Bioinformatics Seminar
Time:
Venue: Na
5 February 2019
NaEnhanced detection of circulating tumour DNA by fragment size analysis
Dineika ChandranandaPeterMac
Genomic alterations underlying tumour development ; progression and its recurrence can be tracked in the plasma of cancer patients through analysis of circulating tumour DNA (ctDNA). Current methods for detection of ctDNA are limited by biological and analytical factors. Harnessing biological differences between tumour- and non-tumour-derived cell-free DNA ; coupled with developments in genomic and bioinformatic methods ; can expand the scope and sensitivity for ctDNA analysis. These can enhance its utility for early detection ; identification of minimal residual disease ; and longitudinal monitoring of genetic changes during patient treatment.
We hypothesized that differences in fragment lengths of circulating DNA could be exploited to enhance sensitivity for detecting ctDNA. We surveyed ctDNA fragment sizes in 344 plasma samples from 200 patients with cancer using low-pass whole-genome sequencing (0.4x). To establish the size distribution of mutant ctDNA ; tumour-guided personalized deep sequencing was performed in 19 patients. We detected enrichment of ctDNA in fragment sizes between 90 and 150 bp and developed methods for in vitro and in silico size selection of these fragments. Selecting fragments between 90 and 150 bp improved detection of tumour DNA ; with more than two-fold median enrichment in >95% of cases and more than four-fold enrichment in >10% of cases. Analysis of size-selected cfDNA identified clinically actionable mutations and copy number alterations that were otherwise not detected.
Identification of plasma samples from patients with advanced cancer was improved by predictive models integrating fragment length and copy number analysis of cfDNA ; with area under the curve (AUC) >0.99 compared to AUC <0.80 without fragmentation features. Increased identification of cfDNA from patients with glioma ; renal ; and pancreatic cancer was achieved with AUC > 0.91 compared to AUC < 0.5 without fragmentation features. Fragment size analysis and selective sequencing of specific fragment sizes can boost ctDNA detection and could complement or provide an alternative to deeper sequencing of cfDNA.;Actual Venue : Davis Auditorium