Genetic changes and DNA damage responses in the prostate

Hällström, Taija M. Kiviharju-af; Laiho, Marikki

doi:10.1002/pros.20746

Cited by 27 publications

(10 citation statements)

References 157 publications

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“…HG PIN lesions that form after deletion of Brca2 and Trp53 contained many cells with DNA damage, indicating increased genomic instability [17]. Multi-focal lesions are a common feature of human prostate cancer and may be due to defects in the DNA damage response [37]. The formation of HG PIN lesions in Brca2;Trp53 mutant prostates may reflect the loss of key regulatory p53-dependent functions in response to DNA damage controlling cell-cycle checkpoints, apoptosis and senescence [38].…”

Section: Discussionmentioning

confidence: 99%

Brca2 and Trp53 Deficiency Cooperate in the Progression of Mouse Prostate Tumourigenesis

et al. 2010

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Epidemiological studies have shown that one of the strongest risk factors for prostate cancer is a family history of the disease, suggesting that inherited factors play a major role in prostate cancer susceptibility. Germline mutations in BRCA2 predispose to breast and ovarian cancer with its predominant tumour suppressor function thought to be the repair of DNA double-strand breaks. BRCA2 has also been implicated in prostate cancer etiology, but it is unclear the impact that mutations in this gene have on prostate tumourigenesis. Here we have undertaken a genetic analysis in the mouse to determine the role of Brca2 in the adult prostate. We show that deletion of Brca2 specifically in prostate epithelia results in focal hyperplasia and low-grade prostate intraepithelial neoplasia (PIN) in animals over 12 months of age. Simultaneous deletion of Brca2 and the tumour suppressor Trp53 in prostate epithelia gave rise to focal hyperplasia and atypical cells at 6 months, leading to high-grade PIN in animals from 12 months. Epithelial cells in these lesions show an increase in DNA damage and have higher levels of proliferation, but also elevated apoptosis. Castration of Brca2;Trp53 mutant animals led to regression of PIN lesions, but atypical cells persisted that continued to proliferate and express nuclear androgen receptor. This study provides evidence that Brca2 can act as a tumour suppressor in the prostate, and the model we describe should prove useful in the development of new therapeutic approaches.

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Section: Discussionmentioning

confidence: 99%

Brca2 and Trp53 Deficiency Cooperate in the Progression of Mouse Prostate Tumourigenesis

et al. 2010

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“…There is growing evidence that genes involved in DNA damage response play a predisposing role for PrCa [4]. This includes DNA repair processes as well related mechanisms like apoptotic pathways.…”

Section: Introductionmentioning

confidence: 99%

Prostate Cancer Risk Is not Altered by TP53AIP1 Germline Mutations in a German Case-Control Series

et al. 2012

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Prostate cancer susceptibility has previously been associated with truncating germline variants in the gene TP53AIP1 (tumor protein p53 regulated apoptosis inducing protein 1). For two apparently recurrent mutations (p.Q22fs and p.S32X) a remarkable OR of 5.1 was reported for prostate cancer risk. Since these findings have not been validated so far, we genotyped p.Q22fs and p.S32X in two German series with a total of 1,207 prostate cancer cases and 1,495 controls. The truncating variants were not significantly associated with prostate cancer in none of the two cohorts, nor in the combined analysis [odds ratio (OR) = 1.16; 95% confidence interval (CI 95%) = 0.62–2.15; p = 0.66]. Carriers showed no significant differences in family history of prostate cancer, age at diagnosis, Gleason score or PSA at diagnosis when compared to non-carrier prostate cancer cases. The large sample size of the combined cohort rejects a high-risk effect greater than 2.2 and indicates a limited role of TP53AIP1 in prostate cancer predisposition.

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“…This indicates potentially important functions for these genes in prostate cancer. For example, the loss of CHEK1 transcriptional activity may link to the recently reviewed deficient DNA repair process in PRCa [50]. The most prominent functional associations of kinase genes whose expression was lost in prostate cancer were linked to cytoskeletal organization, cell adhesion and mesodermal development (Figure 4).…”

Section: Resultsmentioning

confidence: 99%

Analysis of Kinase Gene Expression Patterns across 5681 Human Tissue Samples Reveals Functional Genomic Taxonomy of the Kinome

2010

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Kinases play key roles in cell signaling and represent major targets for drug development, but the regulation of their activation and their associations with health and disease have not been systematically analyzed. Here, we carried out a bioinformatic analysis of the expression levels of 459 human kinase genes in 5681 samples consisting of 44 healthy and 55 malignant human tissues. Defining the tissues where the kinase genes were transcriptionally active led to a functional genomic taxonomy of the kinome and a classification of human tissues and disease types based on the similarity of their kinome gene expression. The co-expression network around each of the kinase genes was defined in order to determine the functional context, i.e. the biological processes that were active in the cells and tissues where the kinase gene was expressed. Strong associations for individual kinases were found for mitosis (69 genes, including AURKA and BUB1), cell cycle control (73 genes, including PLK1 and AURKB), DNA repair (49 genes, including CHEK1 and ATR), immune response (72 genes, including MATK), neuronal (131 genes, including PRKCE) and muscular (72 genes, including MYLK2) functions. We then analyzed which kinase genes gain or lose transcriptional activity in the development of prostate and lung cancers and elucidated the functional associations of individual cancer associated kinase genes. In summary, we report here a systematic classification of kinases based on the bioinformatic analysis of their expression in human tissues and diseases, as well as grouping of tissues and tumor types according to the similarity of their kinome transcription.

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Genetic changes and DNA damage responses in the prostate

Cited by 27 publications

References 157 publications

Brca2 and Trp53 Deficiency Cooperate in the Progression of Mouse Prostate Tumourigenesis

Brca2 and Trp53 Deficiency Cooperate in the Progression of Mouse Prostate Tumourigenesis

Prostate Cancer Risk Is not Altered by TP53AIP1 Germline Mutations in a German Case-Control Series

Analysis of Kinase Gene Expression Patterns across 5681 Human Tissue Samples Reveals Functional Genomic Taxonomy of the Kinome

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