Clinical Features and Magnetic Resonance Imaging Findings in 7 Dogs with Central Nervous System Aspergillosis.

BACKGROUND: Systemic aspergillosis is a manifestation of Aspergillus sp. infection that can result in central nervous system (CNS) involvement with marked alterations in CNS function. Information regarding the clinical presentation and magnetic resonance imaging (MRI) findings in cases of aspergillosis with CNS involvement is lacking, resulting in a need for better understanding of this disease. HYPOTHESIS/OBJECTIVES: The primary objectives were to describe the clinical features and MRI findings in dogs with CNS aspergillosis. The secondary objectives were to describe clinicopathologic findings and case outcome. ANIMALS: Seven dogs with CNS aspergillosis. METHODS: Archived records from 6 institutions were reviewed to identify cases with MRI of CNS aspergillosis confirmed with serum galactomannan enzyme immunoassay (EIA) testing, culture, or supported by histopathology. Signalment, clinical, MRI, clinicopathologic, histopathologic, and microbiologic findings were recorded and evaluated. RESULTS: Aspergillosis of the CNS was identified in 7 dogs from 3 institutions. The median age was 3 years and six were German Shepherd dogs. Five dogs had signs of vestibular dysfunction as a component of multifocal neurological abnormalities. The MRI findings ranged from normal to abnormal, including hemorrhagic infarction and mass lesions. CONCLUSIONS AND CLINICAL IMPORTANCE: Until now, all reported MRI findings in dogs with CNS aspergillosis have been abnormal. We document that CNS aspergillosis in dogs, particularly German Shepherd dogs, can be suspected based on neurologic signs, whether MRI findings are normal or abnormal. Confirmatory testing with galactomannan EIA, urine, cerebrospinal fluid (CSF) or tissue culture should be performed in cases where aspergillosis is a differential diagnosis.

Quantitative magnetic resonance imaging in a naturally occurring canine model of spinal cord injury.

STUDY DESIGN: Retrospective cohort study. OBJECTIVES: To analyze magnetic resonance imaging (MRI) evaluator agreement in dogs with spinal cord injury (SCI) caused by intervertebral disk herniation (IVDH) using semiautomated and manual lesion segmentation and to analyze the associations between MRI and functional outcome. SETTING: United States of America. METHODS: T2-weighted MRIs from dogs with SCI resulting from thoracolumbar IVDH were identified from a database. Evaluators categorized MRIs on the basis of the presence or absence of a T2-hyperintense spinal cord lesion in axial and sagittal images. A semiautomated segmentation algorithm was developed and used to estimate the lesion volume. Agreement between evaluators and between semiautomated and manual segmentation was analyzed. The relationships of qualitative and quantitative MRIs with behavioral functional outcome were analyzed. RESULTS: Axial images more commonly depicted lesions compared with sagittal images. Lesions in axial images had more consistent associations with functional outcome compared with sagittal images. There was imperfect qualitative agreement, and lesion volume estimation was imprecise. However, there was improved precision using semiautomated segmentation compared with manual segmentation. CONCLUSION: Lesion volume estimation in dogs with naturally occurring SCI caused by IVDH is challenging, and axial images have important advantages compared with sagittal images. The semiautomated segmentation algorithm described herein shows promise but may require further refinement.

Lymphocytic ganglioneuritis secondary to intervertebral disc extrusion in a dog.

This study presents a case of lymphocytic ganglioneuritis in a dog secondary to intervertebral disc extrusion that mimicked a peripheral nerve sheath tumour on magnetic resonance imaging. A four-year-old spayed female dachshund with lumbar pain was imaged via magnetic resonance. A tubular, space-occupying, contrast-enhancing lesion was noted in the right intervertebral foramen at L6 to L7. This was presumed to represent focal enlargement of the right sixth lumbar spinal nerve. A right-sided haemilaminectomy was performed at L6 to L7 and material that grossly resembled extruded nucleus pulposus was removed. The right L6 dorsal root ganglion, dorsal nerve root and proximal spinal nerve were severely enlarged and a partial thickness biopsy was collected from the dorsal root ganglion. Results of histopathological examination of the submitted tissue samples were consistent with extruded disc material and lymphocytic ganglioneuritis. To the author's knowledge, this is the first published report of lymphocytic ganglioneuritis secondary to intervertebral disc disease in a dog.

