The genomic complexity of primary human prostate cancer.

The Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
Nature (Impact Factor: 42.35). 02/2011; 470(7333):214-20. DOI: 10.1038/nature09744
Source: PubMed

ABSTRACT Prostate cancer is the second most common cause of male cancer deaths in the United States. However, the full range of prostate cancer genomic alterations is incompletely characterized. Here we present the complete sequence of seven primary human prostate cancers and their paired normal counterparts. Several tumours contained complex chains of balanced (that is, 'copy-neutral') rearrangements that occurred within or adjacent to known cancer genes. Rearrangement breakpoints were enriched near open chromatin, androgen receptor and ERG DNA binding sites in the setting of the ETS gene fusion TMPRSS2-ERG, but inversely correlated with these regions in tumours lacking ETS fusions. This observation suggests a link between chromatin or transcriptional regulation and the genesis of genomic aberrations. Three tumours contained rearrangements that disrupted CADM2, and four harboured events disrupting either PTEN (unbalanced events), a prostate tumour suppressor, or MAGI2 (balanced events), a PTEN interacting protein not previously implicated in prostate tumorigenesis. Thus, genomic rearrangements may arise from transcriptional or chromatin aberrancies and engage prostate tumorigenic mechanisms.

Download full-text


Available from: Kyung Park, Jan 13, 2014
1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objectives: In this review, we will discuss the latest advances in our understanding of the relationship between the cellular DNA damage response and genomic instability in prostate cancer and the emerging possibilities to exploit these aberrations as prognostic biomarkers and guides for personalized patient management. Methods: Important findings related to genomic instability in prostate cancer were retrieved from the literature and combined with our own results and a translational perspective. Results: Prostate cancer is characterized by a highly altered genomic landscape with a wide spectrum of genomic alterations, including somatic mutations, copy number alterations (CNAs), gene fusions, complex chromosomal rearrangements, and aneuploidy. In addition, massive DNA damaging events, including chromothripsis and chromoplexy, which can lead to extensive genomic insults in a single step, have been identified. A number of these genomic aberrations have been found to provide prognostic information and can therefore help to identify high-risk patients. In addition, defects in the DNA damage checkpoint and repair machinery can potentially be harnessed for therapeutic purposes. Conclusions: Genomic instability plays a crucial role in the malignant progression of prostate cancer and can be exploited for the development of novel prognostic biomarkers and innovative therapies.
    Urologic Oncology 06/2014; 32(8). DOI:10.1016/j.urolonc.2014.02.005 · 3.36 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Prostate adenocarcinoma is one of the leading causes of cancer related mortality in men but still limited knowledge is available about its associated functional SNPs including rs1042522 (Pro72Arg). The present study was undertaken to explore the association of this SNP with susceptibility to prostate adenocarcinoma along with its structural and functional impacts in the Pakistani population in a case-control study. Three-dimensional structure of human TP53 with Pro72Arg polymorphism was predicted through homology modeling, refined and validated for detailed structure-based assessment. We also carried out a HuGE review of the previous available data for this polymorphism. Different genetic models were used to evaluate the genotypes association with the increased risk of PCa (Allelic contrast: OR=0.0.34, 95%CI 0.24-0.50, p=0.000; GG vs CC: OR=0.17, 95%CI 0.08-0.38, p=0.000; Homozygous: OR=0.08, 95%CI 0.04-0.15, p=0.000; GC vs CC: OR=2.14, 95%CI 1.01-4.51, p=0.046; Recessive model: OR=0.10, 95%CI 0.05-0.18, p=0.000; Log Additive: OR=3.54, 95%CI 2.13-5.89, p=0.000) except the Dominant model (OR=0.77, 95%CI 0.39-1.52, p=0.46). Structure and functional analysis revealed that the SNP in the proline rich domain is responsible for interaction with HRMT1L2 and WWOX. In conclusion, it was observed that the Arg coding G allele is highly associated with increased risk of prostate adenocarcinoma in the Pakistani population (p=0.000).
    Asian Pacific journal of cancer prevention: APJCP 05/2014; 15(9):3973-80. DOI:10.7314/APJCP.2014.15.9.3973 · 1.50 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Somatically-acquired translocations may serve as important markers for assessing the cause and nature of diseases like cancer. Algorithms to locate translocations may use next-generation sequencing (NGS) platform data. However, paired-end strategies do not accurately predict precise translocation breakpoints, and "split-read" methods may lose sensitivity if a translocation boundary is not captured by many sequenced reads. To address these challenges, we have developed "Bellerophon", a method that uses discordant read pairs to identify potential translocations, and subsequently uses "soft-clipped" reads to predict the location of the precise breakpoints. Furthermore, for each chimeric breakpoint, our method attempts to classify it as a participant in an unbalanced translocation, balanced translocation, or interchromosomal insertion. Results We compared Bellerophon to four previously published algorithms for detecting structural variation (SV). Using two simulated datasets and two prostate cancer datasets, Bellerophon had overall better performance than the other methods. Furthermore, our method accurately predicted the presence of the interchromosomal insertions placed in our simulated dataset, which is an ability that the other SV prediction programs lack. Conclusions The combined use of paired reads and soft-clipped reads allows Bellerophon to detect interchromosomal breakpoints with high sensitivity, while also mitigating losses in specificity. This trend is seen across all datasets examined. Because it does not perform assembly on soft-clipped subreads, Bellerophon may be limited in experiments where sequence read lengths are short. Availability The program can be downloaded from
    BMC Bioinformatics 01/2014; 14(5). DOI:10.1186/1471-2105-14-S5-S6 · 2.67 Impact Factor