Loss of heterozygosity (LOH), malignancy grade and clonality in microdissected prostate cancer

Hügel, A; Wernert, Nicolas

doi:10.1038/sj.bjc.6690087

Cited by 39 publications

(27 citation statements)

References 24 publications

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“…1,2,11,26,32,33) An analysis of 9 polymorphic markers in 52 tumors uncovered a common region of deletion in 6q14-21 19 cM between markers D6S251 and D6S286 in 13 of 17 (76.5%) informative neoplasias.…”

Section: Discussionmentioning

confidence: 99%

“…In previous LOH studies of this disease, a random discordant pattern of allelic deletion emerged. [19][20][21] Hügel et al 26) analyzed 25 chromosomal loci in 47 prostate carcinomas and demonstrated a significant correlation between frequency of focal LOH and malignant progression of affected foci. In our current study, only a single focus in 4 of 10 tumors positive for 6q LOH actually showed the deletion in 6q.…”

Section: Discussionmentioning

confidence: 99%

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Genetic mapping of allelic loss on chromosome 6q within heterogeneous prostate carcinoma

et al. 2003

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A number of genetic events have been reported in prostate carcinogenesis, including frequent loss of heterozygosity (LOH) on chromosomes 8q, 10q, 16q and 18q. In samples of heterogeneous, multifocal prostate carcinomas, we focused on chromosome 6q using PCR-based techniques with 15 microsatellite markers to identify the specific 6q deletion within tumors. LOH of one or more polymorphic markers was detected in 10 of 21 tumors (48%). Two of these 10 tumors demonstrated LOH in all cancerous foci at specific loci and 4 tumors showed deletion in one focus. Different deletion patterns were found in 3 tumors when different polymorphic markers were used. In 90% of tumors showing LOH in one or more foci, however, two common regions of LOH were identified; one at 1.81 cM on 6q15-16.3 between markers D6S1631 and D6S1056, and the other at 5.11 cM on 6q16-21 between markers D6S424 and D6S283. By RT-PCR analysis, the TAK1 gene located at these loci did not correlate with LOH status, indicating that TAK1 is not a target gene in prostate carcinoma. The 6q deletion occurs heterogeneously and LOH was more frequent in tumors of higher pathological stages, implying that this alteration is a late event in prostate carcinogenesis. ytogenetic studies of prostate carcinomas indicate that various chromosomal deletions containing tumor suppressor genes contribute to the development and progression of tumors. Recent intensive investigations using PCR of polymorphic microsatellite markers, fluorescent in situ hybridization (FISH), and comparative genomic hybridization (CGH) have shown consistent genetic alterations on chromosomes 2q, 3q, 5q, 6q, 7q, 8q, 9q, 10q, 13q, 16q and 18q.1, 2) Although malignant tumors are now believed to develop through a multi-step process involving both oncogene activation and tumor suppressor gene (TSG) inactivation, 3) putative TSG are postulated to be the primary targets of these carcinogenesis-associated events.Allelic losses on 6q have been described in a number of cancers including melanoma and breast, ovarian, and renal cancers. [4][5][6][7][8][9] Genes associated with prostate carcinoma in the 6q region have also been reported and, while the incidences varied, 6q alterations have been found to occur in up to 48% of prostate cancers.1, 2, 10, 11) However, the role of these chromosomal aberrations remains unclear. At least two common regions of 6q deletion have been identified in prostate carcinoma. Using 13 polymorphic markers, Srikantan et al.2) reported that 6q16, 6q3-21, and the distal region 6q23-24 were deleted. Hyytinen et al.11) examined two regions, 6q16-21 and 6q22, and claimed that deletion of 6q16-22 is a frequent event in prostate cancer. They further showed that loss of 6q24 was associated with androgen-independence and tumorigenicity.12) Several candidate genes, such as the insulin-like growth factor II receptor (IGF2R) at 6q26 or cyclin C (CCNC) at 6q21, may participate in prostate carcinogenesis.1) A novel gene located on chromosome 6q23-24 and designated UROC28 was recently identified as ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genetic mapping of allelic loss on chromosome 6q within heterogeneous prostate carcinoma

et al. 2003

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“…TP53 (14) and PTEN (15) are among tumour suppressor genes shown to be inactivated in prostate cancer. Comparative genomic hybridization (CGH) and loss of heterozygosity (LOH) analyses suggest further oncogenes and tumour suppressor genes (16)(17)(18)(19)(20) (reviewed in ref. 21).…”

Section: Introductionmentioning

confidence: 99%

Tumour-stroma interactions between metastatic prostate cancer cells and fibroblasts

