymorphisms as risk factors in the development of acute myeloid leukemia (AML). We used the polymerase chain reaction restriction fragment length polymorphism method to genotyping 182 AML and 315 healthy individuals. The genotype 677 CT was associated with decreased risk [odds ratio (OR), 0.37; confidence interval (CI) 95%, 0.14 – 0.92], whereas 1298 AC genotype was linked with an increased risk [OR, 2.90; CI 95%, 1.26 – 6.71] of developing AML in non-white children. Further epidemiological study is needed to unravel the complex multiple gene-environment interactions in the role of the AML leukemogenesis.

Banding and molecular cytogenetic studies detected a CBFB-MYH11 fusion gene that appeared as abnormal chromosomes 1 and 16 in a baby with acute myeloid leukemia FAB M4-Eo.

The acute myeloid leukemia (AML) subtype M4Eo occurs in 5% of all AML cases and is usually associated with either an inv(16)(p13.1q22) or a t(16;16)(p13.1;q22) chromosomal abnormality. At the molecular level, these abnormalities generate a CBFB-MYH11 fusion gene. Patients with this genetic alteration are usually assigned to a low-risk group and thus receive standard chemotherapy. AML-M4Eo is rarely found in infants. We describe clinical, conventional banding, and molecular cytogenetic data for a 12-month-old baby with AML-M4Eo and a chimeric CBFB-MYH11 fusion gene masked by a novel rearrangement between chromosomes 1 and 16. This rearrangement characterizes a new type of inv(16)(p13.1q22) masked by a chromosome translocation.

Polymorphisms Involved in Folate Metabolism Pathways and the Risk of the Development of Childhood Acute Leukemia

OBJECTIVE Polymorphisms that reduce the activity of reduced folate carrier (RFC) and methylenetetrahydrofolate reductase (MTHFR) and double (2R2R) or triple (3R3R) 28-bp tandem repeats in the promoter region of thymidylate synthase (TS) have been associated with the risk of childhood acute leukemia (AL). A case-control genotyping study was conducted in Brazilian children with the aim of investigating RFC, MTHFR, and TS polymorphisms as risk factors. METHODS The polymerase chain reaction-restriction fragment length polymorphism method was employed in 177 AL cases and 390 controls. RESULTS The presence of the mutant 1298C, also RFC 80A, was linked to a decreased risk of developing acute lymphoid leukemia (ALL) (odds ratio (OR)=0.46, 95% confidence interval (CI)=0.30-071 and OR=0.51, 95% CI=0.28-0.0.93, respectively). CONCLUSIONS The genotype 677 CT was associated with increased risk of developing ALL (OR=1.6, 95% CI=1.1-2.7). Further epidemiological study is needed to unravel the role of complex multiple gene-environment interactions in leukemogenesis.

A rare cryptic and complex rearrangement leading to MLL-MLLT10 gene fusion masked by del(10)(p12) in a child with acute monoblastic leukemia (AML-M5)

Acute myeloid leukemia (AML) in young children, defined as hose younger than 24 months of age, occurs in 3–5% of all peditric leukemias. Rearrangements involving the MLL gene, located n the 11q23 region, are between the most common cytogenetic berrations found in M4 or M5 AML subtypes. MLL rearrangement s highly heterogeneous with more than 60 different fusion parters described to date. An association between the type of MLL earrangement and prognosis has been reported [1]. Most of the MLL rearrangements result from simple reciproal translocations. However, rearrangements between MLL and LLT10 gene (also AF10) on chromosome 10p12 frequently result rom complex chromosomal rearrangement. Several types of chroosomal rearrangements involving three or more chromosomal reaks, such as inversions and insertions, have been reported. The atter occurs because MLL is transcribed from centromere to telomre and MLLT10 from telomere to centromere [2]. In some instances the accurate recognition of the t(10;11) via anding cytogenetics methods is difficult. Thus, more sophistiated molecular approaches such as multicolor fluorescence in situ ybridization (FISH), specific RT-PCR, and/or genomic PCR methds are required to uncover these MLL rearrangements, especially nusual, complex, and/or cryptic rearrangements [3,4]. Here, we escribe a rare case of cryptic insertion of chromosome 10 mateial in a derivative chromosome 11 in which the combination of everal molecular approaches was decisive to reveal the nature of complex and cryptic rearrangement leading to the MLL-MLLT10 ene fusion in a child with AML-M5.

