Loh and mutation analysis of <i>CDKN2</i> in primary human ovarian cancers

Campbell, Ian; Beynon, Gareth; Davis, Michael A.; Englefield, P.

doi:10.1002/ijc.2910630213

Cited by 35 publications

(29 citation statements)

References 17 publications

(14 reference statements)

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“…The tissues were freed from necrotic, haemorrhagic and connective tissue, minced and stored at -80°C in cryotubes (Nunc) until processed. (Kamb et al, 1994;Campbell et al, 1995). The p16 gene homozygous deletion was investigated by PCR for the ability to amplify a region of the gene compared with the ability to amplify, as an internal control, the human ,-actin gene.…”

Section: Patient Characteristicsmentioning

confidence: 99%

“…The cycles of amplification were as described previously (Kamb et al, 1994) and reduced to 30 in the 0-actin coamplification to maintain the amplification in the exponential phase (Campbell et al, 1995). Samples were loaded on 4% agarose gel and visualized by ethidium bromide staining.…”

Section: Patient Characteristicsmentioning

confidence: 99%

“…Mutations and homozygous deletion of pl6 have been reported in melanoma, glioblastoma, pancreatic adenocarcinoma, bladder carcinoma, non-small-cell lung cancer, acute lymphocytic leukaemia, chronic myeloid leukaemia and nonHodgkin's lymphoma (Hirama and Koeffler, 1995;Sheaff and Roberts, 1995). It was initially reported that the p16 gene was homozygously deleted in two out of seven ovarian cancer cell lines (Kamb et al, 1994), but a lower incidence was recently found in primary tumours (Campbell et al, 1995;Rodabaugh et al, 1995;Schultz et al, 1995;Devlin et al, 1996).…”

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Absence of deletions but frequent loss of expression of p16INK4 in human ovarian tumours

Marchini

Codegoni²,

Bonazzi³

et al. 1997

Br J Cancer

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Summary The cyclin-dependent kinase inhibitor p16 gene (P16, MTS1, CDKN2) has been shown to be altered by deletion or point mutation in some human tumours and cancer cell lines, suggesting that it works as a tumour suppressor. We analysed p16 gene mutation and p16 protein expression in 42 primary ovarian carcinomas and in five human ovarian cancer cell lines. Polymerase chain reaction (PCR) amplifications of exons 1 and 2 of the gene showed no deletion or gross rearrangement in the p16 gene. The lack of deletion was further demonstrated by Southern blot analysis. Looking for point mutations, we used single-strand confirmation polymorphism (SSCP) analysis and, in half of the tumours, we sequenced both strands of exons 1 and 2. No mutations were detected. In 11 out of 42 patients (26%), however, we detected no protein expression by Western blot analysis, suggesting that decreased expression of p16 rather than deletion of the gene can occur in a significant percentage of human ovarian cancers. In the same experiment CDK4 protein was found homogeneously expressed in all the tumour specimens and in the five cell lines. The lack of expression of p16 was not due to hypermethylation of the gene assessed by digestion of genomic DNAs with a methylation sensitive enzyme, suggesting that other mechanisms, not yet identified, are involved in the decreased expression of the p16 gene in human ovarian tumours.

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Section: Patient Characteristicsmentioning

confidence: 99%

Section: Patient Characteristicsmentioning

confidence: 99%

mentioning

confidence: 99%

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Absence of deletions but frequent loss of expression of p16INK4 in human ovarian tumours

Marchini

Codegoni²,

Bonazzi³

et al. 1997

Br J Cancer

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“…Indeed, several groups have reported frequencies of loss of heterozygosity on chromosome 9p ranging from 30 ± 48% in ovarian cancers with the consensus minimally deleted region encompassing the p16 locus at 9p21 (Chenevix-Trench et al, 1994;Osborn and Leach, 1994;Campbell et al, 1995;Schultz et al, 1995). However, in those cases where the remaining homologue was sequenced, none were found to harbor inactivating mutations of p16 (Chenevix-Trench et al, 1994;Campbell et al, 1995;Schultz et al, 1995). Additional SSCP-based studies of the p16 gene by Schuyer et al (1996) yielded no evidence of inactivating mutations in 37 primary ovarian tumors.…”

