ABSTRACT
Angioimmunoblastic T-cell lymphoma (AILT) and peripheral T-cell lymphoma, unspecified (PTCL-u) are relatively frequent subtypes of T- or natural killer cell lymphoma. To characterize the structural anomalies of chromosomes associated with these disorders, we here determined chromosome copy number alterations (CNAs) and loss of heterozygosity (LOH) at >55,000 single nucleotide polymorphism loci for clinical specimens of AILT (n=40) or PTCL-u (n=33). Recurrent copy number gain common to both conditions was detected on chromosomes 8, 9 and 19, whereas common LOH was most frequent for a region of chromosome 2. AILT- or PTCL-u-specific CNAs or LOH were also identified at 21 regions, some spanning only a few hundred base pairs. We also identified prognosis-related CNAs or LOH by several approaches, including Cox's proportional hazard analysis. Among the genes that mapped to such loci, a poor prognosis was linked to overexpression of CARMA1 at 7p22 and of MYCBP2 at 13q22, with both genes being localized within regions of frequent copy number gain. For a frequent LOH region at 2q34, we also identified IKAROS family zinc-finger 2 cDNAs encoding truncated proteins. Our data indicate that AILT and PTCL-u consist of heterogeneous subgroups with distinct transforming genetic alterations.
Subject(s)
Chromosome Aberrations , Loss of Heterozygosity , Lymphoma, T-Cell, Peripheral/genetics , Lymphoma, T-Cell/genetics , Oligonucleotide Array Sequence Analysis , Polymorphism, Single Nucleotide , Adult , Aged , Aged, 80 and over , CARD Signaling Adaptor Proteins/genetics , DNA-Binding Proteins/genetics , Female , Guanylate Cyclase/genetics , Humans , Ikaros Transcription Factor/genetics , Lymphoma, T-Cell/mortality , Lymphoma, T-Cell, Peripheral/mortality , Male , Middle Aged , Neprilysin/analysis , Prognosis , Transcription Factors/geneticsSubject(s)
Leukemia, Myeloid, Acute/genetics , MicroRNAs/genetics , Myelodysplastic Syndromes/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adult , Aged , Antigens, CD34/metabolism , Base Sequence , Cluster Analysis , Female , Gene Expression/physiology , Humans , Leukemia, Myeloid, Acute/pathology , Male , Middle Aged , Molecular Sequence Data , Myelodysplastic Syndromes/pathology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Sequence Homology, Nucleic AcidABSTRACT
Mutation or epigenetic silencing of mismatch repair genes, such as MLH1 and MSH2, results in microsatellite instability (MSI) in the genome of a subset of colorectal carcinomas (CRCs). However, little is yet known of genes that directly contribute to tumor formation in such cancers. To characterize MSI-dependent changes in gene expression, we have now compared transcriptomes between fresh CRC specimens positive or negative for MSI (n=10 for each) with the use of high-density oligonucleotide microarrays harboring >44,000 probe sets. Correspondence analysis of the expression patterns of isolated MSI-associated genes revealed that the transcriptome of MSI+ CRCs is clearly distinct from that of MSI- CRCs. Such MSI-associated genes included that for AXIN2, an important component of the WNT signaling pathway. AXIN2 was silenced, apparently as a result of extensive methylation of its promoter region, specifically in MSI+ CRC specimens. Forced expression of AXIN2, either by treatment with 5'-azacytidine or by transfection with AXIN2 cDNA, resulted in rapid cell death in an MSI+ CRC cell line. These data indicate that epigenetic silencing of AXIN2 is specifically associated with carcinogenesis in MSI+ CRCs.
