Genetic mutational profiling analysis of T cell acute lymphoblastic leukemia reveal mutant FBXW7 as a prognostic indicator for inferior survival.

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive neoplasm for which there are currently no adequate biomarkers for developing risk-adapted therapeutic regimens to improve the treatment outcome. In this prospective study of 83 Chinese patients (54 children and 29 adults) with de novo T-ALL, we analyzed mutations in 11 T-ALL genes: NOTCH1, FBXW7, PHF6, PTEN, N-RAS, K-RAS, WT1, IL7R, PIK3CA, PIK3RA, and AKT1. NOTCH1 mutations were identified in 51.9 and 37.9 % of pediatric and adult patients, respectively, and these patients showed improved overall survival (OS) and event-free survival (EFS). The FBXW7 mutant was present in 25.9 and 6.9 % of pediatric and adult patients, respectively, and was associated with inferior OS and EFS in pediatric T-ALL. Multivariate analysis revealed that mutant FBXW7 was an independent prognostic indicator for inferior EFS (hazard ratio [HR] 4.38; 95 % confidence interval [CI] 1.15-16.71; p = 0.03) and tended to be associated with reduced OS (HR 2.81; 95 % CI 0.91-8.69; p = 0.074) in pediatric T-ALL. Mutant PHF6 was present in 13 and 20.7 % of our childhood and adult cohorts, respectively, while PTEN mutations were noted in 11.1 % of the pediatric patients. PTEN and NOTCH1 mutations were almost mutually exclusive, while IL7R and WT1 mutations were rare in pediatric T-ALL and PTPN11 and AKT1 mutations were infrequent in adult T-ALL. This study revealed differences in the mutational profiles of pediatric and adult T-ALL and suggests mutant FBXW7 as an independent prognostic indicator for inferior survival in pediatric T-ALL.

HLA class II alleles may influence susceptibility to adult dermatomyositis and polymyositis in a Han Chinese population.

BACKGROUND: Polymyositis (PM) and dermatomyositis (DM) are idiopathic inflammatory myopathies. Genetic variability in human leukocyte antigen (HLA) genes plays an important role in the pathogenesis of PM and DM. However, few studies on the subject in Chinese populations have been reported thus far. METHODS: We studied the influence of HLA polymorphisms on DM and PM susceptibility by analyzing HLA-DRB1, HLA-DQA1, and HLA-DQB1 alleles in 71 adult DM patients, 20 adult PM patients, and 113 controls in a Han Chinese population. RESULTS: A positive association was found between HLA-DQA1*0104 and DM (p = 0.01; corrected p (pcorr) NS; odds ratio (OR) = 2.58; 95% confidence interval (CI): 1.18-5.64), while an inverse correlation was noted between HLA-DQB1*0303 and myositis patients with interstitial lung inflammation (p = 0.01; pcorr NS; OR = 0.25; 95% CI: 0.07-0.73). A positive relationship was also observed between HLA-DRB1*07 and DM (p = 0.01; pcorr NS; OR = 2.26; 95% CI: 1.12-4.59), while HLA-DRB1*03 seems to be protective against DM (p = 0.01; pcorr NS; OR = 0.26; 95% CI: 0.06-0.81). The lung complication was closely associated with HLA-DRB1*04 (p = 0.01; pcorr NS; OR = 2.82; 95% CI: 1.15-6.76) and HLA-DRB1*12 (p = 0.02; pcorr NS; OR = 2.52; 95% CI: 1.02-6.07). The frequency of HLA-DRB1*07 was significantly higher among myositis patients with dysphagia than among controls (p = 0.01; pcorr NS; OR = 4.78; 95% CI: 1.03-24.42). The putative haplotype DRB1*07-DQA1*01-DQB1*02 was positively correlated with DM (p = 0.03; pcorr NS; OR = 2.90; 95% CI: 1.02-8.93) and the lung complication (p = 0.02; pcorr NS; OR = 3.45; 95% CI: 1.04-11.58). CONCLUSIONS: Our results demonstrate that HLA alleles may be involved in susceptibility to adult DM and PM in the Han Chinese population.

A study of two Chinese patients with tetrasomy and pentasomy 15q11q13 including Prader-Willi/Angelman syndrome critical region present with developmental delays and mental impairment.