Necrotizing meningoencephalitis in atypical dog breeds: a case series and literature review.

BACKGROUND: Canine necrotizing meningoencephalitis (NME) is a fatal, noninfectious inflammatory disease of unknown etiology. NME has been reported only in a small number of dog breeds, which has led to the presumption that it is a breed-restricted disorder. HYPOTHESIS/OBJECTIVES: Our objective was to describe histopathologically confirmed NME in dog breeds in which the condition has not been reported previously and to provide preliminary evidence that NME affects a wider spectrum of dog breeds than previously reported. ANIMALS: Four dogs with NME. METHODS: Archives from 3 institutions and from 1 author's (BS) collection were reviewed to identify histopathologically confirmed cases of NME in breeds in which the disease has not been reported previously. Age, sex, breed, survival from onset of clinical signs, and histopathologic findings were evaluated. RESULTS: Necrotizing meningoencephalitis was identified in 4 small dog breeds (Papillon, Shih Tzu, Coton de Tulear, and Brussels Griffon). Median age at clinical evaluation was 2.5 years. Histopathologic abnormalities included 2 or more of the following: lymphoplasmacytic or histiocytic meningoencephalitis or encephalitis, moderate-to-severe cerebrocortical necrosis, variable involvement of other anatomic locations within the brain (cerebellum, brainstem), and absence of detectable infectious agents. CONCLUSIONS AND CLINICAL IMPORTANCE: Until now, NME has only been described in 5 small dog breeds. We document an additional 4 small breeds previously not shown to develop NME. Our cases further illustrate that NME is not a breed-restricted disorder and should be considered in the differential diagnosis for dogs with signalment and clinical signs consistent with inflammatory brain disease.

Neurological disease in lambs associated with exposure to high environmental temperature and humidity.

BACKGROUND: We detected a pattern of lambs presenting with hyperthermia and neurological signs during the summer. OBJECTIVES: The main objectives of this study were to compare clinical findings and results of diagnostic testing and to identify a potential etiology. ANIMALS: Fifteen clinical cases of lambs less than 12 months of age presenting with neurological signs, tachypnea, and hyperthermia over 4 summers. METHODS: Retrospective case series. Medical records were searched for lambs less than 12 months of age that presented with neurological signs including the following: kyphosis, pelvic limb hyperextension, treading of feet, muscle tremors and recumbency, and hyperthermia of greater than 104°F. A grading system was established to describe severity of presenting neurological signs. Weather data were collected from weather stations near the farm of origin for 3 days prior to presentation. RESULTS: The lambs were from 7 flocks in central Texas. All cases occurred between July and September, with a median heat index of 90.5 for the 3 days before presentation. Complete blood count, serum chemistry, necropsy examination, rumen content, virology, brain MRI, liver copper, selenium, and vitamin E failed to identify a consistent etiology for the signs presented. The only common factor was high heat and humidity. Histopathological examination identified axonal degeneration and skeletal muscle necrosis in some lambs. CONCLUSIONS AND CLINICAL IMPORTANCE: These clinical cases appeared similar to the Australian disease humpyback and indicate that lambs exposed to high environmental temperatures and humidity might be at risk of developing the described clinical presentation.

Magnetic resonance imaging for the differentiation of neoplastic, inflammatory, and cerebrovascular brain disease in dogs.

