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A methylation classifier for detection of hpv-induced invasive cancers, nonhpv- induced gynaecological and anogenital cancers and their high-grade precursor lesions

A technology for precancerous lesions and gynecological cancers, applied in the field of markers for premalignant lesions, can solve the problem of low sensitivity of endometrial cancer detection

Inactive Publication Date: 2020-02-04
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, routine cytology of cervical swabs has very low sensitivity for detection of endometrial cancer

Method used

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  • A methylation classifier for detection of hpv-induced invasive cancers, nonhpv- induced gynaecological and anogenital cancers and their high-grade precursor lesions
  • A methylation classifier for detection of hpv-induced invasive cancers, nonhpv- induced gynaecological and anogenital cancers and their high-grade precursor lesions
  • A methylation classifier for detection of hpv-induced invasive cancers, nonhpv- induced gynaecological and anogenital cancers and their high-grade precursor lesions

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0099] Example 1. Discovery of LHX8, ASCL1 and ST6GALNAC5 as useful for detecting cervical cancer and Optimal panel of methylation markers for precancerous lesions

[0100] A comprehensive analysis of genome-wide DNA methylation changes detectable in autologous samples and associated with cervical carcinogenesis has been performed by means of Infinium 450K BeadChip arrays on hrHPV-positive autologous samples. The included sample series consisted of 68 hrHPV-positive autologous samples from 39 women with high-grade cervical intraepithelial neoplasia grade 3 (CIN3) and 29 women with low-grade cervical intraepithelial neoplasia grade 0 or 1 (≤CIN1) composition. The InfiniumHumanMethylation450 BeadChip array analyzes more than 485,000 methylation sites per sample at single-nucleotide resolution in the human genome (Illumina, San Diego, CA, USA). With this approach, we identified 12 methylated targets specifically associated with the presence of CIN3. Next, multiplex qMSP ass...

Embodiment 2

[0103] Example 2 Validation of methylation classifiers in lavage and brush autologous samples

[0104] To validate the clinical performance of the methylation classifier, we analyzed another independent large series of hrHPV-positive lavage autologous samples (n = 198) and brush autologous samples (n = 278) using the multiplex qMSP assay. As observed in the above sample series, the methylation classifier showed good and comparable clinical performance for CIN3 detection for both hrHPV positive lavage (AUC=0.88) and brushing (AUC=0.90) autologous samples (See Figure 4ROC curve of C). In the validation set, 74% (26 of 35) of lavage autologous samples and 88% (49 of 56) of brushing autologous samples from women with CIN3 showed methylation positivity, in hrHPV-positive The corresponding specificities in controls were 79% and 81%, respectively.

Embodiment 3

[0105] Example 3. Methylation of LHX8, ASCL1 and ST6GALNAC5 as used in autologous cervicovaginal samples Markers for primary screening

[0106] Methylation markers tested so far are not well suited for primary screening as specificity is too low at acceptable sensitivity for CIN2 / 3 and cancer. When evaluating the use of a methylation classifier consisting of LHX8, ASCL1, and ST6GALNAC5 as markers for primary screening, it was surprisingly found that when analyzing autologous HPV-negative samples and autologous samples from women with CIN3, the classifier was The detection of CIN3 also had a very high AUC of 0.895 on autologous lavage samples, as well as on autologous brushing samples (AUC was 0.828).

[0107] The present findings indicate that methylation classifiers that detect hypermethylation of the genes LHX8, ASCL1, and ST6GALNAC5 and their regulatory sequences, when applied not only to autologous cervicovaginal douche samples, but also to autologous Potential CIN2+ ...

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Abstract

The invention relates to method for detecting HPV-induced high-grade precancerous lesions, HPV-induced invasive cancers and nonHPV-induced gynaecological and anogenital cancers, said method comprisingdetection of a methylation classifier consisting of the genes LHX8, ASCL1 and ST6GALNAC5 and their regulatory sequence in a cell whereby such hypermethylation indicates the presence of HPV- induced precursor lesions with invasive potential, HPV-induced invasive cancers and nonHPV-induced gynaecological and anogenital cancers. The invention further comprises the use of the methylation classifier consisting of genes LHX8, ASCL1 and ST6GALNAC5 and their regulatory sequence in such a method and a test kit for the detection of LHX8. ASCL1 and / or ST6GALNAC5 methylation.

Description

technical field [0001] The present invention relates to the fields of cancer prevention and medical diagnosis; and is concerned with cancers, particularly human papillomavirus (HPV)-induced invasive cancers and their advanced precursor lesions (such as invasive cervical cancer and premalignant cervical lesions), non-HPV Molecular diagnostic assays for induced gynecologic and anogenital cancers. In particular, the present invention relates to methylation classifiers based on the genes LHX8, ASCL1 and ST6GALNAC5 and their regulatory sequences as useful for hrHPV-induced invasive cancers, non-HPV-induced gynecological and anogenital cancers and their invasive Use of markers of potential premalignant lesions. Background technique [0002] Cervical cancer is the fourth most common cancer in women worldwide and is responsible for approximately 250,000 cancer deaths each year. [0003] The development of squamous cell carcinoma of the cervix is ​​characterized by a series of prem...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/6886
CPCC12Q1/6886C12Q2600/112C12Q2600/154
Inventor 克里斯托夫·约翰内斯·兰贝图斯·玛丽亚·梅耶尔伦塞克·丹尼拉·玛丽亚·斯坦伯根彼得鲁斯·约瑟夫斯·费丁南德斯·斯尼德丹妮尔·安妮·玛丽·海德曼
Owner SELF SCREEN
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