Significance of molecular-cytogenetic aberrations for the achievement of first remission in de novo acute myeloid leukemia.

OBJECTIVE: The majority of adults diagnosed with acute myeloid leukemia (AML) display acquired cytogenetic aberrations at presentation. In this article, we present the major cytogenetic findings regarding AML and review their clinical significance for achievement of the first complete remission. METHODS: We studied 71 adult patients with de novo AML, without previous myelodysplasia or alkylating therapy. Conventional cytogenetics and FISH were performed on bone marrow cells. The patients with AML were assigned to 12 subgroups according to established data for cytogenetic, molecular and general laboratory results. The selection of the analyzed parameters is consistent with internationally accepted "prognostic factors" in adult AML. RESULTS: Complete remission upon induction therapy was achieved in 40% of cases (in a mean period of 2.3 months from therapy initiation). The patients with t(15;17) PML-RARA and inv(16)/CBFbeta-MYH11ë demonstrated the highest frequency of complete remission. Patients with hypodiploidy, t(9;22)/bcr-abl and complex karyotypes were therapy-resistant or died within the first three months after AML diagnosis. CONCLUSION: Molecular-cytogenetic findings have an important significance for achievement of first complete remission. However, laboratory and biologic features (age, WBC and LDH) and type of AML have a large influence on the disease outcome.

Profile of chromosomal aberrations in different gestational age spontaneous abortions detected by comparative genomic hybridization.

OBJECTIVE: To determine the frequency and type of chromosomal aberrations in different gestational age spontaneous abortions. STUDY DESIGN: In the study, 106 spontaneous abortions (SAs) were studied by comparative genomic hybridization. RESULTS: The frequency of detected chromosomal aberrations was 37.7%. Numerical chromosomal aberrations were disclosed in 82.5% of the aberrant cases, while structural chromosomal aberrations-in 17.5%. Highest frequency of aberrations was detected in the blighted ovum specimens (62.5%) compared to missed and second trimester SAs (respectively, 36.0% and 34.8%). With regard to structural aberrations, the difference in the frequencies between blighted ovum specimens and second trimester SAs nearly reached statistical significance (p=0.0847). However, due to the low number of blighted ovum specimens analyzed (n=8), this result should be interpreted with due caution. The most frequently affected chromosomal arms were Xp and Xq (13.7% of aberrant chromosomal arms, each), followed by 16p (8.4%), 16q (8.4%), 15q (4.2%) and 19q (4.2%). CONCLUSIONS: We describe for the first time a profile of chromosomal aberrations in SAs from different gestational ages, detected by CGH. Our results showed highest frequency of chromosome aberrations in blighted ovum specimens compared to other types of spontaneous abortions, higher rate of structural aberrations than reported before (17.5%) and some aberrations that so far were not found by CGH.

High-throughput tissue microarray analysis of 11q13 gene amplification (CCND1, FGF3, FGF4, EMS1) in urinary bladder cancer.

Gene amplification is a common mechanism for oncogene overexpression. High-level amplifications at 11q13 have been repeatedly found in bladder cancer by comparative genomic hybridization (CGH) and other techniques. Putative candidate oncogenes located in this region are CCND1 (PRAD1, bcl-1), EMS1, FGF3 (Int-2), and FGF4 (hst1, hstf1). To evaluate the involvement of these genes in bladder cancer, a tissue microarray (TMA) containing 2317 samples was screened by fluorescence in situ hybridization (FISH). The frequency of gains and amplifications of all genes increased significantly from stage pTa to pT1-4 and from low to high grade. In addition, amplification was associated with patient survival and progression of pT1 tumours. Among 123 tumours with amplifications, 68.3% showed amplification of all four genes; 19.5% amplification of CCND1, FGF4, and FGF3; and 0.8% co-amplification of FGF4, FGF3, and EMS1. Amplification of CCND1 alone was found in 9% of the tumours, while EMS1 alone was amplified in 1.6% and FGF4 in 0.8%. Overall, the amplification frequency decreased with increasing genomic distance from CCND1, suggesting that, among the genes examined, CCND1 is the major target gene in the 11q13 amplicon in bladder cancer.

High-throughput tissue microarray analysis of erbB-2 gene amplification in urinary bladder cancer. A study of Bulgarian patients.

INTRODUCTION: Overexpression of the receptor Her-2 leads to increased proliferative response to epidermal growth factors which plays a key role in tumor development and growth. Increased oncoprotein level, in the majority of cases, is caused by erbB-2 gene amplification. To define the frequency of amplifications of erbB-2 in bladder cancer, and to determine their association with the tumor phenotype we utilized tissue microarray (TMA) approach. MATERIALS AND METHODS: We analyzed a TMA consisting of 159 transitional cell bladder carcinomas for erbB-2 gene amplification by dual-color FISH. RESULTS: The frequency of erbB-2 amplification was 5.3% of all successfully analyzed samples (4 of 75). It increased from minimally invasive (pT1) to muscle-invasive (pT2-4) tumors, as well as with advanced tumor grade (G1 to G2 to G3). All amplifications were cluster amplifications confirming the fact that erbB-2 amplification occurs intrachromosomally in bladder cancer. CONCLUSIONS: We concluded that despite its low incidence, erbB-2 amplification is of importance for the bladder tumor invasion and progression.

Genetic changes in uroepithelial tumors of patients with Balkan endemic nephropathy.

BACKGROUND: Balkan endemic nephropathy (BEN) is seen in certain regions of the Balkan Peninsula. The patients are predisposed to epithelial cell tumors of the urinary tract. These tumors have not been genetically investigated so far. METHODS: We studied the loss of heterozygosity (LOH) in three BEN-associated tumors at seven microsatellite loci at 3q21.3 - 3q27.3. Comparative genomic hybridization (CGH) was also done and one of the tumors was investigated by 24-color FISH as well. RESULTS: LOH in locus D3S1299 (3q24) was established in one case. CGH showed genetic gains at 1q, 3q, 7p, 7q, 15q, and 19q in at least two of the three tumors. Genetic loss was found in one case at 4q. Most frequent aberrations detected by 24-color FISH were der(X), der(X)t(X;18), der(16), der(3)t(3;15) and der(12). CONCLUSION: The LOH suggests the presence of a new, so far unidentified tumor-suppressor gene at 3q24. In pTa BEN tumor CGH showed genome instability was extremely high. The 24-color FISH indicated highly complex chromosomal rearrangements. Chromosome 3 anomalies support our previous data on 3q24 - 3q26.3 association with BEN.