A case of childhood acute myeloid leukemia AML (M5) with a neocentric chromosome neo(1)(qter→q23∼24::q23∼24→q43→neo→q43→qter) and tetrasomy of chromosomes 8 and 21

Hyperdiploidy is rarely observed in childhood acute myeloid leukemia (AML). Described here is the case of a 2(1/2)-year-old girl with AML-M5 and 51 chromosomes characterized by double tetrasomy of chromosomes 8 and 21 and also a neocentric derivative chromosome neo(1)(qter-->q23 approximately 24::q23 approximately 24-->q43-->neo-->q43-->qter). Little is known about the prognostic significance of these chromosomal abnormalities in childhood AML. In the actual case, complete remission was achieved after chemotherapy, which continued for 7 months. No acquired neocentric chromosome 1 has been described previously, even though neocentromere formation has been reported for other chromosomes in neoplasms.

Conventional and molecular cytogenetic characterization of Burkitt lymphoma with bone marrow involvement in Brazilian children and adolescents.

Burkitt lymphoma/leukemia (BL/L) is cytogenetically characterized by the t(8;14)(q24;q32) or its variants, t(2;8)(p11;q21), and t(8;22)(q24;q11.2), which juxtapose the MYC oncogene to one of the three immunoglobulin loci. The overall cure rate of BL/L in children is 70–90%, but patients diagnosed with advanced‐stage disease have a less favorable prognosis. It is possible that secondary chromosomal abnormalities contribute to this unfavorable prognosis via chemotherapy resistance, but the results of genetic studies have been inconsistent. This study aimed to identify and characterize secondary chromosomal abnormalities associated with the t(8;14) and its variants in children with French‐American‐British‐L3 leukemia or Burkitt lymphoma with bone marrow involvement at the time of diagnosis.

Identification of a de novo inv dup(X)(pter--> q22) by multicolor banding in a girl with Turner syndrome.

We report on a 23-year-old girl with short stature, short and wide neck, low posterior hairline, hypogonadism, underdeveloped breasts, infantile uterus, ovaries not visualized, and primary amenorrhea. Cytogenetic G-banding analysis revealed a mosaic karyotype of 46,X,dup(X)(q22)[35]/45,X[15], confirming the clinical suspicion of Turner syndrome. Molecular cytogenetics using a multicolor banding probe set for the X-chromosome characterized an inverted dup(X). The karyotype of the patient was therefore interpreted as 46,X,inv dup(X) (pter --> q22::q22 --> pter). This patient had a mosaic Turner syndrome with a cell line comprising partial trisomy Xpter to Xq22 and partial monosomy Xq22 to Xqter.

A new chromosomal three-way rearrangement involving MLL masked by a t(9;19)(p11;p13) in an infant with acute myeloid leukemia

Infants diagnosed with acute myelogenous leukemia (AML) are likely to have subtypes M4 or M5 characterized by 11q23 abnormalities like a t(9;11)(p22;q23). Detection of all possible types of chromosomal abnormalities, including mixed lineage leukemia (MLL) gene rearrangements at 11q23, is of importance for the identification of biological subgroups, which might differ in drug resistance and/or clinical outcome. Here, we report the clinical, conventional banding and molecular cytogenetics data of a 6-month-old boy with an AML-M5 presenting with a unique cryptic rearrangement involving the MLL gene: a three-way t(9;19;11)(p11.2;p13.1;q23).

