Systemic mastocytosis associated with t(8;21)(q22;q22) acute myeloid leukemia

Although KIT mutations are present in 20–25% of cases of t(8;21)(q22;q22) acute myeloid leukemia (AML), concurrent development of systemic mastocytosis (SM) is exceedingly rare. We examined the clinicopathologic features of SM associated with t(8;21)(q22;q22) AML in ten patients (six from our institutions and four from published literature) with t(8;21) AML and SM. In the majority of these cases, a definitive diagnosis of SM was made after chemotherapy, when the mast cell infiltrates were prominent. Deletion 9q was an additional cytogenetic abnormality in four cases. Four of the ten patients failed to achieve remission after standard chemotherapy and seven of the ten patients have died of AML. In the two patients who achieved durable remission after allogeneic hematopoietic stem cell transplant, recipient-derived neoplastic bone marrow mast cells persisted despite leukemic remission. SM associated with t(8;21) AML carries a dismal prognosis; therefore, detection of concurrent SM at diagnosis of t(8;21) AML has important prognostic implications.     

A case of acute myeloid leukemia-M2 with trisomy 4 in addition to t(8;21)

t(8;21)(q22;q22) is the most frequently observed karyotypic abnormality associated with acute myeloid leukemia (AML), specifically in FAB-M2. Short-term unstimulated bone marrow (BM) and peripheral blood lymphocyte culture showed 47,XX, +4,t(8;21) in all metaphase plates; and interphase and metaphase results of AML-ETO fusion was positive and trisomy of 4 was confirmed with WCP probes. Trisomy 4 in AML with t(8;21) is a rare numerical abnormality. Here we present such case of patient which may constitute a distinctive subtype.     

The effect of XPD/ERCC2 Lys751Gln polymorphism on acute leukemia risk: A systematic review and meta-analysis

Aims

Epidemiological studies have assessed the association between xeroderma pigmentosum group D (XPD) Lys751Gln and acute leukemia risk with conflicting results. We performed this meta-analysis to derive a more precise estimation of the relationship. Pooled odds ratio (OR) with 95% confidence interval (95% CI) was used to assess the strength of the association.

Results

Ten published case–control studies including a total of 1494 cases and 2259 controls were identified. Overall, significant risk effects of Lys751Gln genotype was found under the dominant model (OR = 1.16; 95% CI = 1.01–1.34; P = 0.032). When stratified by clinical types, the variant genotype was associated with the acute myeloid leukemia (AML) risk under the heterozygote comparison (OR = 1.20; 95% CI = 1.00–1.43; P = 0.048), the homozygote comparison (OR = 1.35; 95% CI = 1.05–1.74; P = 0.019) and the dominant model (OR = 1.23; 95% CI = 1.04–1.45; P = 0.015), respectively. Furthermore, significantly increased risks were also pronounced in Caucasian AML patients (the homozygote comparison: OR = 1.38; 95% CI = 1.07–1.78; P = 0.013; the dominant model: OR = 1.23; 95% CI = 1.03–1.46; P = 0.020; and the recessive model: OR = 1.26; 95% CI = 1.00–1.60; P = 0.050). No evident heterogeneities were observed for the overall data under all genetic models. In addition, no statistical evidence for publication bias was found using the method of Begg's and Egger's tests.

Conclusion

This meta-analysis suggested that XPD Lys751Gln polymorphism might be a risk factor for AML and Caucasian acute leukemia patients.     

XRCC3 Thr241Met polymorphism and risk of acute myeloid leukemia in a Romanian population

Background

DNA repair systems have a critical role in maintaining the genome integrity and stability. DNA repair gene polymorphisms may influence the capacity to repair DNA damage, and thus lead to an increased cancer susceptibility. X-ray repair cross-complementing groups 3 (XRCC3), a DNA repair gene, may be involved in acute myeloid leukemia susceptibility. The objective of the current study was to investigate the association of Thr241Met polymorphism of XRCC3 gene with the risk of acute myeloid leukemia (AML).

Methods

This study included 78 AML patients and 121 healthy individuals without cancer. We used polymerase chain reaction-restriction fragment length polymorphism assay to determine XRCC3 genotypes.

Results

The XRCC3 variant genotype (Thr/Met+Met/Met) was more frequent in AML patients than in healthy controls (OR = 2.76, 95% CI: 1.52-4.98, P = 0.001). Our study revealed a statistically significant association between variant genotype (Thr/Met+Met/Met) and AML de novo compared to secondary AML (P = 0.007). No significant associations were found between any genotype and age at diagnosis, number of white blood cells and subtype of AML. Overall survival of patients with Thr/Thr genotype was better than those of variant Thr/Met and Met/Met genotypes.

Conclusions

Our findings indicate that the XRCC3 Thr241Met polymorphism may be a genetic risk factor for AML, particularly in male patients with de novo AML from the central part of Romania.     

