Identification of FBXL4 as a Metastasis Associated Gene in Prostate Cancer.

Prostate cancer is the most common cancer among western men, with a significant mortality and morbidity reported for advanced metastatic disease. Current understanding of metastatic disease is limited due to difficulty of sampling as prostate cancer mainly metastasizes to bone. By analysing prostate cancer bone metastases using high density microarrays, we found a common genomic copy number loss at 6q16.

High Throughput Sequencing Analysis of the Immunoglobulin Heavy Chain Gene from Flow-Sorted B Cell Sub-Populations Define the Dynamics of Follicular Lymphoma Clonal Evolution.

Understanding the dynamics of evolution of Follicular Lymphoma (FL) clones during disease progression is important for monitoring and targeting this tumor effectively. Genetic profiling of serial FL biopsies and examples of FL transmission following bone marrow transplant suggest that this disease may evolve by divergent evolution from a common ancestor cell. However where this ancestor cell resides and how it evolves is still unclear.

ATM mutation rather than BIRC3 deletion and/or mutation predicts reduced survival in 11q-deleted chronic lymphocytic leukemia: data from the UK LRF CLL4 trial.

ATM mutation and BIRC3 deletion and/or mutation have independently been shown to have prognostic significance in chronic lymphocytic leukemia. However, the relative clinical importance of these abnormalities in patients with a deletion of 11q encompassing the ATM gene has not been established. We screened a cohort of 166 patients enriched for 11q-deletions for ATM mutations and BIRC3 deletion and mutation and determined the overall and progression-free survival among the 133 of these cases treated within the UK LRF CLL4 trial.

Loss of imprinting at the 14q32 domain is associated with microRNA overexpression in acute promyelocytic leukemia.

Distinct patterns of DNA methylation characterize the epigenetic landscape of promyelocytic leukemia/retinoic acid receptor-α (PML-RARα)-associated acute promyelocytic leukemia (APL). We previously reported that the microRNAs (miRNAs) clustered on chromosome 14q32 are overexpressed only in APL. Here, using high-throughput bisulfite sequencing, we identified an APL-associated hypermethylation at the upstream differentially methylated region (DMR), which also included the site motifs for the enhancer blocking protein CCCTC-binding factor (CTCF).

Identification of ZDHHC14 as a novel human tumour suppressor gene.

Genomic changes affecting tumour suppressor genes are fundamental to cancer. We applied SNP array analysis to a panel of testicular germ cell tumours to search for novel tumour suppressor genes and identified a frequent small deletion on 6q25.3 affecting just one gene, ZDHHC14.

High-resolution genome-wide copy-number analysis suggests a monoclonal origin of multifocal prostate cancer.

Many human cancers present as multifocal lesions. Understanding the clonal origin of multifocal cancers is of both etiological and clinical importance. The molecular basis of multifocal prostate cancer has previously been explored using a limited number of isolated markers and, although independent origin is widely believed, the clonal origin of multifocal prostate cancer is still debatable.

Chromosome rearrangement associated inactivation of tumour suppressor genes in prostate cancer.

Prostate cancer, the most common male cancer in Western countries, is commonly detected with complex chromosomal rearrangements. Following the discovery of the recurrent TMPRSS2:ETS fusions in prostate cancer and EML4:ALK in non-small-cell lung cancer, it is now accepted that fusion genes not only are the hallmark of haematological malignancies and sarcomas, but also play an important role in epithelial cell carcinogenesis. However, previous studies aiming to identify fusion genes in prostate cancer were mainly focused on expression changes and fusion transcripts.

Integrated genomic analysis of sézary syndrome.

Sézary syndrome (SS) is a rare variant of primary cutaneous T-cell lymphoma. Little is known about the underlying pathogenesis of S. To address this issue, we used Affymetrix 10K SNP microarray to analyse 13 DNA samples isolated from 8 SS patients and qPCR with ABI TaqMan SNP genotyping assays for the validation of the SNP microarray results.

