Finding a needle in the haystack: ctDNA detection for tracking cancer evolution and refining cancer risk
- Research Opportunity
- Masters by Research
- Department / Centre
- Clinical Pathology
- Victorian Comprehensive Cancer Centre (VCCC)
|Associate Professor Daniel Buchananfirstname.lastname@example.org||85597004||Personal web page|
|Dr Ryan Hutchinsonemail@example.com||85597112||Personal web page|
|Dr Mark Clendenningfirstname.lastname@example.org|
Summary This project will explore the correlation between ctDNA and somatic mutation status derived from formalin fixed paraffin embedded tissue. This will involve micro-dissecting normal colonic epithelium and tumour region that will then be profiled using next generation sequencing techniques. The project will also explore the correlation between immune indices determined from the blood and the quantity of ctDNA.
Colorectal cancer (CRC) is a leading cause of cancer mortality in developed countries and there are over 15,000 new cases diagnosed annually in Australia. Although mortality associated with CRC diagnoses has declined progressively in recent decades, the incidence of CRC is estimated to be increasing worldwide, particularly in young adults. However, CRC is also one of the most preventable cancers as it normally arises from benign neoplasms, and this polyp-tumour progression is a multistep process, likely occurring over many years1. The increasing incidence of CRC emphasises the urgent clinical need to identify biomarkers that can predict which patients are at risk of developing metastatic disease. Tumour cells and non-malignant cells shed DNA, cell free DNA (cfDNA), into the bloodstream. cfDNA is a small amount of DNA in the circulation that has escaped degradation. Circulating tumour DNA (ctDNA) are DNA fragments up to 200 bp with a half-life of ~2 hours and there are a number of variables that impact the quantification of ctDNA such as tumour heterogeneity and inflammation. However, the biggest technical challenge in ctDNA detection from solid tumours is the rarity of tumour DNA within the several thousand genome equivalents of normal DNA that is released by bone marrow, skin and gastrointestinal tract (~5 ctDNA fragments per 10,000 normal DNA fragments). Liquid biopsies can be used for screening, recurrence detection (monitoring known mutation profile of primary tumour) and metastatic disease (heterogeneity and resistance monitoring), thus, the application of molecular biomarkers in minimally invasive sampling opens a promising perspective for the early detection of malignancy. Although the TCGA has defined 17 somatic recurrently mutated genes in CRC which can be used to distinguish tumour derived DNA from normal circulating DNA, not all somatic mutations are cancer2.
Aims : This project will explore the correlation between ctDNA and somatic mutation status derived from formalin fixed paraffin embedded tissue. This will involve micro-dissecting normal colonic epithelium and tumour region that will then be profiled using next generation sequencing techniques. The project will also explore the correlation between immune indices determined from the blood and the quantity of ctDNA.
- Fearon, E.R. and Vogelstein, B., 1990. A genetic model for colorectal tumorigenesis. cell, 61(5), pp.759-767.
- Anglesio, M.S., Papadopoulos, N., Ayhan, A., Nazeran, T.M., Noë, M., Horlings, H.M., Lum, A., Jones, S., Senz, J., Seckin, T. and Ho, J., 2017. Cancer-associated mutations in endometriosis without cancer. New England Journal of Medicine, 376(19), pp.1835-1848.
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Masters by Research
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Department / Centre
Research NodeVictorian Comprehensive Cancer Centre (VCCC)
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