Cytogenetic analysis of 130 renal oncocytomas identify three distinct and mutually exclusive diagnostic classes of chromosome aberrations.

The cytogenetic alterations in renal oncocytoma (RO) are poorly understood. We analyzed 130 consecutive RO for karyotypic alterations. Clonal chromosome abnormalities were identified in 63 (49%) cases, which could be categorized into three classes of mutually exclusive cytogenetic categories.

A genomic algorithm for the molecular classification of common renal cortical neoplasms: development and validation.

Purpose: Accurate discrimination of benign oncocytoma and malignant renal cell carcinoma is useful for planning appropriate treatment strategies for patients with renal masses. Classification of renal neoplasms solely based on histopathology can be challenging, especially the distinction between chromophobe renal cell carcinoma and oncocytoma. In this study we develop and validate an algorithm based on genomic alterations for the classification of common renal neoplasms.

PCDH10 promoter hypermethylation is frequent in most histologic subtypes of mature lymphoid malignancies and occurs early in lymphomagenesis.

PCDH10 is epigenetically inactivated in multiple tumor types; however, studies in mature lymphoid malignancies are limited. Here, we have investigated the presence of promoter hypermethylation of the PCDH10 gene in a large cohort of well-characterized subsets of lymphomas. PCDH10 promoter hypermethylation was identified by methylation-specific PCR in 57 to 100% of both primary B- and T-cell lymphoma specimens and cell lines.

Real-time PCR-based analysis of BRAF V600E mutation in low and intermediate grade lymphomas confirms frequent occurrence in hairy cell leukaemia.

Hairy cell leukaemia (HCL) is a rare type of B-cell non-Hodgkin lymphoma (B-NHL), which is not known to be associated with any characteristic recurrent karyotypic abnormality. A recent study that used massively parallel whole exome sequencing identified an activating V600E mutation in BRAF, which appeared specific for HCL. Here, we confirm the specificity of BRAF V600E for HCL among low and intermediate grade B-NHL and describe a real-time polymerase chain reaction method for detecting this mutation in cases with low tumour burden.

Polysomy and p16 deletion by fluorescence in situ hybridization in the diagnosis of indeterminate biliary strictures.

Background: The diagnosis of indeterminate biliary strictures is limited because of the low sensitivity of cytology. However, an accurate diagnosis of malignancy is critical in the management of patients with suspected biliary malignancy. Testing for chromosomal aneuploidy by fluorescence in situ hybridization (FISH) may increase the yield.

Promoter methylation-mediated inactivation of PCDH10 in acute lymphoblastic leukemia contributes to chemotherapy resistance.

PCDH10 has been implicated as a tumor suppressor, since epigenetic alterations of this gene have been noted in multiple tumor types. However, to date, studies regarding its role in acute and chronic leukemias are lacking. Here, we have investigated the presence of promoter hypermethylation of two CpG islands of the PCDH10 gene by methylation-specific PCR in 215 cases of various subsets of myeloid- and lymphoid-lineage leukemias.

Cytogenetic abnormalities in reactive lymphoid hyperplasia: byproducts of the germinal centre reaction or indicators of lymphoma?

Non-random karyotypic abnormalities associated with non-Hodgkin lymphomas (NHLs) have been described in cases of reactive lymphoid hyperplasia (RLH). However, the frequency and types of cytogenetic aberrations detected and their clinical relevance are unknown. To address these questions, we undertook a retrospective analysis of a large series of RLH diagnosed at our institute over 8 years.

3-Phosphoinositide-dependent kinase 1 potentiates upstream lesions on the phosphatidylinositol 3-kinase pathway in breast carcinoma.

Lesions of ERBB2, PTEN, and PIK3CA activate the phosphatidylinositol 3-kinase (PI3K) pathway during cancer development by increasing levels of phosphatidylinositol-3,4,5-triphosphate (PIP(3)). 3-Phosphoinositide-dependent kinase 1 (PDK1) is the first node of the PI3K signal output and is required for activation of AKT. PIP(3) recruits PDK1 and AKT to the cell membrane through interactions with their pleckstrin homology domains, allowing PDK1 to activate AKT by phosphorylating it at residue threonine-308.

Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL), the most common form of lymphoma in adulthood, comprises multiple biologically and clinically distinct subtypes including germinal centre B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL. Gene expression profile studies have shown that its most aggressive subtype, ABC-DLBCL, is associated with constitutive activation of the NF-kappaB transcription complex. However, except for a small fraction of cases, it remains unclear whether NF-kappaB activation in these tumours represents an intrinsic program of the tumour cell of origin or a pathogenetic event.