Section: Introductionmentioning

confidence: 99%

“…Additional SSCP-based studies of the p16 gene by Schuyer et al (1996) yielded no evidence of inactivating mutations in 37 primary ovarian tumors. Similarly, homozygous deletions of the p16 gene have rarely been detected in ovarian tumors, at frequencies ranging from 0 ± 17% (Campbell et al, 1995;Schultz et al, 1995;Radabaugh et al, 1995;Marchini et al, 1997;Kanuma et al, 1997;Shih et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Ovarian cancer cells that coexpress endogenous Rb and p16 are insensitive to overexpression of functional p16 protein

2000

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Defects of the`Rb/cyclin D1/p16 pathway' have been shown to play a critical role in the development of virtually all human malignancies assessed. To determine the contribution of G1 phase cell cycle defects to ovarian tumorigenesis, we have examined a panel of normal and tumor ovarian tissues and ovarian cancer cell lines for the expression of Rb, p16 and cyclin D1 proteins. Unlike most types of human cancer whose development involves the loss of either Rb or p16 expression, we observed the coexpression of Rb, p16 and cyclin D1 in 82% of ovarian cancer tissues and cell lines. Furthermore, the growth and cell cycle distribution pro®les of three ovarian cancer cell lines (ES-2, PA-1 and NIH OVCAR-3) that coexpressed Rb and p16, were found to be una ected by adenoviral-mediated overexpression of functional p16 protein, indicating the existence of a defect(s) downstream from p16 in these cells. By contrast overexpression of ectopic p16 in the one ovarian cancer cell line (SK-OV-3) that expressed Rb but lacked p16 protein, resulted in a G1 growth arrest. These data suggest that defects of the`Rb/cyclin D1/p16 pathway', other than the loss of Rb or p16, may play a major role in the development of ovarian cancer. Oncogene (2000) 19, 258 ± 264.

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Increased expression of cyclin-dependent kinase inhibitor 2 (CDKN2A) gene product P16INK4A in ovarian cancer is associated with progression and unfavourable prognosis

et al. 1997

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Paraffin sections from 190 epithelial ovarian tumours, including 159 malignant and 31 benign epithelial tumours, were analysed immunohistochemically for expression of cyclin-dependent kinase inhibitor 2 (CDKN2A) gene product p16INK4A (p16). Most benign tumours showed no p16 expression in the tumour cells, whereas only 11% of malignant cancers were p16 negative. A high proportion of p16-positive tumour cells was associated with advanced stage and grade, and with poor prognosis in cancer patients. For FIGO stage I tumours, a high proportion of p16-positive tumour cells was associated with poorer survival, suggesting that accumulation of p16 is an early event of ovarian tumorigenesis. In contrast to tumour cells, high expression of p16 in the surrounding stromal cells was not associated with the stage and grade, but was associated with longer survival. When all parameters were combined in a multivariate analysis, high p16 expression in stromal cells was not an independent predictor for survival, indicating that low p16 expression in stromal cells is associated with other markers of tumour progression. High expression of p16 in the stromal cells of tumours from long-term survivors suggests that tumour growth is limited to some extent by factors associated with p16 expression in the matrix.

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Loh and mutation analysis of CDKN2 in primary human ovarian cancers

Cited by 35 publications

References 17 publications

Absence of deletions but frequent loss of expression of p16INK4 in human ovarian tumours

Absence of deletions but frequent loss of expression of p16INK4 in human ovarian tumours

Ovarian cancer cells that coexpress endogenous Rb and p16 are insensitive to overexpression of functional p16 protein

Increased expression of cyclin-dependent kinase inhibitor 2 (CDKN2A) gene product P16INK4A in ovarian cancer is associated with progression and unfavourable prognosis

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