MAL and CADM1 Methylation Markers for HPV Lesion Detection
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Solution Overview
Problem
Current cervical cancer screening methods, particularly those involving high-risk human papillomavirus (hrHPV) testing, face challenges in accurately differentiating between women with and without high-grade premalignant lesions, leading to unnecessary follow-up procedures and anxiety, as they lack sufficient specificity and cannot effectively diagnose non-cervical HPV-induced invasive cancers.
Innovation Solution
The use of MAL gene and its regulatory sequences as molecular diagnostic markers, specifically through reduced MAL mRNA and protein expression, and MAL promoter hypermethylation, to identify HPV-induced high-grade premalignant lesions and invasive cancers, combined with methylation analysis of CADM1, for enhanced sensitivity and specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If hrHPV testing is used as primary screening tool, then sensitivity for detecting high-risk lesions is improved, but specificity deteriorates leading to substantial number of false positives and unnecessary follow-up procedures
Solution Approach 1:
The screening process is segmented into multiple stages: primary hrHPV testing followed by secondary triage using MAL and CADM1 methylation markers. This segmentation allows the system to maintain high sensitivity at the primary stage while improving specificity through additional discriminatory testing only for positive cases, thereby reducing false positives and unnecessary procedures
Solution Approach 2:
MAL and CADM1 methylation markers serve as intermediary biomarkers between hrHPV detection and final diagnosis of high-grade lesions. These intermediate markers provide additional layers of discrimination, allowing the system to filter out false positives from hrHPV testing while maintaining sensitivity for true high-grade lesions
2Measurement precision
If cytology is used as secondary triage test for hrHPV positive women, then some differentiation is achieved, but it fails to adequately stratify women with normal cytology who still have high-grade lesions
Solution Approach 1:
The invention changes the biological parameter being measured from cellular morphology (cytology) to epigenetic modification status (DNA methylation). MAL and CADM1 methylation status provides a molecular signature that is more reliable for stratifying hrHPV positive women, particularly those with normal cytology but high-grade lesions, overcoming the limitations of cytological assessment
3Adaptability or versatility
If traditional screening methods are used, then detection of cervical lesions is possible, but they cannot diagnose non-cervical HPV-induced invasive cancers
Solution Approach 1:
The MAL and CADM1 methylation markers serve universal functions across multiple HPV-induced cancer types including cervical, anal, penile, and oropharyngeal cancers. The same molecular diagnostic approach can be applied to detect and stratify risk across different anatomical sites, providing a versatile platform that maintains high diagnostic accuracy for HPV-induced malignancies regardless of location
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach provides a more accurate method for detecting high-grade cervical and non-cervical HPV-induced lesions, reducing unnecessary procedures and improving treatment options by offering a higher sensitivity than traditional cytology, and enabling detection in self-sampled specimens.
Implementation Method 1
MAL promoter hypermethylation
Data Source
Figure 1
AI summary
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.