KHSV(-) EBV(-) post-transplant effusion lymphoma with plasmablastic features: variant of primary effusion lymphoma?

Primary effusion lymphoma (PEL) is a rare type of B-cell non-Hodgkin lymphoma (NHL), which predominantly occurs in HIV-infected individuals, and is pathogenetically linked with Kaposi sarcoma (KS)-associated herpes virus/human herpes virus-8 (KSHV/HHV-8) infection with or without evidence of Epstein-Barr virus (EBV) co-infection. Although uncommon, PELs have been reported in immunocompetent patients and recipients of solid organ allografts. Rare cases of KSHV(-) EBV(+) post-transplant effusion lymphomas resembling PEL have also been described, as have KSHV(-) EBV(-) effusion lymphomas, the latter including those arising in individuals with chronic liver disease.

The NF-{kappa}B negative regulator TNFAIP3 (A20) is inactivated by somatic mutations and genomic deletions in marginal zone lymphomas.

Unique and shared cytogenetic abnormalities have been documented for marginal zone lymphomas (MZLs) arising at different sites. Recently, homozygous deletions of the chromosomal band 6q23, involving the tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20) gene, a negative regulator of NF-kappaB, were described in ocular adnexal MZL, suggesting a role for A20 as a tumor suppressor in this disease. Here, we investigated inactivation of A20 by DNA mutations or deletions in a panel of extranodal MZL (EMZL), nodal MZL (NMZL), and splenic MZL (SMZL).

Irs2 inactivation suppresses tumor progression in Pten+/- mice.

Mutations in the phosphatase and tensin homologue (PTEN)/phosphatidylinositol-3 kinase-alpha (PI3K) signaling pathway are frequently found in human cancer. In addition, Pten(+/-) mice develop tumors in multiple organs because of the activation of the PI3K signaling cascade. Because activation of PI3K signaling leads to feedback inhibition of insulin receptor substrate-2 (IRS2) expression, an upstream activator of PI3K, we therefore anticipated that IRS2 expression would be low in tumors that lack PTEN.

Diffuse large B-cell lymphoma with TEL/ETV6 translocation.

Cytogenetic abnormalities of chromosome 12p involving the TEL/ETV6 gene are observed in a variety of hematopoietic neoplasms including acute leukemias, myelodysplastic syndromes, and myeloproliferative disorders. Karyotypic aberrations, including rearrangements, deletions, and amplifications of chromosome 12p, have been documented in B-cell non-Hodgkin lymphoma; however, rearrangements targeting TEL have rarely been reported. Here we describe a diffuse large B-cell lymphoma that had a complex karyotype including t(9;12)(q22;p13), which was confirmed by fluorescence in situ hybridization to represent rearrangement of TEL.

The spectrum of B-cell non-Hodgkin lymphomas with dual IgH-BCL2 and BCL6 translocations.

Dual IgH/BCL2 and BCL6 translocations are rarely observed in B-cell non-Hodgkin lymphomas (B-NHLs). We investigated the morphologic, phenotypic, and cytogenetic spectrum of B-NHL with such dual translocations. Dual IgH/BCL2 and BCL6 translocations were detected in follicular lymphomas (FLs) and diffuse large B-cell lymphomas (DLBCLs), representing 6.

Identification of copy number gain and overexpressed genes on chromosome arm 20q by an integrative genomic approach in cervical cancer: potential role in progression.

Recurrent karyotypic abnormalities are a characteristic feature of cervical cancer (CC) cells, which may result in deregulated expression of important genes that contribute to tumor initiation and progression. To examine the role of gain of the long arm of chromosome 20 (20q), one of the common chromosomal gains in CC, we evaluated CC at various stages of progression using single nucleotide polymorphism (SNP) array, gene expression profiling, and fluorescence in situ hybridization (FISH) analyses. This analysis revealed copy number increase (CNI) of 20q in >50% of invasive CC and identified two focal amplicons at 20q11.

The basal-like mammary carcinomas induced by Brca1 or Bard1 inactivation implicate the BRCA1/BARD1 heterodimer in tumor suppression.

Women with germ-line mutations of the BRCA1 tumor suppressor gene are highly susceptible to breast and ovarian cancer. The protein product of BRCA1 is involved in a broad spectrum of biological processes and interacts with many diverse proteins. One of these, BARD1, associates with BRCA1 to form a heterodimeric complex that is enzymatically active as an ubiquitin E3 ligase.

Molecular cytogenetic applications in analysis of the cancer genome.

