Absence ofp15andp16Gene Alterations in Primary Cervical Carcinoma Tissues and Cell Lines with Human Papillomavirus Infection

Kim, Jin Woo; Namkoong, Sung Eun; Ryu, Soon Won; Kim, Ho Shik; Shin, Jong Cheol; Lee, Joon Mo; Kim, Daehoon; Kim, In Kyung

doi:10.1006/gyno.1998.5041

Cited by 36 publications

(30 citation statements)

References 20 publications

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“…Our data confirm previous studies in HPV-transformed cells, cervical cancer cell lines and primary clinical lesions, 50,51,53,54,[61][62][63][64] suggesting that p16 INK4a is indeed overexpressed in cells transformed by HR-HPV types; thus evidence is provided against reports claiming reduced p16 INK4a expression in cervical lesions. 50 -52 In 14 of 32 CIN II lesions, 9 of 60 CIN III lesions and 5 of 60 cervical carcinoma samples, no HR-HPV infection could be identified despite strong and diffuse expression of p16 INK4a in the dysplastic cell layers.…”

Section: Discussionsupporting

confidence: 91%

Overexpression of p16INK4A as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri

et al. 2001

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Cytological screening for cervical cancer or its precursors using Papanicolaou's smear test (Pap test) has been highly efficient to reduce the morbidity and mortality of cervical cancer. However, evaluation of the Pap test relies on subjective diagnostic parameters and is affected by a high rate of false-positive and false-negative results. More objective diagnostic parameters to identify truly dysplastic or neoplastic cells in cervical smears as well as in cervical biopsy samples would therefore avoid insecurity for many patients and the high screening costs associated with repeated testing. Cervical dysplasia is induced by persistent infections through highrisk types of human papillomaviruses (HPVs). Outgrowth of dysplastic lesions is triggered by increasing expression of two viral oncogenes, E6 and E7, which both interact with various cell cycle-regulating proteins. Among these is the retinoblastoma gene product pRB, which is inactivated by E7. pRB inhibits transcription of the cyclin-dependent kinase inhibitor gene p16 INK4a . Increasing expression of the viral oncogenes in dysplastic cervical cells might thus be reflected by increased expression of p16 INK4a . In line with this hypothesis, we observed marked overexpression of p16 INK4a in all cervical intraepithelial neoplasm (CIN) I lesions (n ‫؍‬ 47) except those associated with low-risk HPV types (n ‫؍‬ 7), all CIN II lesions (n ‫؍‬ 32), all CIN III lesions (n ‫؍‬ 60) and 58 of 60 invasive cervical cancers. In contrast, no detectable expression of p16 INK4a was observed in normal cervical epithelium (n ‫؍‬ 42), inflammatory lesions (n ‫؍‬ 48) and low-grade cervical lesions (CIN I) associated with low-risk HPV types (n ‫؍‬ 7). Dysplastic cells could also be identified in cervical smears using a specific p16 INK4a monoclonal antibody. These data demonstrate that p16 INK4a is a specific biomarker to identify dysplastic cervical epithelia in sections of cervical biopsy samples or cervical smears.

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Section: Discussionsupporting

confidence: 91%

Overexpression of p16INK4A as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri

et al. 2001

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“…Our findings should be considered in light of previous reports regarding p16 and/or p15 in human uterine tumours (Hatta et al, 1995;Kelly et al, 1995;Peiffer et al, 1995;Hirama et al, 1996;Wong et al, 1997;Kim et al, 1998;Munirajan et al, 1998). Hatta et al (1995) found no mutations, deletions, or rearrangements in 15 endometrial carcinomas.…”

Section: Discussionsupporting

confidence: 74%

“…Wong et al, found no somatic p16 point mutations in any of the 128 cervical or 41 endometrial carcinomas. Kim et al (1998) found no mutations or homozygous deletions of p15 or p16 in 57 cervical carcinomas. Munirajan et al (1998) found no p16 mutations in 43 cervical carcinomas.…”

Section: Discussionmentioning

confidence: 75%

Alteration of p16 and p15 genes in human uterine tumours

et al. 1999

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A large variety of human tumours manifest a heterozygous or homozygous deletion in the 9p21 chromosome region. The list includes malignant melanoma, glioma, lung, bladder, pancreatic and renal cancers (Kamb et al, 1994;Nobori et al, 1994), as well as gynaecological tumours (reviewed by Wong et al, 1997). Two putative tumour suppressor genes have been identified in this region: p16 (also known as p16 INK4A , cyclin-dependent kinase 4 inhibitor, CDK4I, CDKN2, and MTS1), and p15 (p15 INK4B ).The p16 gene makes two different proteins, p16 and p19 ARF (p19 alternative reading frame), using different overlapping reading frames, starting with different first exons. The p16 protein uses exon 1α, and p19 ARF uses exon 1β; these two exons are alternatively spliced to the same second and third exons. The p16 and p15 proteins belong to a family of negative regulators of the cell cycle. Specific binding of p16 protein to the CDK4 or CDK6 cyclindependent protein kinases inhibits the phosphorylation activity of CDK-cyclin D complexes towards the nuclear RB/E2F protein complex (Serrano et al, 1993). p16 normally prevents phosphorylation of RB, resulting in RB's retention of E2F. Failure to release E2F at the late G1 checkpoint blocks the cell from entering the S phase (Hengstschläger et al, 1996;Lukas et al, 1996). The p19 ARF protein, although it has an unrelated amino acid sequence, has cell cycle arresting functions. It is the p16 protein that now appears to be the major target of mutations and deletions at the 9p21 loci.The p15 (MTS2) putative tumour suppressor gene is located 25 kb centromeric of the p16 gene on 9p. p15 contains sequences highly homologous to exon 2 of p16 and, like p16, inhibits both CDK4 and CDK6 kinase activities (Guan et al, 1994;Hannon and Beach, 1994). Homozygous deletions of p15 and hypermethylation-associated loss of p15 expression have been reported in glioblastomas (Jen et al, 1994).The p16/p19 ARF and p15 genes appear to play variably important roles in human tumorigenesis, with critical tissue specificities and uncertain implications for clinical prognoses. Little is currently known about the potential role of these genes in reproductive tract biology, and specifically in uterine tumours. We have begun to examine the expression of the p16 gene at the level of mRNA and protein, the methylation status of the 5′-CpG island of p16 exon 1α, and for p16 point mutations and homozygous deletions in these tumours. We have also analysed the p15 gene for mutations and homozygous deletions. We report that the inactivation of the p16 gene, either by homozygous gene deletion, mutation or loss of protein expression, occurs in a small but significant subset of these uterine tumours. Summary The roles of the p16 and p15 inhibitor of cyclin-dependent kinase tumour suppressor genes were examined in human uterine cervical and endometrial cancers. p16 mRNA, examined by reverse transcription polymerase chain reaction (RT-PCR), was significantly reduced in five of 19 (26%) cervical and four of 25 (16%) endometrial tu...

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“…INK4a in the cell, because the levels of p16 INK4a and Rb are maintained through a negative feedback loop (12).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of an ELISA for p16INK4a as a Screening Test for Cervical Cancer

Balasubramanian

Hughes

Mao

et al. 2009

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Absence ofp15andp16Gene Alterations in Primary Cervical Carcinoma Tissues and Cell Lines with Human Papillomavirus Infection

Cited by 36 publications

References 20 publications

Overexpression of p16INK4A as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri

Overexpression of p16INK4A as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri

Alteration of p16 and p15 genes in human uterine tumours

Evaluation of an ELISA for p16INK4a as a Screening Test for Cervical Cancer

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