Kaminski

Hahne²,

Haddouti³

et al. 2006

Int J Mol Med

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Abstract.Previous work has shown the importance of tumourstroma interactions for prostate cancer development at the primary site. The aim of the present study was to find out whether evidence can be found for a tumour-stroma crosstalk also between metastatic prostate cancer cell lines and non-prostatic stromal fibroblasts which are encountered by metastatic cells at most sites. We addressed this issue in cell culture systems using 3 metastatic human prostate cancer cell lines (LnCaP, PC-3 and DU-145) on the one hand, and a human fibroblast line (HFF, human foreskin fibroblasts) on the other. We incubated fibroblasts with tumour cell-and tumour cells with fibroblast-conditioned media and evaluated several parameters important for the establishment of metastases such as cell proliferation, migration and expression of matrix degrading proteases. We also determined in the conditioned media the concentrations of several growth factors and cytokines which might be responsible for the observed effects. We found that media conditioned by all 3 metastatic prostate cancer cell lines stimulated fibroblast proliferation which corresponds to fibrous stroma induction in vivo. DU-145 cell conditioned media induced in fibroblasts expression of mmp-1 mRNA known to be important for tumour invasion. ELISA assays revealed that tumour cells secrete bFGF, PDGF and TNF· known to stimulate fibroblast proliferation and/or MMP-1 expression. Cultivation of DU-145 carcinoma cells in fibroblast conditioned medium resulted in an enhanced proliferation and anchorage-independent growth of this cell line in soft agar. Fibroblast conditioned medium also increased migration of PC-3 cells in the wound assay and slightly augmented mmp-1 expression. KGF (able to stimulate proliferation of normal and neoplastic prostate epithelial cells) was secreted by fibroblasts at higher concentrations than by all 3 tumour cell lines. In addition, fibroblasts secreted TNF·, bFGF, PDGF, HGF and also VEGF, the most important factor for tumour vascularization. Our results provide evidence that tumour-stroma interactions do not only exist at the primary site but also between metastatic prostate cancer cell lines and their fibroblastic microenvironment. These interactions, which are mediated through secreted factors, affect several steps of the metastatic cascade including proliferation, anchorage-independent growth, migration and the secretion of matrix-degrading proteases.

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“…[10][11][12][13][14][15][16][17][18][19][20][21][22][23] The sites most frequently lost in somatic cancers include 8p, 10q, 13q, 16q and 18q, [11][12][13]15,20,22,23 and losses on 1q are associated with hereditary prostate cancer. 19 Some losses, such as those on 8p and 13q, are associated with early prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

“…11,12,22,23 Others, such as those on 11p and 16q, 15,[20][21][22]24 are more frequent in advanced disease. Several studies have reported an association of AI at certain loci with histopathological features of the RP specimen, including advanced stage, 13,[25][26][27] high Gleason grade 13,26 and perineural invasion. 23 Current predictive factors, including Gleason grade, pathological stage, preoperative serum PSA and surgical margin status, are not always reliable.…”

Section: Introductionmentioning

confidence: 99%

Allelic imbalance and biochemical outcome after radical prostatectomy

Bott

Masters

Parkinson

et al. 2006

Prostate Cancer Prostatic Dis

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Objective: To compare the incidence of allelic imbalance (AI) in men with rapid disease progression with those who remained disease free after radical prostatectomy, with the aim of identifying genetic markers to predict prognosis and guide further treatment. Patients and methods: Tumour and normal DNA were extracted from two matched groups of 31 men with extracapsular node-negative (pT3N0) prostate cancer who had undergone radical prostatectomy. One group comprised men who developed biochemical recurrence within 2 years of surgery and one group were prostate-specific antigen (PSA) free for at least 3 years. Men were matched for Gleason grade, preoperative PSA and pathological stage. Analysis was performed by genotyping. Results: Allelic imbalance was analysed using 30 markers, and was seen in at least one marker in 57 (92%) of the cases. Deletion at marker D10S211 (10p12.1) was significantly more common in the relapse group than the non-relapse group (35 vs 5%, P ¼ 0.03). Conclusions: This study demonstrates significant association between AI on chromosome 10 and biochemical progression after radical prostatectomy.

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Loss of heterozygosity (LOH), malignancy grade and clonality in microdissected prostate cancer

Cited by 39 publications

References 24 publications

Genetic mapping of allelic loss on chromosome 6q within heterogeneous prostate carcinoma

Genetic mapping of allelic loss on chromosome 6q within heterogeneous prostate carcinoma

Tumour-stroma interactions between metastatic prostate cancer cells and fibroblasts

Allelic imbalance and biochemical outcome after radical prostatectomy

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