BACKGROUND: The proximal chromosome 15q is prone to unequal crossover, leading to rearrangements. Although 15q11q13 duplications are common in patients with developmental delays and mental impairment, 15q aneusomies resulting in greater or equal to 4 copies of 15q11q13 are rare and no pentasomy 15q11q13 has been reported in the literature. Thus far, all reported high copy number 15q11q13 cases are from the West populations and no such study in Chinese patients have been documented. Dosage-response pattern of high copy number 15q11q13 on clinical presentations is still a subject for further study. CASE PRESENTATION: In this study, we characterized two Han Chinese patients with high copy number 15q11q13. Using chromosome banding, high resolution SNP-based cytogenomic array, Fluorescence in situ hybridization, and PCR-based microsatellite analysis, we identified two patients with tetrasomy 15q11q13 and pentasomy 15q11q13. Both 15q11q13 aneusomies resulted from a maternally inherited supernumerary marker chromosome 15, and each was composed of two different sized 15q11q13 segments covering the Prader-Willi/Angelman critical region: one being about 10 Mb with breakpoints at BP1 and BP5 regions on 15q11 and 15q13, respectively, and another about 8 Mb in size with breakpoints at BP1 and BP4 regions on 15q. Both patients presented with similar clinical features that included neurodevelopmental delays, mental impairment, speech and autistic behavior, and mild dysmorphism. The patient with pentasomy 15q11q13 was more severely affected than the patient with tetrasomy 15q11q13. Low birth weight was noted in patient with pentasomy 15q1q13. CONCLUSIONS: To the best of our knowledge, this is the first case of pentasomy 15q11q13 and the first study of high copy number 15q11q13 in Han Chinese patients. Our findings demonstrate that patients with tetrasomy and pentasomy of chromosome 15q11q13 share similar spectrum of phenotypes reported in other high copy number 15q11q13 patients in the West, and positive correlation between 15q11q13 copy number and degree of severity of clinical phenotypes. Low birth weight observed in the pentasomy 15q11q13 patient was not reported in other patients with high copy number 15q11q13. Additional studies would be necessary to further characterize high copy number 15q11q13 aneusomies.

Detecting 22q11.2 deletion in Chinese children with conotruncal heart defects and single nucleotide polymorphisms in the haploid TBX1 locus.

BACKGROUND: Conotruncal heart defects (CTDs) are present in 75-85% of patients suffering from the 22q11.2 deletion syndrome. To date, no consistent phenotype has been consistently correlated with the 22q11.2 deletions. Genetic studies have implicated TBX1 as a critical gene in the pathogenesis of the syndrome. The aim of study was to determine the incidence of the 22q11.2 deletion in Chinese patients with CTDs and the possible mechanism for pathogenesis of CTDs. METHODS: We enrolled 212 patients with CTDs and 139 unrelated healthy controls. Both karyotypic analysis and multiplex ligation-dependent probe amplification were performed for all CTDs patients. Fluorescence in situ hybridization was performed for the patients with genetic deletions and their relatives. The TBX1 gene was sequenced for all patients and healthy controls. The χ2 and Fisher's exact test were used in the statistical analysis. RESULTS: Thirteen of the 212 patients with CTDs (6.13%) were found to have the 22q11.2 deletion syndrome. Of the 13 cases, 11 presented with a hemizygous interstitial microdeletion from CLTCL1 to LZTR1; one presented with a regional deletion from CLTCL1 to DRCR8; and one presented with a regional deletion from CDC45L to LZTR1. There were eight sequence variants in the haploid TBX1 genes of the del22q11 CTDs patients. The frequency of one single nucleotide polymorphism (SNP) in the del22q11 patients was different from that of the non-del patients (P < 0.05), and the frequencies of two other SNPs were different between the non-del CTDs patients and controls (P < 0.05). CONCLUSIONS: CTDs, especially pulmonary atresia with ventricular septal defect and tetralogy of Fallot, are the most common disorders associated with the 22q11.2 deletion syndrome. Those patients with both CTDs and 22q11.2 deletion generally have a typical or atypical deletion region within the TBX1 gene. Our results indicate that TBX1 genetic variants may be associated with CTDs.

Case-control study of risk factors of myelodysplastic syndromes according to World Health Organization classification in a Chinese population.