Distinct genomic alterations in prostate cancers in Chinese and Western populations suggest alternative pathways of prostate carcinogenesis.

Prostate cancer is significantly more common in Western men than in Asian men, but the basis for this difference remains unknown. Because genomic studies of Asian prostate cancer are very limited, we used a genome-wide approach to reveal the genomic alterations in Chinese prostate cancers. We found a significant reduction in the frequency of certain somatic genomic changes that are commonly found in Western prostate cancers, including the 21q22.

The association of CCND1 overexpression and cisplatin resistance in testicular germ cell tumors and other cancers.

Development of chemoresistance limits the clinical efficiency of platinum-based therapy. Although many resistance mechanisms have been demonstrated, genetic/molecular alterations responsible for drug resistance in the majority of clinical cases have not been identified. We analyzed three pairs of testicular germ cell tumor cell lines using Affymetrix expression microarrays and revealed a limited number of differentially expressed genes across the cell lines when comparing the parental and resistant cells.

Upregulation of FOXM1 induces genomic instability in human epidermal keratinocytes.

Background: The human cell cycle transcription factor FOXM1 is known to play a key role in regulating timely mitotic progression and accurate chromosomal segregation during cell division. Deregulation of FOXM1 has been linked to a majority of human cancers. We previously showed that FOXM1 was upregulated in basal cell carcinoma and recently reported that upregulation of FOXM1 precedes malignancy in a number of solid human cancer types including oral, oesophagus, lung, breast, kidney, bladder and uterus.

Angiotensin II-induced expression of brain-derived neurotrophic factor in human and rat adrenocortical cells.

Angiotensin II (Ang II) is a major regulator of steroidogenesis in adrenocortical cells, and is also an effective inducer of cytokine and growth factor synthesis in several cell types. In microarray analysis of H295R human adrenocortical cells, the mRNA of brain-derived neurotrophic factor (BDNF), a neurotrophin widely expressed in the nervous system, was one of the most up-regulated genes by Ang II. The aim of the present study was the analysis of the Ang II-induced BDNF expression and BDNF-induced effects in adrenocortical cells.

Acquisition of genome-wide copy number alterations in monozygotic twins with acute lymphoblastic leukemia.

Chimeric fusion genes are highly prevalent in childhood acute lymphoblastic leukemia (ALL) and are mostly prenatal, early genetic events in the evolutionary trajectory of this cancer. ETV6-RUNX1-positive ALL also has multiple ( approximately 6 per case) copy number alterations (CNAs) as revealed by genome-wide single-nucleotide polymorphism arrays. Recurrent CNAs are probably "driver" events contributing critically to clonal diversification and selection, but at diagnosis, their developmental timing is "buried" in the leukemia's covert natural history.

Activation of the ERK/MAPK pathway: a signature genetic defect in posterior fossa pilocytic astrocytomas.

We report genetic aberrations that activate the ERK/MAP kinase pathway in 100% of posterior fossa pilocytic astrocytomas, with a high frequency of gene fusions between KIAA1549 and BRAF among these tumours. These fusions were identified from analysis of focal copy number gains at 7q34, detected using Affymetrix 250K and 6.0 SNP arrays.

FOXM1 upregulation is an early event in human squamous cell carcinoma and it is enhanced by nicotine during malignant transformation.

Background: Cancer associated with smoking and drinking remains a serious health problem worldwide. The survival of patients is very poor due to the lack of effective early biomarkers. FOXM1 overexpression is linked to the majority of human cancers but its mechanism remains unclear in head and neck squamous cell carcinoma (HNSCC).

Single nucleotide polymorphism array analysis defines a specific genetic fingerprint for well-differentiated cutaneous SCCs.