Molecular cytogenetics reveals complex karyotype in apparent t(8;13) therapy-related acute myeloid leukemia M2 after fibrosarcoma

Therapy-related acute myeloid leukemia (t-AML) accounts for 0–30% of all AML and it is a known complication derived from ytotoxic chemotherapy and radiation therapy, which are known utagenic causative agents, namely, alkylanting agents and DNAopoisomerase II inhibitors [1]. In childhood, most cases of t-AML ccur following soft tissue sarcoma such as osteosarcoma and rabomiosarcoma, although it is rarely observed after fibrosarcoma ases. The fibrosarcoma is a neoplasm derived from fibroblasts in oft tissue such as muscles, connective tissues, blood vessels, joints nd/or fat and occurs in approximately 5% of all primary bone saromas [2]. t-AML with t(8;21)(q22;q22) harbors similar pathologic feaures as “de novo” AML. At molecular genetic level this neoplasm s defined by the involvement of the AML1 (RUNX1) gene on chroosome 21q22 and ETO (RUNX1T1) gene on chromosome 8q22, esulting in the AML1/ETO (RUNX1/RUNXT1) fusion gene product. his translocation disrupts the core biding factor (CBF) trancription complex affecting cell differentiation, proliferation and poptosis, thus causing leukemogenesis. However, the poor progosis related to t-AML suggests that other factors may certainly be lso involved [3]. To date, a detailed study on t-AML in children and adolescents is acking to show which chromosome abnormalities associated with (8;21) are prone to alter prognosis. Here we present an interesting ase of t-AML after treatment of fibrosarcoma that showed a t(8;13) n conventional karyotype but after molecular cytogenetic studies FISH, M-FISH and mMCB) presented an unmasked complex variant f t(8;21). A 14-year-old male was admitted to our institution, in January 001, because he had undergone an amputation of his left leg due a umor suspected to be an osteosarcoma. Upon admission, the histoogical diagnosis was a mesenchymal malignant neoplasm, but the munohistochemical studies revealed a high degree fibrosarcoma. he tumor was positive for vimentine and also positive for Ki-67 n 30% of neoplastic cells, but negative to pancytokeratin AE1-AE3, rotein S100, actin HHF35, smooth muscle actin, desmin and CD34. Both radiography and computerized tomography revealed iffuse medullar infiltrates in lungs. The patient was reated following metastatic osteosarcoma 2000 protocol [4] ith ifosfamide + mesna 54 g/m2 + 2.7 g/m2/day, cyclophoshamide + mesna 8 g/m2 + 2.7 g/m2/day, doxorubicin 320 mg/m2, isplatinum 480 mg/m2 associated with granulocyte-colonytimulating factors (G-CSF) for five days. In November 2002, the atient completed the treatment. After 34 additional months uring revision routine exams, he presented a platelet count of 3 × 109/L, hemoglobin level was 14 g/dL and white blood cell ount 6.3 × 109/L in his peripheral blood. Bone marrow aspiration

Complex karyotype defined by molecular cytogenetic FISH and M-FISH in an infant with acute megakaryoblastic leukemia and neurofibromatosis.

Acute myeloid leukemia in childhood is a heterogeneous group of diseases, and different epidemiologic factors are involved in the etiopathogenesis. Genetic syndromes are one of the predisposing factors of acute myeloid leukemia (AML), including Down syndrome, Bloom syndrome, and neurofibromatosis. Acute megakaryoblastic leukemia (AMKL) is the main subtype in Down syndrome infants, and acquired chromosomal anomalies are closely related to the physiopathology of the illness. The main chromosomal anomalies in AMKL are structural, such as t(1;22); however, complex karyotypes are also common. Here we describe the case of an infant with neurofibromatosis developing AMKL with a complex karyotype including 5q and 17q deletions, TP53 deletion, and an unusual unbalanced chromosomal translocation t(11;19)(q13;p13), leading to three copies of the MLL gene.