Detection and prognosis of cervical cancer

a cervical cancer and prognosis technology, applied in the field of cervical cancer diagnosis and treatment, can solve the problems of limited reproducibility, low specificity of high-risk hpv testing for high-grade cervical neoplasia, and limitations of present pap test, and achieve accurate and effective early diagnostic assays.

Inactive Publication Date: 2011-08-04
MDXHEALTH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012]The present invention is based on the finding that several genes are identified as being differentially methylated in cervical cancers. This information is useful for cervical cancer screening, risk-assessment, prognosis, disease identification, disease staging, and identification of therapeutic targets. The identification of new genes that are methylated in cervical cancer allows accurate and effective early diagnostic assays, methylation profiling using multiple genes and identification of new targets for therapeutic intervention.
[0019]Epigenetic loss of gene function can be rescued by the use of DNA demethylating agents and / or DNA methyltransferase inhibitors. Accordingly, the invention also provides for a method for predicting the likelihood of successful treatment or resistance to treatment of cancer with such agent. If the gene is methylated, the likelihood of successful treatment is higher than if the gene is unmethylated, or methylated to a lesser degree. Conversely, if the gene is unmethylated, or methylated to a lesser degree, the likelihood of resistance to treatment is higher than if the gene is methylated.

Problems solved by technology

But, present PAP test has some limitations and is not completely ideal for screening as it suffers from suboptimal single-test sensitivity, limited reproducibility, and many equivocal.
Although it has been suggested that high-risk HPV testing may improve cervical cancer screening, the specificity for high grade cervical neoplasia of high risk HPV testing is relatively low.
This low specificity of HPV testing leads to a higher number of unnecessarily follow-up diagnostic workups (e.g. colposcopy) and unnecessarily treatment with cryotherapy or loop electrosurgical excision procedure, which permanently alters the cervix and have unknown consequences on fertility and pregnancy.
However, co-testing substantially increases the cost of screening.
But, immunization will only protect against HPV types that are targeted by the vaccine; protection will not be absolute and its longevity is uncertain; as yet, the possibility of genotype replacement cannot be excluded; and older women not covered by vaccination programs will continue to be at risk.

Method used

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  • Detection and prognosis of cervical cancer
  • Detection and prognosis of cervical cancer

Examples

Experimental program
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Effect test

example 1

Discovery of Methylation Markers in Cervical Cancer, Using Relaxation Ranking

[0137]To identify genes that are downregulated in cervical cancer due to promoter hypermethylation and to enrich for those genes that are most frequently involved in cervical cancer, a multistep approach was used combining:[0138]Affymetrix expression microarray analysis on a panel of frozen tissue samples from 39 human primary cervical cancers to identify cancer-specific down-regulated genes.[0139]Affymetrix expression microarray analysis on a panel of 4 different cervical cancer cell lines in which the expression of (hyper)methylated genes was re-activated upon treatment with 5-aza-2′deoxycytidine (DAC) (blocking DNA methylation), and / or trichostatin A (TSA) (inhibiting histone deacetylase—HDAC).

[0140]Data from both approaches were combined, and a novel non-parametrical ranking and selection method was applied to identify and rank candidate genes. Using in silico promoter analysis we restricted the analysi...

example 2

BROAD Analysis

Genome-Wide Promoter Alignment

[0188]The “Database of Transcription Start Sites” (DBTSS) (Suzuki et al., 2004) mapped each transcript sequence on the human draft genome sequence to identify its transcriptional start site, providing more detailed information on distribution patterns of transcriptional start sites and adjacent regulatory regions. The promoters of the above identified TOP3000 genes were separately mapped on the genome-wide alignment of all promoter associated CpG islands. All the promoter sequences were subsequently aligned by clustalW algorithm (Li 2003; Thompson et al., 1994). Treeillustrator (Trooskens et al., 2005) was used to visualize the large guide tree in addition to indicating the location of the known markers. Some regions on the “circle” are denser in known markers than others, indicating that there might be a sequence mechanism located in the small region around the TSS which makes certain genes more methylation-prone. The genes were selected ...

example 3

Further Assay Selection

Base 5-Lightcycler Platform

[0199]Of the different assays listed in Table 1 previously identified using the Base5 methylation platform, the top 63 ranked assays plus β-actin (ACTB) were transferred to the Lightcycler platform in order to further fine-tune the selection of the best cervical cancer methylation markers. This platform allows the assessment of markers in a system which is closer to, and provides information valuable for the subsequent development of, a final, scaled up MSP assay. The 64 assays (Table 6) were applied on a 384 well plate by Sigma. Six repeats of the assay set fitted on a 384 well plate. The samples were randomized per plate.

[0200]The sample set selected for the Lightcycler analysis was also previously used in the Base 5 analysis in order to make a compared analysis: a total of 27 cervical tumor samples and 20 controls (frozen tissue) were collected by UMC Groningen.

TABLE 6The 64 selected assays which were applied on the Lightcycler pl...

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Abstract

The present invention relates to methods and kits for identifying, diagnosing, prognosing, and monitoring cervical cancer. These methods include determining the methylation status or the expression levels of particular genes, or a combination thereof.

Description

FIELD OF THE INVENTION[0001]The present invention relates to the area of cancer diagnostics and therapeutics. In particular, it relates to methods and kits for identifying, diagnosing, prognosing, and monitoring cervical cancer. These methods include determining the methylation status or the expression levels of particular genes, or a combination thereof.BACKGROUND TO THE INVENTION[0002]Cervical cancer is the fifth most deadly cancer in women. Worldwide, approximately 500,000 cases of cervical cancer are diagnosed and about 250,000 women die from this disease annually (www.who.int / mediacentre / factsheets).[0003]Most (80-90%) invasive cervical cancer develops in flat, scaly surface cells that line the cervix (called squamous cell carcinomas, SCC). Approximately 10-15% of cases develop in glandular surface cells (called adenocarcinomas, AdC). Less commonly, cervical cancers have features of both SCC and AdC. These are called adenosquamous carcinomas or mixed carcinomas (www.cancer.org)...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12Q1/70C12Q1/68C07H21/04
CPCC12Q1/6886C12Q2600/112C12Q2600/16C12Q2600/154
Inventor VAN CRIEKINGE, WIMDEREGOWSKI, VALERIEDEHASPE, LUCWISMAN, G.BEA A.VAN DER ZEE, ATE G.J.SCHUURING, E. M.D.
Owner MDXHEALTH
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