Cancer cells exhibit nonrandom and complex chromosome abnormalities. The role of genomic changes in cancer is well established. However, the identification of complex and cryptic chromosomal changes is beyond the resolution of conventional banding methods.

Structural requirements for the BARD1 tumor suppressor in chromosomal stability and homology-directed DNA repair.

The BRCA1 tumor suppressor exists as a heterodimeric complex with BARD1, and this complex is thought to mediate many of the functions ascribed to BRCA1, including its role in tumor suppression. The two proteins share a common structural organization that features an N-terminal RING domain and two C-terminal BRCT motifs, whereas BARD1 alone also contains three tandem ankyrin repeats. In normal cells, the BRCA1/BARD1 heterodimer is believed to enhance chromosome stability by promoting homology-directed repair (HDR) of double strand DNA breaks.

Gene dosage alterations revealed by cDNA microarray analysis in cervical cancer: identification of candidate amplified and overexpressed genes.

Cervical cancer (CC) cells exhibit complex karyotypic alterations, which is consistent with deregulation of numerous critical genes in its formation and progression. To characterize this karyotypic complexity at the molecular level, we used cDNA array comparative genomic hybridization (aCGH) to analyze 29 CC cases and identified a number of over represented and deleted genes. The aCGH analysis revealed at least 17 recurrent amplicons and six common regions of deletions.

Cytogenetic analysis of B-cell posttransplant lymphoproliferations validates the World Health Organization classification and suggests inclusion of florid follicular hyperplasia as a precursor lesion.

Cytogenetic abnormalities in B-cell posttransplant lymphoproliferative disorders (PTLD) have not been well characterized. We thus performed cytogenetic analysis of 28 cases of B-cell PTLD, 1 infectious mononucleosis (IM)-like lesion, 9 polymorphic PTLD, 17 monomorphic PTLD, and 1 classical Hodgkin lymphoma (HL), and correlated the karyotypic findings with the phenotype, Epstein-Barr virus infection status, and clinical outcome. Karyotypes of 19 cases of posttransplant florid follicular hyperplasia (FFH) were also analyzed.

Intrachromosomal rearrangement of chromosome 3q27: an under recognized mechanism of BCL6 translocation in B-cell non-Hodgkin lymphoma.

Balanced reciprocal translocations involving chromosomal region 3q27, which led to identification of the BCL6 protooncogene, are one of the most common recurrent chromosomal abnormalities reported in B-cell non-Hodgkin lymphomas (B-NHL). Cloning of the breakpoints of these translocations has facilitated the identification of a number of BCL6 partners including immunoglobulin genes and more than 20 non-immunoglobulin genes on almost all human chromosomes. Fusion of BCL6 with these genes leads to deregulated BCL6 expression because of substitution of its promoter with that of the translocation partner.

Inactivation of the PRDM1/BLIMP1 gene in diffuse large B cell lymphoma.

PR domain containing 1 with zinc finger domain (PRDM1)/B lymphocyte-induced maturation protein 1 (BLIMP1) is a transcriptional repressor expressed in a subset of germinal center (GC) B cells and in all plasma cells, and required for terminal B cell differentiation. The BLIMP1 locus lies on chromosome 6q21-q22.1, a region frequently deleted in B cell lymphomas, suggesting that it may harbor a tumor suppressor gene.

Congenital MLL-positive B-cell acute lymphoblastic leukemia (B-ALL) switched lineage at relapse to acute myelocytic leukemia (AML) with persistent t(4;11) and t(1;6) translocations and JH gene rearrangement.

Congenital acute leukemia is a rare form of childhood leukemia, in which lineage conversion at relapse is very rarely reported. Here we describe a case of congenital B-cell acute lymphoblastic leukemia (B-ALL) with t(4;11) and t(1;6) translocations, which at relapse underwent a switch to monocytic lineage with persistence of the original cytogenetic translocations and clonal rearrangement of the JH gene. Similar to the other described cases of congenital acute leukemia with lineage conversion, our case had a MLL gene rearrangement and followed an aggressive clinical course.

Deregulated BCL6 expression recapitulates the pathogenesis of human diffuse large B cell lymphomas in mice.

Diffuse large B cell lymphomas (DLBCL) derive from germinal center (GC) B cells and display chromosomal alterations deregulating the expression of BCL6, a transcriptional repressor required for GC formation. To investigate the role of BCL6 in DLBCL pathogenesis, we have engineered mice that express BCL6 constitutively in B cells by mimicking a chromosomal translocation found in human DLBCL. These mice display increased GC formation and perturbed post-GC differentiation characterized by a decreased number of post-isotype switch plasma cells.