The genetic analysis of ovarian cancer

Shelling, Andrew N.; Cooke, IE; Ganesan, T. S.

doi:10.1038/bjc.1995.367

Cited by 81 publications

(55 citation statements)

References 70 publications

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“…To our knowledge, no major progress has occurred within the last 10 years in the selection of patients for individual therapy, neither in early-stage nor late-stage disease setting. 33 Clearly, any method that could select patients for individual treatment would make headway.…”

Section: Discussionmentioning

confidence: 99%

Distribution of HER‐2 overexpression in ovarian carcinoma tissue and its prognostic value in patients with ovarian carcinoma

Høgdall

Christensen

Kjær

et al. 2003

Cancer

125

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BACKGROUNDThe HER‐2 (Human Epidermal Growth factor receptor‐2, also known as c‐erb‐2/neu) protooncogene encodes a transmembrane receptor protein, Mr 185,000. Studies have shown that the HER‐2 oncogene is overexpressed in approximately 25–30% of ovarian carcinoma (OC) cases, but to the authors' knowledge, to date no consensus regarding overexpression and prognosis has been possible. The objective of the current study was first to analyze the presence of HER‐2 overexpression in tissue from Danish OC patients and correlate the distribution of HER‐2 overexpression with clinical and biochemical data and second to investigate the value of HER‐2 overexpression as a prognostic marker in OC and to compare this value with the prognostic value of other biochemical markers.METHODSThe study population was comprised of the first 181 patients diagnosed with epithelial OC who were included in the MALOVA study. The staining procedure for HER‐2 overexpression was performed using the p185 antibody.RESULTSHER‐2 overexpression was found in 95 of the 181 investigated cases (52.5%), in which 71 carcinomas (39.2%) were weakly positive (1+) and 24 carcinomas (13.3%) were moderately (2+) to intensely positive (3+). Increased HER‐2 expression was found to be correlated with reduced survival. Significant differences in survival between patients with (1+, 2+, and 3+) and those without HER‐2 overexpression were found for patients with International Federation of Gynecology and Obstetrics (FIGO) Stage I, Stage III, and Stage III/IV OC (Stage I: P = 0.021; Stage III: P = 0.0078; and Stage III/IV: P = 0.0054). Multivariate survival analyses including all 181 OC patients demonstrated that HER‐2 overexpression is a prognostic marker (P = 0.003) together with disease stage, serum tetranectin level, and patient age. For patients with Stage III OC, the only independent prognostic factors detected were HER‐2 overexpression (P = 0.009) and serum tetranectin level (P ≤ 0.0001).CONCLUSIONSThe results of the current study show that HER‐2 overexpression has prognostic value both in univariate and multivariate survival analyses. Therefore, the clinical relevance of this observation should be established conclusively by therapy that targets HER‐2 in a prospective Phase II clinical trial. Cancer 2003;98:66–73. © 2003 American Cancer Society.DOI 10.1002/cncr.11476

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Section: Discussionmentioning

confidence: 99%

Distribution of HER‐2 overexpression in ovarian carcinoma tissue and its prognostic value in patients with ovarian carcinoma

Høgdall

Christensen

Kjær

et al. 2003

Cancer

125

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“…Moreover, a normal TP53 mutation spectrum was observed since, of all tumours studied, 46% showed a TP53 alteration as determined by SSCP. A recent review by Shelling et al (1995) reported that 44% (46 out of 105) ovarian tumours showed TP53 mutations, measured by SSCP.…”

Section: Discussionmentioning

confidence: 99%

Sporadic CDKN2 (MTS1/p16ink4) gene alterations in human ovarian tumours

Schuyer

Staveren²,

Klijn³

et al. 1996

Br J Cancer

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Cyclins, cyclin-dependent kinases (CDKs) and cyclindependent kinase inhibitors (CKIs) play a key role in cell cycle control. To achieve an orderly progression through the cell cycle, different cyclin -CDK complexes need to be activated and deactivated at appropriate times. Cyclin D-CDK4 is one of the complexes that promotes cell passage through the G1 phase of the cell cycle. It increases the phosphorylation state of the retinoblastoma protein which then releases transcription factors (e.g. E2F) essential for progression into the S-phase (reviewed by Sherr, 1993;Hartwell and Kastan, 1994;Hunter and pines, 1994 al., 1994).Another negative regulator of cyclin D-CDK4/6 activity is the p16 protein, encoded by the CDKN2 (MTSIpl6in'k4/ CDK4I) gene (Serrano et al., 1993;Nobori et al., 1994 (1979) classification the primary and metastatic carcinomas were subtyped into serous (n = 14 primary, n = 5 metastatic), mucinous (n = 4), endometroid (n = 7), clear cell (n = 2), mixed (n = 3), poorly differentiated (n = 1) and unknown (n = 1). To estimate the percentage of tumour cells, frozen sections were made from a representative part of each tumour and stained with haematoxylin and eosin. The

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“…Chromosome 6 has been implicated to contain a putative tumour suppressor gene important in the pathogenesis of ovarian cancer, both by karyotypic analysis and allele loss studies (Shelling et al, 1995;Liu and Ganesan, 2002). Initially, a minimal region of allele loss was delineated between D6S193 and D6S149 (1.9 cM, 0.6 Mb) on chromosome 6q based on one tumour (Saito et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

RPS6KA2, a putative tumour suppressor gene at 6q27 in sporadic epithelial ovarian cancer

et al. 2006

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We had previously defined by allele loss studies a minimal region at 6q27 (between D6S264 and D6S297) to contain a putative tumour suppressor gene. The p90 ribosomal S6 kinase-3 gene (p90 Rsk-3, RPS6KA2) maps in this interval. It is a serine-threonine kinase that signals downstream of the mitogen-activated protein kinase pathway. It is expressed in normal ovarian epithelium, whereas reduced or absent in tumours or cell lines. We show that RPS6KA2 is monoallelically expressed in the ovary suggesting that loss of a single expressed allele is sufficient to cause complete loss of expression in cancer cells. Further, we have identified two new isoforms of RPS6KA2 with an alternative start codon. Homozygous deletions were identified within the RPS6KA2 gene in two cell lines. Re-expression of RPS6KA2 in ovarian cancer cell lines suppressed colony formation. In UCI101 cells, the expression of RPS6KA2 reduced proliferation, caused G1 arrest, increased apoptosis, reduced levels of phosphorylated extracellular signal-regulated kinase and altered other cell cycle proteins. In contrast, small interfering RNA against RPS6KA2 showed the opposite effect in 41M cells. The above results suggest that RPS6KA2 is a putative tumour suppressor gene to explain allele loss at 6q27.

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The genetic analysis of ovarian cancer

Cited by 81 publications

References 70 publications

Distribution of HER‐2 overexpression in ovarian carcinoma tissue and its prognostic value in patients with ovarian carcinoma

Distribution of HER‐2 overexpression in ovarian carcinoma tissue and its prognostic value in patients with ovarian carcinoma

Sporadic CDKN2 (MTS1/p16ink4) gene alterations in human ovarian tumours

RPS6KA2, a putative tumour suppressor gene at 6q27 in sporadic epithelial ovarian cancer

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