BACKGROUND: The reliability and validity of magnetic resonance imaging (MRI) for detecting neoplastic, inflammatory, and cerebrovascular brain lesions in dogs are unknown. OBJECTIVES: To estimate sensitivity, specificity, and inter-rater agreement of MRI for classifying histologically confirmed neoplastic, inflammatory, and cerebrovascular brain disease in dogs. ANIMALS: One hundred and twenty-one client-owned dogs diagnosed with brain disease (n = 77) or idiopathic epilepsy (n = 44). METHODS: Retrospective, multi-institutional case series; 3 investigators analyzed MR images for the presence of a brain lesion with and without knowledge of case clinical data. Investigators recorded most likely etiologic category (neoplastic, inflammatory, cerebrovascular) and most likely specific disease for all brain lesions. Sensitivity, specificity, and inter-rater agreement were calculated to estimate diagnostic performance. RESULTS: MRI was 94.4% sensitive (95% confidence interval [CI] = 88.7, 97.4) and 95.5% specific (95% CI = 89.9, 98.1) for detecting a brain lesion with similarly high performance for classifying neoplastic and inflammatory disease, but was only 38.9% sensitive for classifying cerebrovascular disease (95% CI = 16.1, 67.0). In general, high specificity but not sensitivity was retained for MR diagnosis of specific brain diseases. Inter-rater agreement was very good for overall detection of structural brain lesions (κ = 0.895, 95% CI = 0.792, 0.998, P < .001) and neoplastic lesions, but was only fair for cerebrovascular lesions (κ = 0.299, 95% CI = 0, 0.761, P = .21). CONCLUSIONS AND CLINICAL IMPORTANCE: MRI is sensitive and specific for identifying brain lesions and classifying disease as inflammatory or neoplastic in dogs. Cerebrovascular disease in general and specific inflammatory, neoplastic, and cerebrovascular brain diseases were frequently misclassified.

Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding.

The t(8;21) translocation fuses the DNA-binding domain of the hematopoietic master regulator RUNX1 to the ETO protein. The resultant RUNX1/ETO fusion protein is a leukemia-initiating transcription factor that interferes with RUNX1 function. The result of this interference is a block in differentiation and, finally, the development of acute myeloid leukemia (AML). To obtain insights into RUNX1/ETO-dependant alterations of the epigenetic landscape, we measured genome-wide RUNX1- and RUNX1/ETO-bound regions in t(8;21) cells and assessed to what extent the effects of RUNX1/ETO on the epigenome depend on its continued expression in established leukemic cells. To this end, we determined dynamic alterations of histone acetylation, RNA Polymerase II binding and RUNX1 occupancy in the presence or absence of RUNX1/ETO using a knockdown approach. Combined global assessments of chromatin accessibility and kinetic gene expression data show that RUNX1/ETO controls the expression of important regulators of hematopoietic differentiation and self-renewal. We show that selective removal of RUNX1/ETO leads to a widespread reversal of epigenetic reprogramming and a genome-wide redistribution of RUNX1 binding, resulting in the inhibition of leukemic proliferation and self-renewal, and the induction of differentiation. This demonstrates that RUNX1/ETO represents a pivotal therapeutic target in AML.

Sequential genetic change at the TP53 and chemokine receptor CXCR4 locus during transformation of human ovarian surface epithelium.

Early genetic events in the development of high-grade serous ovarian cancer (HGSOC) may define the molecular basis of the profound structural and numerical instability of chromosomes in this disease. To discover candidate genetic changes we sequentially passaged cells from a karyotypically normal hTERT immortalised human ovarian surface epithelial line (IOSE25) resulting in the spontaneous formation of colonies in soft agar. Cell lines transformed ovarian surface epithelium 1 and 4 (TOSE 1 and 4) established from these colonies had an abnormal karyotype and altered morphology, but were not tumourigenic in immunodeficient mice. TOSE cells showed loss of heterozygosity (LOH) at TP53, increased nuclear p53 immunoreactivity and altered expression profile of p53 target genes. The parental IOSE25 cells contained a missense, heterozygous R175H mutation in TP53, whereas TOSE cells had LOH at the TP53 locus with a new R273H mutation at the previous wild-type TP53 allele. Cytogenetic and array CGH analysis of TOSE cells also revealed a focal genomic amplification of CXCR4, a chemokine receptor commonly expressed by HGSOC cells. TOSE cells had increased functional CXCR4 protein and its abrogation reduced epidermal growth factor receptor (EGFR) expression, as well as colony size and number. The CXCR4 ligand, CXCL12, was epigenetically silenced in TOSE cells and its forced expression increased TOSE colony size. TOSE cells had other cytogenetic changes typical of those seen in HGSOC ovarian cancer cell lines and biopsies. In addition, enrichment of CXCR4 pathway in expression profiles from HGSOC correlated with enrichment of a mutated TP53 gene expression signature and of EGFR pathway genes. Our data suggest that mutations in TP53 and amplification of the CXCR4 gene locus may be early events in the development of HGSOC, and associated with chromosomal instability.