De novo 3q22.1 q24 deletion associated with multiple congenital anomalies,growth retardation and intellectual disability

We describe a boy with a de novo deletion of 15.67 Mb spanning 3q22.1q24. He has bilateral micropthalmia, ptosis, cleft palate, global developmental delay and brain, skeletal and cardiac abnormalities. In addition, he has bilateral inguinal hernia and his right kidney is absent. We compare his phenotype with seven other patients with overlapping and molecularly defined interstitial 3q deletions. This patient has some phenotypic features that are not shared by the other patients. More cases with smaller deletions defined by high resolution aCGH will enable better genotype–phenotype correlations and prioritizing of candidate genes for the identification of pathways and disease mechanisms.     

Novel chromosomal translocation (17;22)(q12;q12) in a case of myelodisplastic syndrome characterized with signs of hemolytic anemia at presentation

Myelodysplastic syndromes (MDS) are clonal stem cell diseases that can result in cytopenias, dysplasia in one or more cell lineages, infective hematopoiesis, and increase the risk of progression to acute myeloid leukemia (AML). MDSs are characterized by several recurrent cytogenetic defects, which can affect diagnosis, prognosis, and treatment. Some of that chromosomal alterations are associated with very poor prognosis. Conventional cytogenetics cannot accurately define the rearranged karyotype. Instead, molecular cytogenetics analyses can provide important diagnostic and prognostic information for patients affected by MDS, allowing the characterization of the whole mutational spectrum and, mainly, novel chromosomal lesions.In this paper, we report a MDS case with a novel chromosomal translocation [t(17;22)(q12;q22)], described for the first time here. Following Giemsa-banding karyotyping, fluorescent in situ hybridization analyses, by using chromosome-specific probes, displayed the breakpoint regions at chromosomes 17 and 22, within which intra and inter-chromosomal segmental duplications (SD) are present. Because of the occurrence of SDs in breakpoint region, it was not possible to finely define the genomic regions where breaks fell. Further investigations could be required to better understand the molecular basis of the novel translocation t(17;22)(q12;q12) acting in MDS context and to explain if SDs could contribute to the pathogenesis of MDS.     

8q12.1q12.3 de novo microdeletion involving the CHD7 gene in a patient without the major features of CHARGE syndrome: Case report and critical review of the literature

CHARGE syndrome is an autosomal dominant inherited disorder characterized by a specific and recognizable pattern of anomalies. De novo mutations or deletions of the gene encoding chromodomain helicase DNA binding protein 7 (CHD7) are the major cause of CHARGE syndrome. In this report, we describe a patient with a typical phenotype characterized by psychomotor retardation, hypertrichosis, facial asymmetry, synophria, failure to thrive, developmental delay and gastro-esophageal reflux, carrying a de novo 6.04 Mb interstitial deletion in 8q12.1q12.3 detected by single nucleotide polymorphism (SNP) array analysis. Despite the deletion includes CHD7 and although the patient shares some of the clinical features of the CHARGE syndrome, she does not fulfill the clinical criteria for this syndrome. To the best of our knowledge, this is the second case with an entire deletion of the CHD7 gene not leading to CHARGE syndrome and, for this reason, useful to expand and further delineate the clinical features associated with the 8q12.1q12.3 deletion. Furthermore, the literature review revealed that the phenotype secondary to duplications of the same region partially overlaps with the phenotype reported in this study. Selected genes that are present in the hemizygous state and which might be important for the phenotype of this patient, are discussed in context of the clinical features.     

Mutation and expression analysis of the IDH1, IDH2, DNMT3A, and MYD88 genes in colorectal cancer

Colorectal cancer (CRC) is one of the leading causes of death around the world. Its genetic mechanism was intensively investigated in the past decades with findings of a number of canonical oncogenes and tumor-suppressor genes such as APC, KRAS, and TP53. Recent genome-wide association and sequencing studies have identified a series of promising oncogenes including IDH1, IDH2, DNMT3A, and MYD88 in hematologic malignancies. However, whether these genes are involved in CRC remains unknown. In this study, we screened the hotspot mutations of these four genes in 305 CRC samples from Han Chinese by direct sequencing. mRNA expression levels of these genes were quantified by quantitative real-time PCR (RT-qPCR) in paired cancerous and paracancerous tissues. Association analyses between mRNA expression levels and different cancerous stages were performed. Except for one patient harboring IDH1 mutation p.I99M, we identified no previously reported hotspot mutations in colorectal cancer tissues. mRNA expression levels of IDH1, DNMT3A, and MYD88, but not IDH2, were significantly decreased in the cancerous tissues comparing with the paired paracancerous normal tissues. Taken together, the hotspot mutations of IDH1, IDH2, DNMT3A, and MYD88 gene were absent in CRC. Aberrant mRNA expression of IDH1, DNMT3A, and MYD88 gene might be actively involved in the development of CRC.     

