Genome-wide miRNAprofiling of mantle cell lymphoma reveals a distinct subgroup with poor prognosis

miRNA deregulation has been implicated in the pathogenesis of mantle cell lymphoma (MCL). Using a high-throughput quantitative real-time PCR platform, we performed miRNA profiling on cyclin D1–positive MCL (n = 30) and cyclin D1–negative MCL (n =7) and compared them with small lymphocytic leukemia/ lymphoma (n =12), aggressive B-cell lymphomas (n =138), normal B-cell subsets, and stromal cells.We identified a 19-miRNA classifier that included 6 up-regulated miRNAs and 13 down regulated miRNA that was able to distinguish MCL from other aggressive lymphomas. Some of the up-regulated miRNAs are highly expressed in naive B cells. This miRNAclassifier showed consistent results in formalinfixed paraffin-embedded tissues and was able to distinguish cyclin D1–negative MCL from other lymphomas. A 26-miRNA classifier could distinguish MCL from small lymphocytic leukemia/lymphoma, dominated by 23 up-regulated miRNAs in MCL. Unsupervised hierarchical clustering of MCL patients demonstrated a cluster characterized by high expression of miRNAs from the polycistronic miR17-92 cluster and its paralogs, miR-106a-363 and miR-106b-25, and associated with high proliferation gene signature. The other clusters showed enrichment of stroma-associated miRNAs, and also had higher expression of stroma-associated genes. Our clinical outcome analysis in the present study suggested that miRNAs can serve as prognosticators

Molecular distinctions between pediatric and adult mature B-cell non-Hodgkin lymphomas identified through genomic profiling

Burkitt lymphoma (BL) predominates in pediatric patients, whereas diffuse large B-cell lymphoma (DLBCL) is uncommon. In contrast to adults, BL and DLBCL are treated similarly in children and both entities have superior outcomes in children compared with adults. Gene expression profiling (GEP) and miRNA expression profiling clearly differentiated pediatric DLBCL from BL, forming distinct clusters regardless of patient age. However, pathway analysis of GEP data identified minor differences between corresponding pediatric and adult tumors. Predominance (6:1) of the germinal center B-cell subtype to activated B-cell subtype was found among pediatric DLBCL. Two cases were molecularly classified as primary mediastinal B-cell lymphoma. We observed frequent abnormalities in 8q24 in pediatric DLBCL, including MYC rearrangement in 31% (5 of 16) and gain or amplification in 50% (6 of 12) nonrearranged cases. MYC rearrangement was present in 96% (23 of 24) BL cases. Array-based CGH analysis identified abnormalities that are shared between adult and pediatric DLBCL (+12q15, +19q13, -6q), and abnormalities unique to the pediatric cases (-4p14, -19q13.32, +16p11.2), suggesting distinct pathogenetic mechanisms relative to age. Elucidation of the underlying target genes may provide insight into factors that modulate outcome and could provide potential novel therapeutic targets with less toxicity for pediatric patients with B-cell non-Hodgkin lymphoma

Genetic Determination of Susceptibility to Estrogen-Induced Mammary Cancer in the ACI Rat: Mapping of Emca1 and Emca2 to Chromosomes 5 and 18

Hormonal, genetic, and environmental factors play major roles in the complex etiology of breast cancer. When treated continuously with 17β-estradiol (E2), the ACI rat exhibits a genetically conferred propensity to develop mammary cancer. The susceptibility of the ACI rat to E2-induced mammary cancer appears to segregate as an incompletely dominant trait in crosses to the resistant Copenhagen (COP) strain. In both (ACI × COP)F(2) and (COP × ACI)F(2) populations, we find strong evidence for a major genetic determinant of susceptibility to E2-induced mammary cancer on distal rat chromosome 5. Our data are most consistent with a model in which the ACI allele of this locus, termed Emca1 (estrogen-induced mammary cancer 1), acts in an incompletely dominant manner to increase both tumor incidence and tumor multiplicity as well as to reduce tumor latency in these populations. We also find evidence suggestive of a second locus, Emca2, on chromosome 18 in the (ACI × COP)F(2) population. The ACI allele of Emca2 acts in a dominant manner to increase incidence and decrease latency. Together, Emca1 and Emca2 act independently to modify susceptibility to E2-induced mammary cancer

