Semiconductor technology for detection of DNA methylation based biomarkers in early screening of cancer

摘要

The role of DNA methylation based biomarkers in several stages of cancer development is a rapidly advancing area of research. The aberrancies on the methylation profile of gene promoters play a critical role in gene silencing, thus contributing in different phases of tumour initiation, progression and recurrence, also associated with predicting the response to chemotherapeutic agents, therefore leading to a better assessment of the clinical effectiveness of cancer therapies and so of better prognosis. The need for detection of DNA methylation has become one of the most important assays in early cancer screening.udThis work introduces the use of semiconductor technology for detection of DNA methylation based biomarkers in CMOS for early screening of cancer using the Ion-Sensitive Field-Effect Transistor (ISFET). This enables label-free detection of DNA methylation in gene markers of interest associated with tumour development in different organs, ultimately enabling a Point-of-Care (PoC) system for early cancer diagnosis. Towards this goal, we introduce the concept of ratiometric detection using the ``Methylation Cell" which allows continuous computation of the DNA methylation ratio. This was demonstrated through a Lab-on-Chip (LoC) system using low power current-mode translinear circuits fabricated in unmodified CMOS. udComplementary to this, a novel implementation of the ``Gilbert Gain Cell" integrated with ISFET sensors was proposed, referred to as the ISFET based Chemical Gilbert Cell, a current-mode circuit for differential reaction monitoring of pH signals derived from DNA methylation reactions. The Cell achieves elimination of common non-idealities of ISFETs such as drift reduction and temperature variations, while achieving gain tunability.