Dataset Information

Placenta-Specific Protein 1 Expression in Human Papillomavirus 16/18-Positive Cervical Cancers Is Associated With Tumor Histology.

ABSTRACT: OBJECTIVE:Expression of the trophoblast-specific gene placenta-specific protein 1 (PLAC1) has been detected in a wide variety of cancers. However, to date, PLAC1 expression has not been shown in cervical cancer. We have carried out a preliminary study that shows for the first time that PLAC1 is expressed in cervical cancers. METHODS:A total of 16 primary cervical tumors were obtained from patients shown to be human papillomavirus (HPV) 16/18 positive. Total cellular RNA, genomic DNA, and total protein were purified from each tumor. These materials were then used to determine PLAC1 expression, TP53 mutation status, and p53 expression. RESULTS:The PLAC1 expression was demonstrated in all 16 primary cervical tumors. The highest levels of expression were found in the more aggressive squamous and adenosquamous histologic types compared with adenocarcinomas. Moreover, the proportion of total PLAC1 message coming from the P1 promoter, also termed the distal or cancer promoter, was significantly greater in the more aggressive squamous and adenosquamous histologic types compared with adenocarcinomas. Finally, in spite of all 16 tumors being HPV-16/18 positive, 3 of 8 squamous cell cancers and 2 of 5 adenocarcinomas expressed wild-type p53 protein. Consistent with the recently shown suppression of the PLAC1P1 promoter by wild-type p53, these p53 positive tumors displayed among the lowest P1-specific PLAC1 expression levels. CONCLUSIONS:The PLAC1 expression has been demonstrated for the first time in cervical cancers. This preliminary study has further revealed a complex relationship between PLAC1 expression, cervical cancer histologic type, p53, and HPV type that requires further investigation.

SUBMITTER: Devor EJ

PROVIDER: S-EPMC5405019 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Placenta-Specific Protein 1 Expression in Human Papillomavirus 16/18-Positive Cervical Cancers Is Associated With Tumor Histology.

Devor Eric J EJ Reyes Henry D HD Gonzalez-Bosquet Jesus J Warrier Akshaya A Kenzie Susan A SA Ibik Nonye V NV Miller Marina D MD Schickling Brandon M BM Goodheart Michael J MJ Thiel Kristina W KW Leslie Kimberly K KK

International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 20170501 4

<h4>Objective</h4>Expression of the trophoblast-specific gene placenta-specific protein 1 (PLAC1) has been detected in a wide variety of cancers. However, to date, PLAC1 expression has not been shown in cervical cancer. We have carried out a preliminary study that shows for the first time that PLAC1 is expressed in cervical cancers.<h4>Methods</h4>A total of 16 primary cervical tumors were obtained from patients shown to be human papillomavirus (HPV) 16/18 positive. Total cellular RNA, genomic D ...[more]

PMID: 28375929

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Project description:It has been reported that >90% of women with cervical cancer are human papillomavirus (HPV)-positive, with HPV16 and 18 being the most 'highest-risk' HPV genotypes. However, in numerous women, HPV infection will not progress to cervical cancer. Accordingly, more appropriate screening markers need to be explored. In the present study, genome-wide DNA methylomic differences between cervical cancer tissues with HPV-16 or HPV-18 infection and normal cervical tissues were detected by using an Illumina Human Methylation 850 K BeadChip. The Gene Ontology functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted in order to define the nearest neighbouring genes of differentiated methylation sites. Moreover, differentiated methylation sites were verified using pyrosequencing. KEGG analyses suggested that the focal adhesion pathway and pathways in cancer were highly enriched. Bioinformatics and statistical analysis indicated that the nine CpG loci had the most significant differences amongst the genes involved in these pathways. Among these, six CpG sites in the CHRM2, LAMA4, COL11A1, FGF10, IGF1 and TEK genes were highly associated with HPV-16-positive cervical cancer, as validated using pyrophosphate sequencing. Additionally, 10 significantly different CpG sites of the HPV-18-positive group were selected and verified in The Cancer Genome Atlas, indicating their possible diagnostic roles in cervical cancer development and determination. In addition, eight hypermethylated CpG island sites that were associated with HPV-16-positive cervical cancer tissues and 10 hypermethylated CpG island sites that were associated with HPV-18-positive cervical cancer tissues were identified, highlighting their potential roles in screening and evaluating targeted therapy efficacy and prognosis. The main focus of the present study was to identify the genetic variability in HPV-16- and HPV-18-positive samples and to elucidate possible methylation biomarkers in HPV-positive women with a risk of developing cervical cancer.

Project description:BackgroundPersistent infection with oncogenic Human Papillomavirus (HPV) is associated with the development of cervical cancer with each genotype differing in their relative contribution to the prevalence of cervical disease. HPV DNA testing offers improved sensitivity over cytology testing alone but is accompanied by a generally low specificity. Potential molecular markers of cervical disease include type-specific viral load (VL), integration of HPV DNA into the host genome and methylation of the HPV genome. The aim of this study was to evaluate the relationship between HPV type-specific viral load, integration and methylation status and cervical disease stage in samples harboring HPV16, HPV18, HPV31 or HPV45.MethodsSamples singly infected with HPV16 (n=226), HPV18 (n=32), HPV31 (n=75) or HPV45 (n=29) were selected from a cohort of 4,719 women attending cervical screening in England. Viral load and integration status were determined by real-time PCR while 3'L1-URR methylation status was determined by pyrosequencing or sequencing of multiple clones derived from each sample.ResultsViral load could differentiate between normal and abnormal cytology with a sensitivity of 75% and a specificity of 80% (odds ratio [OR] 12.4, 95% CI 6.2-26.1; p<0.001) with some variation between genotypes. Viral integration was poorly associated with cervical disease. Few samples had fully integrated genomes and these could be found throughout the course of disease. Overall, integration status could distinguish between normal and abnormal cytology with a sensitivity of 72% and a specificity of 50% (OR 2.6, 95% CI 1.0-6.8; p=0.054). Methylation levels were able to differentiate normal and low grade cytology from high grade cytology with a sensitivity of 64% and a specificity of 82% (OR 8.2, 95% CI 3.8-18.0; p<0.001). However, methylation varied widely between genotypes with HPV18 and HPV45 exhibiting a broader degree and higher magnitude of methylated CpG sites than HPV16 and HPV31.ConclusionsThis study lends support for HPV viral load and CpG methylation status, but not integration status, to be considered as potential biomarkers of cervical disease.

Dataset Information

Placenta-Specific Protein 1 Expression in Human Papillomavirus 16/18-Positive Cervical Cancers Is Associated With Tumor Histology.

Publications

Placenta-Specific Protein 1 Expression in Human Papillomavirus 16/18-Positive Cervical Cancers Is Associated With Tumor Histology.

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