The Interlaboratory RObustness of Next-generation sequencing (IRON) study: a deep sequencing investigation of TET2, CBL and KRAS mutations by an international consortium involving 10 laboratories.

Massively parallel pyrosequencing allows sensitive deep sequencing to detect molecular aberrations. Thus far, data are limited on the technical performance in a clinical diagnostic setting. Here, we investigated as an international consortium the robustness, precision and reproducibility of amplicon next-generation deep sequencing across 10 laboratories in eight countries. In a cohort of 18 chronic myelomonocytic leukemia patients, mutational analyses were performed on TET2, a frequently mutated gene in myeloproliferative neoplasms. Additionally, hotspot regions of CBL and KRAS were investigated. The study was executed using GS FLX sequencing instruments and the small volume 454 Life Sciences Titanium emulsion PCR setup. We report a high concordance in mutation detection across all laboratories, including a robust detection of novel variants, which were undetected by standard Sanger sequencing. The sensitivity to detect low-level variants present with as low as 1-2% frequency, compared with the 20% threshold for Sanger-based sequencing is increased. Together with the output of high-quality long reads and fast run time, we demonstrate the utility of deep sequencing in clinical applications. In conclusion, this multicenter analysis demonstrated that amplicon-based deep sequencing is technically feasible, achieves high concordance across multiple laboratories and allows a broad and in-depth molecular characterization of cancer specimens with high diagnostic sensitivity.

13q deletion anatomy and disease progression in patients with chronic lymphocytic leukemia.

Historically, genes targeted by recurrent chromosomal deletions have been identified within the smallest genomic region shared in all patients, the minimally deleted region (MDR). However, deletions this small do not occur in all patients and are a simplification of the impact larger heterogeneous deletions have during carcinogenesis. We use the example of 13q14 deletions in chronic lymphocytic leukemia to show that genes outside MDRs are associated with disease progression. Genomic profiling of 224 patients identified 205 copy number alterations on chromosome 13 in 132 cases. Deletions including DLEU2 were heterogeneous (845 Kb-96.2 Mb) and identified two breakpoint cluster regions within short interspersed nuclear elements proximal to DLEU2 and within long interspersed nuclear elements/L1 repeats distal to GUCY1B2. After defining a deletion class on the basis of size and location, we show that (a) at diagnosis, larger deletions (class II) were associated with a significantly increased risk of disease progression (odds ratio=12.3; P=0.005), (b) in progressive patients, class II deletions were enriched (P=0.02) and (c) this association was independent of IgVH mutational status, ZAP70 expression and ATM/TP53 deletion. Deletion of a 1 Mb gene cluster (48.2-49.2 Mb), including SETDB2, PHF11 and RCBTB1, was significantly associated (P<0.01) with disease progression. Here, we show that the deletion of genes outside MDRs can influence clinical outcome.

High-resolution genomic profiling of human papillomavirus-associated vulval neoplasia.