Risk factors of mydelodysplastic syndromes (MDS) remain largely unknown. We conducted a hospital-based case-control study consisting of 403 newly diagnosed MDS patients according to World Health Organization classification and 806 individually gender and age-matched patient controls from 27 major hospitals in Shanghai, China, to examine relation of lifestyle, environmental, and occupational factors to risk of MDS. The study showed that all MDS (all subtypes combined) risk factors included anti tuberculosis drugs [odds ratio (OR)(adj) = 3.15; 95% confidence interval (CI) = 1.22-8.12] as an independent risk factor, benzene (OR(adj) = 3.73; 95% CI = 1.32-10.51), hair dye use (OR = 1.46; 95% CI = 1.03-2.07), new building and renovations (OR = 1.69; 95% CI = 1.11-2.00), pesticides (OR = 2.16; 95% CI = 1.22-3.82), and herbicides (OR = 5.33; 95% CI = 1.41-20.10) as relative risk factors. Risk factors of MDS subtype refractory cytopenia with multiple dysplasia (RCMD) were benzene (OR(adj) = 5.99; 95% CI = 1.19-30.16) and gasoline (OR(adj) = 11.44; 95% CI = 1.31-100.03) as independent risk factors, and traditional Chinese medicines (OR = 2.17; 95% CI = 1.15-4.07), pesticides (OR = 2.92; 95% CI = 1.37-6.25), and herbicides (OR = 12.00; 95% CI = 1.44-99.67) as relative risk factors. Smoking tobacco was significantly associated with refractory anemia with excess of blasts (RAEB) (OR(adj) = 2.43; 95% CI = 1.02-5.77). Education is shown as an independent protective factor against all MDS (OR(adj) = 0.90; 95% CI = 0.83-0.99) and RCMD (OR(adj) = 0.89; 95% CI = 0.79-0.99). These findings suggest that multiple modifiable behavioral, environmental, and occupational factors play a role in MDS etiology, and various MDS subtypes may have different susceptibility.

Prevalence of MDS subtypes in Shanghai, China: a comparison of the World Health Organization and French American British classifications.

The prevalence of subtypes of the myelodysplastic syndromes (MDS) was determined in a prospective series of 176 patients presenting at 28 Shanghai hospitals. Diagnosis was established in a single laboratory, analyzing morphologic, immunophenotypic, and cytogenetic data, using the World Health Organization (WHO) revised classification and directly compared to the French American British (FAB) criteria. The median age at diagnosis for all cases was 53 years. There was a striking increase in the prevalence of RCMD in younger patients relative to other subtypes (WHO). The overall frequency of clonal cytogenetic abnormalities was 26.5% (WHO) and 31% (FAB). The most frequently encountered lesions were trisomy 8, del(20)q, del(7q), and del(5q). These results are consistent with previously reported age-dependent differences in MDS and a decreased frequency of del(5q) abnormalities between China and the West. These results also indicate that multilineage dysplasia is a prominent feature in MDS developing in younger individuals in Shanghai and suggest distinguishing between RCMD and RA may be important in the design of studies to further understand regional differences in subtype prevalence and to elucidate the pathogenesis of this complex and multifactorial disease.

[Cytogenetic analysis of childhood acute lymphoblastic leukemia].

OBJECTIVE: To characterize the genetic aberrations in pediatric acute lymphoblastic leukemia (ALL). METHODS: Ninety ALL cases were enrolled in the study from January 2009 to November 2011. Chromosome banding analysis and fluorescence in situ hybridization (FISH) were used to detect genetic aberrations. RESULTS: (1) Chromosome analysis: 35 (53.0%) of 66 cases who had metaphase were abnormal, and 24 cases had no metaphase. (2) FISH analysis: among the 31 cases who had normal karyotypes and 24 who had no metaphase detected by chromosome banding technique, 7 (22.6%) and 14 (58.3%) cases were abnormal detected by FISH, respectively. There were no statistically significant differences compared with chromosome analysis (P = 0.655). Among these 55 ALL cases TEL/AML1, bcr-abl and MLL fusion genes were observed in 16 (29.1%), 3(5.5%) and 2(3.6%) cases, respectively. (3) Cytogenetic aberration was observed in 56 of total 90 ALL cases (62.2%). CONCLUSIONS: Cytogenetic changes are common in childhood ALL. Conventional cytogenetic study could reliably detected chromosomal abnormalities for ALL with assessable metaphase. FISH should be used as a complementary method for ALL patients who have poor chromosomal morphology or no metaphase cells, and combination of both methods can improve the detection rate of genetic abnormalities in childhood leukemia.

Prospective study of 174 de novo acute myelogenous leukemias according to the WHO classification: subtypes, cytogenetic features and FLT3 mutations.

We report a prospective study of 174 unselected adult de novo acute myeloid leukemia (AML) cases diagnosed using the WHO classification. Of those, 57 (33%) were AML with recurrent cytogenetic abnormalities, 41 were (24%) AML with multilineage dysplasia, 74 (42%) were AML not otherwise categorized, and two were acute leukemias of ambiguous lineage. Clonal cytogenetic abnormalities were detected in 64% of the WHO AML cases with t(15;17) (15%), t(8;21) (12%), +8 (11%), -7/del7q (8%) and del9q (5%) being the most common ones. The FLT3/ITD mutations (FMS-like tyrosine kinase 3/internal tandem duplication) were observed in 12% of the WHO AML cases, which is much lower than ones in the literature, while the 6% incidence of the FLT3-activating loop mutations (either FLT3/D835 or FLT3/I836) was comparable with others. Both mutations were associated with leukocytosis. Our study also suggests that the FLT3 mutations are biomarkers independent of cytogenetic characteristics.