Liquid Pap Smear Mutation Detection for Ovarian and Endometrial Cancer Screening
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Solution Overview
Problem
Current screening methods for ovarian and endometrial cancers lack specificity and sensitivity, leading to high mortality rates as they cannot effectively distinguish between benign and malignant conditions, resulting in unnecessary evaluations and lack of survival benefit.
Innovation Solution
A method using a liquid Pap smear to detect genetic or epigenetic changes in specific genes (CTNNB1, EGFR, PI3KCA, PTEN, TP53, BRAF, KRAS, AKT1, NRAS, PPP2R1A, APC, FBXW7, ARID1A, CDKN2A, MLL2, RFF43, and FGFR2) associated with endometrial or ovarian cancer, employing next-generation sequencing to identify mutations present in cells shed into the cervix.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If cytology or TVS is used for endometrial cancer screening, then the screening can be performed noninvasively, but the specificity is insufficient because benign lesions also result in thickened endometrium
Solution Approach 1:
The patent introduces an intermediary molecular marker (abnormal protein expression pattern in glandular cells) that mediates between the noninvasive sampling method and the specific detection of malignant cells. This intermediary allows differentiation of malignant from benign conditions without requiring invasive procedures.
Solution Approach 2:
The patent changes the detection parameter from macroscopic morphology (endometrial thickness measured by TVS) to molecular-level parameters (protein expression patterns of specific markers). This parameter change enables specific identification of malignant cells while maintaining noninvasive sampling through liquid-based cytology.
2Productivity
If serum CA-125 and TVS are used for ovarian cancer screening, then screening can be performed, but the specificity is limited because CA-125 is also elevated in benign conditions
Solution Approach 1:
The patent segments the detection approach by identifying and testing for multiple distinct molecular markers simultaneously. Instead of relying on a single marker like CA-125, the invention tests for abnormal expression patterns of multiple proteins, allowing differentiation between benign and malignant ovarian conditions through a combination of markers.
Solution Approach 2:
The patent creates a composite diagnostic approach by combining multiple molecular markers into a panel test. This composite strategy, analogous to composite materials, leverages the strengths of multiple markers to achieve higher specificity while maintaining broad screening capability.
3Reliability
If false positive tests are performed to evaluate potential cancers, then early detection may occur, but morbidity increases due to unnecessary laparoscopy or exploratory laparotomy
Solution Approach 1:
The patent performs preliminary molecular testing on easily obtained liquid-based cytology samples before committing patients to invasive diagnostic procedures. This preliminary action using multiple molecular markers filters out false positives early, preventing unnecessary laparoscopy or exploratory laparotomy while maintaining high early detection capability.
4Loss of time
If routine screening for endometrial or ovarian cancers is performed in the general population, then early detection may be achieved, but the potential harms outweigh the potential benefits
Solution Approach 1:
The patent fundamentally changes the detection parameters from non-specific morphological features to specific molecular markers. This parameter change enables highly specific detection that can be performed on routine liquid-based cytology samples, making screening beneficial by reducing false positives and associated harms while maintaining early detection capability.
Data Source
AI summary
The recently developed liquid-based Papanicolaou (Pap) smear allows not only cytologic evaluation but also collection of DNA for detection of HPV, the causative agent of cervical cancer. We tested these samples to detect somatic mutations present in rare tumor cells that might accumulate in the cervix once shed from endometrial and ovarian cancers. A panel of commonly mutated genes in endometrial and ovarian cancers was assembled and used to identify mutations in all 46 endometrial or cervical cancer tissue samples. We were able also able to identify the same mutations in the DNA from liquid Pap smears in 100% of endometrial cancers (24 of 24) and in 41% of ovarian cancers (9 of 22). We developed a sequence-based method to query mutations in 12 genes in a single liquid Pap smear without prior knowledge of the tumor's genotype.