BACKGROUND: The incidence of human papillomavirus-associated vulval neoplasia is increasing worldwide; yet the associated genetic changes remain poorly understood. METHODS: We have used single-nucleotide polymorphism microarray analysis to perform the first high-resolution investigation of genome-wide allelic imbalance in vulval neoplasia. Our sample series comprised 21 high-grade vulval intraepithelial neoplasia and 6 vulval squamous cell carcinomas, with paired non-lesional samples used to adjust for normal copy number variation. RESULTS: Overall the most common recurrent aberrations were gains at 1p and 20, with the most frequent deletions observed at 2q, 3p and 10. Copy-neutral loss of heterozygosity at 6p was a recurrent event in vulval intraepithelial neoplasia. The pattern of genetic alterations differed from the characteristic changes we previously identified in cutaneous squamous cell carcinomas. Vulval neoplasia samples did not exhibit gain at 5p, a frequent recurrent aberration in a series of cervical tumours analysed elsewhere using an identical protocol. CONCLUSION: This series of 27 vulval samples comprises the largest systematic genome-wide analysis of vulval neoplasia performed to date. Despite shared papillomavirus status and regional proximity, our data suggest that the frequency of certain genetic alterations may differ in vulval and cervical tumours.

Relapsed childhood high hyperdiploid acute lymphoblastic leukemia: presence of preleukemic ancestral clones and the secondary nature of microdeletions and RTK-RAS mutations.

Although childhood high hyperdiploid acute lymphoblastic leukemia is associated with a favorable outcome, 20% of patients still relapse. It is important to identify these patients already at diagnosis to ensure proper risk stratification. We have investigated 11 paired diagnostic and relapse samples with single nucleotide polymorphism array and mutation analyses of FLT3, KRAS, NRAS and PTPN11 in order to identify changes associated with relapse and to ascertain the genetic evolution patterns. Structural changes, mainly cryptic hemizygous deletions, were significantly more common at relapse (P<0.05). No single aberration was linked to relapse, but four deletions, involving IKZF1, PAX5, CDKN2A/B or AK3, were recurrent. On the basis of the genetic relationship between the paired samples, three groups were delineated: (1) identical genetic changes at diagnosis and relapse (2 of 11 cases), (2) clonal evolution with all changes at diagnosis being present at relapse (2 of 11) and (3) clonal evolution with some changes conserved, lost or gained (7 of 11), suggesting the presence of a preleukemic clone. This ancestral clone was characterized by numerical changes only, with structural changes and RTK-RAS mutations being secondary to the high hyperdiploid pattern.

The identification of chromosomal translocation, t(4;6)(q22;q15), in prostate cancer.

Our previous work identified a chromosomal translocation t(4;6) in prostate cancer cell lines and primary tumors. Using probes located on 4q22 and 6q15, the breakpoints identified in LNCaP cells, we performed fluorescence in situ hybridization analysis to detect this translocation in a large series of clinical localized prostate cancer samples treated conservatively. We found that t(4;6)(q22;q15) occurred in 78 of 667 cases (11.7%). The t(4;6)(q22;q15) was not independently associated with patient outcome. However, it occurs more frequently in high clinical T stage, high tumor volume specimens and in those with high baseline PSA (P=0.001, 0.001 and 0.01, respectively). The t(4;6)(q22;q15) occurred more frequently in samples with two or more TMPRSS2:ERG fusion genes caused by internal deletion than in samples without these genomic alterations, but this correlation is not statistically significant (P=0.0628). The potential role of this translocation in the development of human prostate cancer is discussed.

Magnetic resonance imaging in dogs with neurologic impairment due to acute thoracic and lumbar intervertebral disk herniation.