Cutaneous squamous cell carcinomas (cSCCs) are the second most frequent cancers in fair-skinned populations; yet, because of their genetic heterogeneity, the key molecular events in cSCC tumorigenesis remain poorly defined. We have used single nucleotide polymorphism microarray analysis to examine genome-wide allelic imbalance in 60 cSCCs using paired non-tumor samples. The most frequent recurrent aberrations were loss of heterozygosity at 3p and 9p, observed in 39 (65%) and 45 (75%) tumors, respectively.

Specific JAK2 mutation (JAK2R683) and multiple gene deletions in Down syndrome acute lymphoblastic leukemia.

Children with Down syndrome (DS) have a greatly increased risk of acute megakaryoblastic leukemia (AMKL) and acute lymphoblastic leukemia (ALL). Both DS-AMKL and the related transient myeloproliferative disorder (TMD) have GATA1 mutations as obligatory, early events. To identify mutations contributing to leukemogenesis in DS-ALL, we undertook sequencing of candidate genes, including FLT3, RAS, PTPN11, BRAF, and JAK2.

Novel regions of acquired uniparental disomy discovered in acute myeloid leukemia.

The acquisition of uniparental disomy (aUPD) in acute myeloid leukemia (AML) results in homozygosity for known gene mutations. Uncovering novel regions of aUPD has the potential to identify previously unknown mutational targets. We therefore aimed to develop a map of the regions of aUPD in AML.

Segmental uniparental disomy is a commonly acquired genetic event in relapsed acute myeloid leukemia.

Despite advances in the curative treatment of acute myeloid leukemia (AML), recurrence will occur in the majority of cases. At diagnosis, acquisition of segmental uniparental disomy (UPD) by mitotic recombination has been reported in 15% to 20% of AML cases, associated with homozygous mutations in the region of loss of heterozygosity. This study aimed to discover if clonal evolution from heterozygous to homozygous mutations by mitotic recombination provides a mechanism for relapse.

Distinctive patterns of microRNA expression associated with karyotype in acute myeloid leukaemia.

Acute myeloid leukaemia (AML) is the most common acute leukaemia in adults; however, the genetic aetiology of the disease is not yet fully understood. A quantitative expression profile analysis of 157 mature miRNAs was performed on 100 AML patients representing the spectrum of known karyotypes common in AML. The principle observation reported here is that AMLs bearing a t(15;17) translocation had a distinctive signature throughout the whole set of genes, including the up regulation of a subset of miRNAs located in the human 14q32 imprinted domain.

Microdeletions are a general feature of adult and adolescent acute lymphoblastic leukemia: Unexpected similarities with pediatric disease.

We present here a genome-wide map of abnormalities found in diagnostic samples from 45 adults and adolescents with acute lymphoblastic leukemia (ALL). A 500K SNP array analysis uncovered frequent genetic abnormalities, with cryptic deletions constituting half of the detected changes, implying that microdeletions are a characteristic feature of this malignancy. Importantly, the pattern of deletions resembled that recently reported in pediatric ALL, suggesting that adult, adolescent, and childhood cases may be more similar on the genetic level than previously thought.

Subtle genomic alterations and genomic instability revealed in diploid cancer cell lines.

To investigate if genomic instability exists in tumors with cytogenetically normal karyotypes, we analyzed four diploid cancer cell lines A204, CAL51, CH1 and SK-UT-1B. We detected subtle genomic changes in all four cell lines. More of these alterations were found in A204 and CH1 than in the microsatellite unstable lines CAL51 and SK-UT-1B.

Identification of genomic changes associated with cisplatin resistance in testicular germ cell tumor cell lines.

Since the introduction of cisplatin into the clinic, the treatment of patients with a variety of solid tumors including testicular germ cell tumors, ovarian and lung cancers, has dramatically improved. One of the main causes for therapeutic failure in these malignancies is the development of drug resistance. Testicular germ cell tumors (TGCTs), the most common malignancy in young men, exhibit extreme sensitivity to cisplatin-based chemotherapy, making them an ideal model for investigating the mechanisms of cisplatin chemo-sensitivity and resistance.