Genetic Etiology of Renal Agenesis : Fine Mapping of Renag1 and Identification of Kit as the Candidate Functional Gene

Congenital anomalies of the kidney and urogenital tract (CAKUT) occur in approximately 0.5% of live births and represent the most frequent cause of end-stage renal disease in neonates and children. The genetic basis of CAKUT is not well defined. To understand more fully the genetic basis of one type of CAKUT, unilateral renal agenesis (URA), we are studying inbred ACI rats, which spontaneously exhibit URA and associated urogenital anomalies at an incidence of approximately 10%. URA is inherited as an incompletely dominant trait with incomplete penetrance in crosses between ACI and Brown Norway (BN) rats and a single responsible genetic locus, designated Renag1, was previously mapped to rat chromosome 14 (RNO14). The goals of this study were to fine map Renag1, identify the causal genetic variant responsible for URA, confirm that the Renag1 variant is the sole determinant of URA in the ACI rat, and define the embryologic basis of URA in this rat model. Data presented herein localize Renag1 to a 379 kilobase (kb) interval that contains a single protein coding gene, Kit (v-kit Hardy-Zukerman 4 feline sarcoma viral oncogene homolog); identify an endogenous retrovirus-derived long terminal repeat located within Kit intron 1 as the probable causal variant; demonstrate aberrant development of the nephric duct in the anticipated number of ACI rat embryos; and demonstrate expression of Kit and Kit ligand (Kitlg) in the nephric duct. Congenic rats that harbor ACI alleles at Renag1 on the BN genetic background exhibit the same spectrum of urogenital anomalies as ACI rats, indicating that Renag1 is necessary and sufficient to elicit URA and associated urogenital anomalies. These data reveal the first genetic link between Kit and URA and illustrate the value of the ACI rat as a model for defining the mechanisms and cell types in which Kit functions during urogenital development

Genetic Etiology of Renal Agenesis: Fine Mapping of <i>Renag1</i> and Identification of <i>Kit</i> as the Candidate Functional Gene

<div><p>Congenital anomalies of the kidney and urogenital tract (CAKUT) occur in approximately 0.5% of live births and represent the most frequent cause of end-stage renal disease in neonates and children. The genetic basis of CAKUT is not well defined. To understand more fully the genetic basis of one type of CAKUT, unilateral renal agenesis (URA), we are studying inbred ACI rats, which spontaneously exhibit URA and associated urogenital anomalies at an incidence of approximately 10%. URA is inherited as an incompletely dominant trait with incomplete penetrance in crosses between ACI and Brown Norway (BN) rats and a single responsible genetic locus, designated <i>Renag1</i>, was previously mapped to rat chromosome 14 (RNO14). The goals of this study were to fine map <i>Renag1</i>, identify the causal genetic variant responsible for URA, confirm that the <i>Renag1</i> variant is the sole determinant of URA in the ACI rat, and define the embryologic basis of URA in this rat model. Data presented herein localize <i>Renag1</i> to a 379 kilobase (kb) interval that contains a single protein coding gene, <i>Kit</i> (v-kit Hardy-Zukerman 4 feline sarcoma viral oncogene homolog); identify an endogenous retrovirus-derived long terminal repeat located within <i>Kit</i> intron 1 as the probable causal variant; demonstrate aberrant development of the nephric duct in the anticipated number of ACI rat embryos; and demonstrate expression of <i>Kit</i> and Kit ligand (<i>Kitlg</i>) in the nephric duct. Congenic rats that harbor ACI alleles at <i>Renag1</i> on the BN genetic background exhibit the same spectrum of urogenital anomalies as ACI rats, indicating that <i>Renag1</i> is necessary and sufficient to elicit URA and associated urogenital anomalies. These data reveal the first genetic link between <i>Kit</i> and URA and illustrate the value of the ACI rat as a model for defining the mechanisms and cell types in which Kit functions during urogenital development.</p></div

BN.ACI-Renag1 congenic rats exhibit the same spectrum and incidence of urogenital anomalies as ACI rats.