Partial monosomy 21 (q11.2→q21.3) combined with 3p25.3→pter monosomy due to an unbalanced translocation in a patient presenting dysmorphic features and developmental delay

We describe a female patient of 1 year and 5 months-old, referred for genetic evaluation due to neuropsychomotor delay, hearing impairment and dysmorphic features. The patient presents a partial chromosome 21 monosomy (q11.2→q21.3) in combination with a chromosome 3p terminal monosomy (p25.3→pter) due to an unbalanced de novo translocation. The translocation was confirmed by fluorescence in situ hybridization (FISH) and the breakpoints were mapped with high resolution array. After the combined analyses with these techniques the final karyotype was defined as 45,XX,der(3)t(3;21)(p25.3;q21.3)dn,-21.ish der(3)t(3;21)(RP11-329A2-,RP11-439F4-,RP11-95E11-,CTB-63H24 +).arr 3p26.3p25.3(35,333-10,888,738)) × 1,21q11.2q21.3(13,354,643-27,357,765) × 1. Analysis of microsatellite DNA markers pointed to a paternal origin for the chromosome rearrangement. This is the first case described with a partial proximal monosomy 21 combined with a 3p terminal monosomy due to a de novo unbalanced translocation.     

Interstitial 2q24.3 deletion including SCN2A and SCN3A genes in a patient with autistic features,psychomotor delay,microcephaly and no history of seizures

Mutations in neuronal voltage-gated sodium channel genes SCN1A, SCN2A, and SCN3A may play an important role in the etiology of neurological diseases and psychiatric disorders, besides various types of epilepsy. Here we describe a 3-year-old boy with autistic features, language delay, microcephaly and no history of seizures. Array-CGH analysis revealed an interstitial deletion of ~ 291.9 kB at band 2q24.3 disrupting the entire SCN2A gene and part of SCN3A. We discuss the effects of haploinsufficiency of SCN2A and SCN3A on the genetic basis of neurodevelopmental and neurobehavioral disorders and we propose that this haploinsufficiency may be associated not only with epilepsy, but also with autistic features.     

A new case of partial 14q31.3-qter trisomy due to maternal pericentric inversion

Chromosome 14 is often involved in chromosome rearrangements, although pericentric inversions are rare. Here we report a mother carrying a pericentric inversion of chromosome 14, and her daughter with recombinant chromosome characterized by a partial distal 14q trisomy. Principal clinical findings of the child include facial anomalies, microcephaly, developmental delay, hypotonia and cardiac malformation. Her final karyotype was 46,XX,rec(14)dup(14q)inv(14)(p12q31)mat[20], arr 14q31.3qter(85,427,839–106,356,482)x3. This report brings new data about clinical features of partial 14q trisomy and molecular analysis enables the visualization of genes involved in the segment duplicated.     

Synthetic strategy for increasing solubility of potential FLT3 inhibitor thieno[2,3-d]pyrimidine derivatives through structural modifications at the C2 and C6 positions

Acute myeloid leukemia (AML) is a clonal disorder of hematopoietic progenitor cell. In AML, a mutation in FLT3 is commonly occurs and is associated with poor prognosis. We have previously reported that thieno[2,3-d]pyrimidine derivative compound 1 exhibited better antiproliferative activity against MV4-11 cells which harbor mutant FLT3 than AC220, which is a well-known FLT3 inhibitor, and has good microsomal stability. However, compound 1 had poor solubility. We then carried out further structural modification at the C₂ and the C₆ positions of thieno[2,3-d]pyrimidine scaffold. Compound 13b, which possesses a thiazole moiety at the C₂ position, exhibited better antiproliferative activity than compound 1 and showed increased solubility and moderate microsomal stability. These results indicate that compound 13b could be a promising potential FLT inhibitor for AML chemotherapy.     

Characterization of the complete mitochondrial genome of Tryporyza incertulas, in comparison with seven other Pyraloidea moths

The complete 15,223-bp mitochondrial genome (mitogenome) of Tryporyza incertulas (Walker) (Lepidoptera: Pyraloidea: Crambidae) was determined, characterized and compared with seven other species of superfamily Pyraloidea. The order of 37 genes was typical of insect mitochondrial DNA sequences described to date. Compared with other moths of Pyraloidea, the A + T biased (77.0%) of T. incertulas was the lowest. Eleven protein-coding genes (PCGs) utilized the standard ATN, but cox1 used CGA and nad4 used AAT as the initiation codons. Ten protein-coding genes had the common stop codon TAA, except nad3 having TAG as the stop codon, and cox2, nad4 using T, TA as the incomplete stop codons, respectively. All of the tRNA genes had typical cloverleaf secondary structures except trnS1(AGN), in which the dihydrouridine (DHU) arm did not form a stable stem-loop structure. There was a spacer between trnQ and nad2, which was common in Lepidoptera moths. A 6-bp motif ‘ATACTA’ between trnS2(UCN) and nad1, a 7-bp motif “AGC(T)CTTA” between trnW and trnC and a 6-bp motif “ATGATA” of overlapping region between atp8 and atp6 were found in Pyraloidea moths. The A + T-rich region contained an ‘ATAGT(A)’-like motif followed by a poly-T stretch. In addition, two potential stem-loop structures, a duplicated 19-bp repeat element, and two microsatellites ‘(TA)₁₂’ and ‘(TA)₉’ were observed in the A + T-rich region of T. incertulas mitogenome. Finally, the phylogenetic relationships of Pyraloidea species were constructed based on amino acid sequences of 13 PCGs of mitogenomes using Bayesian inference (BI) and maximum likelihood (ML) methods. These molecular-based phylogenies supported the morphological classification on relationships within Pyraloidea species.