BACKGROUND: Magnetic resonance imaging (MRI) is a correlate to physical examination in various myelopathies and a predictor of functional outcome. OBJECTIVES: To describe associations among MRI features, neurological dysfunction before MRI, and functional outcome in dogs with disk herniation. ANIMALS: One hundred and fifty-nine dogs with acute thoracolumbar disk herniation. METHODS: Retrospective case series. Signalment, initial neurological function as assessed by a modified Frankel score (MFS), and ambulatory outcome at hospital discharge and >3 months (long-term) follow-up were recorded from medical records and telephone interview of owners. Associations were estimated between these parameters and MRI signal and morphometric data. RESULTS: Dogs with intramedullary T2W hyperintensity had more severe pre-MRI MFS (median 2, range 0-4) and lower ambulatory proportion at long-term follow-up (0.76) than those dogs lacking hyperintensity (median MFS 3, range 0-5; ambulatory proportion, 0.93) (P=.001 and .013, respectively). Each unit of T2W length ratio was associated with a 1.9 times lower odds of long-term ambulation when adjusted for pre-MRI MFS (95% confidence interval 1.0-3.52, P=.05). Dogs with a compressive length ratio >1.31 (which was the median ratio within this population) had more severe pre-MRI MFS (median 3, range 0-5) compared with those with ratios < or =1.31 (median MFS 3, range 0-4; P=.006). CONCLUSIONS AND CLINICAL IMPORTANCE: MRI features were associated with initial injury severity in dogs with thoracolumbar disk herniation. Based on results of this study, the T2W length ratio and presence of T2W intramedullary hyperintensity appear to be predictive of long-term ambulatory status.

Magnetic resonance imaging characteristics of necrotizing meningoencephalitis in Pug dogs.

BACKGROUND: The magnetic resonance imaging (MRI) characteristics of necrotizing meningoencephalitis (NME) are not well documented. OBJECTIVES: To describe common MRI features of NME, to compare the MRI features to histopathologic findings, and to determine whether or not MRI lesions are predictive of survival time. ANIMALS: Eighteen Pugs with NME. METHODS: Retrospective MRI case study of Pugs identified by a search of medical records at 6 veterinary institutions. Eighteen dogs met inclusion criteria of histopathologically confirmed NME and antemortem MRI exam. MRI lesions were characterized and compared with histopathology with the kappa statistic. Survival times were compared with MRI findings by use of Mann-Whitney U-tests and Spearman's rho. RESULTS: Twelve of 18 lesions were indistinctly marginated with mild parenchymal contrast enhancement. Prosencephalic (17/18) lesion distribution included the parietal (16/18), temporal (16/18), and occipital (16/18) lobes. There were cerebellar (4/18) and brainstem (3/18) lesions. Asymmetric lesions were present in both gray and white matter in all dogs. Falx cerebri shift was common (11/18), and 6 dogs had brain herniation. Leptomeningeal enhancement was present in 9/18 dogs. A moderate positive association was found between parenchymal contrast enhancement and both necrosis (kappa= 0.45; P= .045) and monocytic inflammation (kappa= 0.48; P= .025). Higher MRI lesion burden was correlated with longer time from disease onset to MRI (P= .045). MRI lesion burden did not correlate to survival time. CONCLUSIONS AND CLINICAL IMPORTANCE: Asymmetric prosencephalic grey and white matter lesions with variable contrast enhancement were consistent MRI changes in Pugs with confirmed NME. While not pathognomonic for NME, these MRI characteristics should increase confidence in a presumptive diagnosis of NME in young Pugs with acute signs of neurologic disease.

Fingerprinting genomic instability in oral submucous fibrosis.

BACKGROUND: Oral submucous fibrosis (OSF) is a high-risk pre-cancerous condition where 7-13% of these patients develop head and neck squamous cell carcinoma (HNSCC). To date there is no cancer predictive markers for OSF patients. Genomic instability hallmarks early genetic events during malignant transformation causing loss of heterozygosity (LOH) and chromosomal copy number abnormality. However, to date there is no study on genomic instability in OSF. Although this condition is known as a high-risk pre-cancerous condition, there is no data regarding the genomic status of this disease in terms of genetic susceptibility to malignant transformation. METHODS: In this study, we investigated the existence of genetic signatures for carcinogenesis in OSF. We employed the high-resolution genome-wide Affymetrix Mapping single nucleotide polymorphism microarray technique to 'fingerprint' global genomic instability in the form of LOH in 15 patient-matched OSF-blood genomic DNA samples. RESULTS: This rapid high-resolution mapping technique has revealed for the first time that a small number of discrete hot-spot LOH loci appeared in 47-53% of the OSF tissues studied. Many of these LOH loci were previously identified regions of genomic instability associated with carcinogenesis of the HNSCC. CONCLUSION: To our knowledge, this is the first evidence that genomic instability in the form of LOH is present in OSF. We hypothesize that the genomic instability detected in OSF may play an important role in malignant transformation. Further functional association studies on these putative genes may reveal potential predictive oral cancer markers for OSF patients.