<p>The Con1 and Con2 congenic rat strains were generated as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0118147#sec009" target="_blank">Materials and Methods</a>. Each strain is homozygous for ACI alleles across the <i>Renag1</i> interval. <b>A.</b> The incidence of all grossly discernable urogenital anomalies in ACI (n = 216), Con1 (n = 238) and Con2 (n = 298) rats is illustrated. Numeral 1 indicates statistically significant difference relative to ACI. <b>B.</b> The frequency of unilateral renal agenesis (URA), unilateral renal hypoplasia (URH) and hydroureteronephrosis (HUN) in ACI, Con1 and Con2 rats is illustrated as a percent of total urogenital anomalies. <b>C.</b> The frequency of URA in ACI, Con1 and Con2 rats observed on the left (L) versus right (R) sides is illustrated. The asterisk indicates a statistically significant right side bias.</p

MicroRNA Expression Profiling Identifies Molecular Diagnostic Signatures for Anaplastic Large Cell Lymphoma

Medicine, Research &amp; ExperimentalPathologySCI(E)CPCI-S(ISTP)0MEETING ABSTRACT342A-342A9

Genome-wide copy-number analyses reveal genomic abnormalities involved in transformation of follicular lymphoma

Follicular lymphoma (FL), the second most common type of non-Hodgkin lymphoma in the western world, is characterized by the t(14; 18) translocation, which is present in up to 90% of cases. We studied 277 lymphoma samples (198 FL and 79 transformed FL [tFL]) using a single-nucleotide polymorphism array to identify the secondary chromosomal abnormalities that drive the development of FL and its transformation to diffuse large B-cell lymphoma. Common recurrent chromosomal abnormalities in FL included gains of 2, 5, 7, 6p, 8, 12, 17q, 18, 21, and X and losses on 6q and 17p. We also observed many frequent small abnormalities, including losses of 1p36.33-p36.31, 6q23.3-q24.1, and 10q23.1-q25.1 and gains of 2p16.1-p15, 8q24.13-q24.3, and 12q12-q13.13, and identified candidate genes that may be driving this selection. Recurrent abnormalities more frequent in tFL samples included gains of 3q27.3-q28 and chromosome 11 and losses of 9p21.3 and 15q. Four abnormalities, gain of X or Xp and losses of 6q23.2-24.1 or 6q13-15, predicted overall survival. Abnormalities associated with transformation of the disease likely impair immune surveillance, activate the nuclear factor-kappa B pathway, and deregulate p53 and B-cell transcription factors

(BNxACI)F₂ rats exhibit a diverse spectrum of urogenital anomalies.

<p>Urogenital anomalies were evaluated in a population of (BNxACI)F₂ rats (n = 4994) that was generated by intercrossing BN females to ACI males. <b>A.</b> The incidence of all grossly discernable urogenital anomalies in (BNxACI)F₂ rats is illustrated relative to that observed in ACI and BN rats. <b>B.</b> The incidence of unilateral renal agenesis (URA), unilateral renal hypoplasia (URH) and hydroureteronephrosis (HUN) in the (BNxACI)F₂ population is illustrated. <b>C.</b> The frequencies of URA, URH and HUN observed on the left (L) versus right (R) sides are illustrated. An asterisk indicates statistically significant right side bias (<i>p</i> ≤ 0.05). Two (BNxACI)F₂ rats exhibited bilateral HUN and were excluded from this analysis.</p