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Vereniging Voor Christelijk Hoger Onderwijs, Wetenschappelijk Onderzoek En Patientenzorg

Stiching Researchfonds Pathologie

Christophorus Joannes Lambertus Maria Meijer

Petrus Josephus Ferdinandus Snijders

Renske Daniëla Maria Steenbergen

Daniëlle Anne Marie Heideman

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 comprising detection 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.

Methylation classifier for detection of HPV-induced invasive cancers, nonHPV-induced gynaecological and anogenital cancers and their high-grade precursor lesions

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 comprising detection 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.

The invention relates to method for detecting HPV-induced high-grade precancerous lesions and HPV-induced invasive cancers, said method comprising detection of hypermethylation in the PRDM14 and/or FAM19A4 gene in a cell whereby such hypermethylation indicates the presence of HPV-induced precursor lesions with invasive potential and HPV-induced invasive cancers. The invention further comprises the use of the PRDM14 and/or FAM19A4 gene in such a method and a testkit for the detection of PRDM14 and/or FAM19A4 methylation.

PRDM14 and FAM19A4, molecular diagnostic markers for HPV-induced invasive cancers and their high-grade precursor lesions

The invention describes a consensus PCR based method (i.e. HRE7-PCR) for the simultaneous detection of 14 Human Papilloma Virus types (i.e. HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) that are classified as (probably) high-risk, relating to the causation of cervical cancer) and a candidate hrHPV type (i.e. HPV 67) using sets of 6 overlapping forward primers and 9 overlapping backward primers that together amplify a fragment of about (215) to (245) base pairs of the E7 open reading frame of these hrHPV types. For the detection of reaction products an EIA format can be used with the aid of a cocktail of type-specific oligoprobes as exemplified herein. Furthermore, we have developed a method for an efficient typing of these (15) HPVs that is compatible with the method for detection. This RLB typing system involves hybridization of PCR products with immobilized type-specific oligoprobes.

Detection method for cervical HPVS

The inventors now have developed a (molecular) diagnostic marker based on MAL alterations, in particular reduced MAL mRNA and protein expression as well as MAL promoter hypermethylation, to identify human papillomavirus (HPV)-induced high-grade precancerous lesions such as premalignant cervical lesions of invasive cervical cancer, and high-risk human papillomavirus (HPV)-induced precursor lesions of non-cervical invasive cancers within, cell material obtained via scraping, lavage or by other means and/or tissue. In particular, the present invention relates to the use of the MAL gene (including its promoter) and the gene products thereof as marker for HPV-induced high-grade premalignant lesions, allowing early detection and better treatment option for the individual patient.

Combination of MAL and CADM1 markers for HPV induced invasive cancers and their high-grade precursor lesions

The invention is in the field of medicine and is concerned with a molecular diagnostic marker for progression to invasiveness of HPV-induced premalignant lesions and future metastatic potential of HPV-induced premalignant lesions and carcinomas. In particular the present invention relates to the use of the TSLC1 gene as marker for progression to invasive cervical cancer and metastatic potential of cervical lesions. The invention provides methods for detecting HPV-induced invasive cancers and their precursor lesions associated with tumor suppressor lung cancer 1 (TSLC1), comprising contacting a target cellular component of a test cell with a reagent that detects TSLC1 and detecting a reduction in the TSLC1 as compared to that of a comparable normal cell. The invention also provides molecular diagnostic markers for premalignant cervical lesions with invasive potential associated with tumor suppressor lung cancer 1 (TSLC1) in cytologically abnormal cervical smears and/or biopsies.

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Leiden, Netherlands

Christophorus Joannes Lambertus Maria Meijer