Genome-wide DNA copy number analysis in pancreatic cancer using high-density single nucleotide polymorphism arrays.

To identify genomic abnormalities characteristic of pancreatic ductal adenocarcinoma (PDAC) in vivo, a panel of 27 microdissected PDAC specimens were analysed using high-density microarrays representing approximately 116 000 single nucleotide polymorphism (SNP) loci. We detected frequent gains of 1q, 2, 3, 5, 7p, 8q, 11, 14q and 17q (> or =78% of cases), and losses of 1p, 3p, 6, 9p, 13q, 14q, 17p and 18q (> or =44%). Although the results were comparable with those from array CGH, regions of those genetic changes were defined more accurately by SNP arrays. Integrating the Ensembl public data, we have generated 'gene' copy number indices that facilitate the search for novel candidates involved in pancreatic carcinogenesis. Copy numbers in a subset of the genes were validated using quantitative real-time PCR. The SKAP2/SCAP2 gene (7p15.2), which belongs to the src family kinases, was most frequently (63%) amplified in our sample set and its recurrent overexpression (67%) was confirmed by reverse transcription-PCR. Furthermore, fluorescence in situ hybridization and in situ RNA hybridization analyses for this gene have demonstrated a significant correlation between DNA copy number and mRNA expression level in an independent sample set (P<0.001). These findings indicate that the dysregulation of SKAP2/SCAP2, which is mostly caused by its increased gene copy number, is likely to be associated with the development of PDAC.

Genome-wide detection of recurring sites of uniparental disomy in follicular and transformed follicular lymphoma.

Single-nucleotide polymorphism (SNP) array analysis was performed using the 10K GeneChip array on a series of 26 paired follicular lymphoma (FL) and transformed-FL (t-FL) biopsies and the lymphoma cell lines SCI-1, DoHH2 and RL2261. Regions of acquired homozygosity were detected in 43/52 (83%) primary specimens with a mean of 1.7 and 3.0 aberrations in the FL and t-FL, respectively. A notable feature was the occurrence of recurring sites of acquired uniparental disomy (aUDP) on 6p, 9p, 12q and 17p in cell lines and primary samples. Homozygosity of 9p and 17p arose predominantly in t-FL and in three cases rendered the cell homozygous for a pre-existing mutation of either CDKN2A or TP53. These data suggest that mutation precedes mitotic recombination, which leads to the removal of the remaining wild-type allele. In all, 18 cases exhibited abnormalities in both FL and t-FL samples. In 10 cases blocks of homozygosity were detected in FL that were absent in the subsequent t-FL sample. These differences support the notion that FL and t-FL may arise in a proportion of patients by divergence from a common malignant ancestor cell rather than by clonal evolution from an antecedent FL.

MicroRNA miR-181a correlates with morphological sub-class of acute myeloid leukaemia and the expression of its target genes in global genome-wide analysis.

MicroRNAs (miRNAs) are short single-stranded RNAs that have a potentially important role in gene regulation. Using a quantitative real-time polymerase chain reaction assay specific to the mature miRNA, the expression level of a selected group of haematopoietic tissue-specific miRNAs was measured across a set of 30 primary adult acute myeloid leukaemia (AML) with a normal karyotype. The expression levels of each miRNA were correlated with the genome-wide mRNA expression profiles in the same leukaemias. This revealed that miR-181a correlated strongly with the AML morphological sub-type and with the expression of genes previously identified through sequence analysis as potential interaction targets. Three other miRNAs, miR-10a, miR-10b and miR-196a-1, showed a clear correlation with HOX gene expression.