Molecular Characterization of Adenocarcinoma of the Cervix

Parker, Megan N.; Arroyo, Gerardo F.; Geradts, Joseph; Sabichi, Anita L.; Park, R.C.; Taylor, RW; Birrer, Michael J.

doi:10.1006/gyno.1996.4580

Cited by 52 publications

(35 citation statements)

References 23 publications

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“…Uchiyama et al dealt with this issue and showed that hr-HPV-negative AC had a poorer prognosis compared with hr-HPV-positive AC through univariate analysis. 46 Parker et al showed that p53 protein overexpression is much more common among hr-HPV-negative ACs, 47 and Suzuki et al reported radioresistance of ACs overexpressing the p53 protein. 48 These observations suggest an aggressive nature of hr-HPV-unrelated ACs.…”

Section: Discussionmentioning

confidence: 99%

Absence of High-Risk Human Papillomavirus (HPV) Detection in Endocervical Adenocarcinoma with Gastric Morphology and Phenotype

Kusanagi

Kojima

Mikami

et al. 2010

The American Journal of Pathology

140

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A subset of endocervical-type mucinous adenocarcinomas (ACs) of the uterine cervix exhibit a gastric phenotype and morphology, as reported in cases of minimal deviation AC in which the presence of human papillomavirus (HPV) has been rarely detected. To investigate the HPV-independent pathway of carcinogenesis in cases of gastric-type AC, we investigated the common high-risk HPV (hr-HPV) status in 52 nonsquamous cell carcinomas , using a PCRbased typing method and immunohistochemistry of p16INK4a (a cyclin-dependent kinase inhibitor that is overexpressed in both cancerous and precancerous cervical tissue, making it an ideal biomarker for cervical cancer cases). Using novel morphological criteria, seven of 52 (13.5%) carcinomas were designated as gastric-type ACs, all of which were negative for both hr-HPV DNA and p16INK4a . Nongastric-type ACs were frequently positive for both hr-HPV DNA (90%, 28/31) and p16INK4a (94%, 29/31) with adenosquamous and neuroendocrine carcinomas demonstrating the presence of hr-HPV DNA in 86% (6/7) and 83% (5/6) of cases , respectively. In these two types of carcinoma , 86% (6/7) and 100% (6/6) were positive for p16 INK4a , respectively. Our data suggests that gastric-type AC appears to represent an oncogenic hr-HPV-independent neoplasm and therefore is a potential pitfall of HPV DNA testing and vaccination.

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Section: Discussionmentioning

confidence: 99%

Absence of High-Risk Human Papillomavirus (HPV) Detection in Endocervical Adenocarcinoma with Gastric Morphology and Phenotype

Kusanagi

Kojima

Mikami

et al. 2010

The American Journal of Pathology

140

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“…HPV infection can thus often substitute for mutations in both these pathways. For example, Parker et al (1997) found that HPV and p53 overexpression were mutually exclusive in cervical carcinomas, whereas Munirajan et al (1998) found that, of 43 tumours studied with p53 mutations, three of four tumours had HPV infections.…”

Section: Discussionmentioning

confidence: 99%

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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“…Although HPV DNA is consistently detected in Ͼ90% of squamous cell carcinomas of the cervix, 2 the reported prevalence of HPV DNA in AdCx varies significantly, from 32% to 100%, depending on the detection method used. [3][4][5][6][7][8][9][10][11][12][13] …”

mentioning

confidence: 99%

Prevalence of Human Papillomavirus DNA in Different Histological Subtypes of Cervical Adenocarcinoma

Pirog

Kleter

Olgac

et al. 2000

The American Journal of Pathology

305

228

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The prevalence of human papilloma virus (HPV) DNA in different histological subtypes of cervical adenocarcinoma and related tumors was examined using formalin-fixed, paraffin-embedded tissue samples from 105 primary cervical adenocarcinomas and adenosquamous carcinomas. Broad-spectrum HPV DNA amplification and genotyping was performed with the SPF10 primer set and line probe assay (LiPA), respectively. HPV DNA was detected in 82 of 90 (91%) mucinous adenocarcinomas, encompassing endocervical, intestinal, and endometrioid histological subtypes, and in nine of nine adenosquamous tumors (100%). HPV DNA was not detected in any nonmucinous adenocarcinomas including clear cell, serous, and mesonephric carcinomas (0/6). The most common viral types detected in adenocarcinoma were HPV 16 (50%) and HPV 18 (40%), followed by HPV 45 (10%), HPV52 (2%), and HPV 35 (1%). Multiple HPV types were detected in 9.7% of the cases. Adenocarcinoma of the cervix (AdCx) accounts for approximately 15% of cervical cancers and has been increasing in incidence during the last few decades, particularly in younger women. 1 The etiology of squamous cell carcinoma of the cervix, the most common type of cervical malignancy, is linked to infection with oncogenic types of human papillomavirus (HPV), but the pathogenesis of AdCx is less well understood. Although HPV DNA is consistently detected in Ͼ90% of squamous cell carcinomas of the cervix, 2 the reported prevalence of HPV DNA in AdCx varies significantly, from 32% to 100%, depending on the detection method used. [3][4][5][6][7][8][9][10][11][12][13]

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Molecular Characterization of Adenocarcinoma of the Cervix

Cited by 52 publications

References 23 publications

Absence of High-Risk Human Papillomavirus (HPV) Detection in Endocervical Adenocarcinoma with Gastric Morphology and Phenotype

Absence of High-Risk Human Papillomavirus (HPV) Detection in Endocervical Adenocarcinoma with Gastric Morphology and Phenotype

Alteration of p16 and p15 genes in human uterine tumours

Prevalence of Human Papillomavirus DNA in Different Histological Subtypes of Cervical Adenocarcinoma

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