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Detecting and Tracking Circulating Tumour DNA Copy Number Profiles during First Line Chemotherapy in Oesophagogastric Adenocarcinoma

1
Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation Trust, Sutton, London SM2 5PT, UK
2
Translational Oncogenomics Laboratory, Centre for Evolution and Cancer, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2019, 11(5), 736; https://doi.org/10.3390/cancers11050736
Received: 25 April 2019 / Revised: 20 May 2019 / Accepted: 23 May 2019 / Published: 27 May 2019
(This article belongs to the Special Issue Liquid Biopsy for Cancer)
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Abstract

DNA somatic copy number aberrations (SCNAs) are key drivers in oesophagogastric adenocarcinoma (OGA). Whether minimally invasive SCNA analysis of circulating tumour (ct)DNA can predict treatment outcomes and reveal how SCNAs evolve during chemotherapy is unknown. We investigated this by low-coverage whole genome sequencing (lcWGS) of ctDNA from 30 patients with advanced OGA prior to first-line chemotherapy and on progression. SCNA profiles were detectable pretreatment in 23/30 (76.7%) patients. The presence of liver metastases, primary tumour in situ, or of oesophageal or junctional tumour location predicted for a high ctDNA fraction. A low ctDNA concentration associated with significantly longer overall survival. Neither chromosomal instability metrics nor ploidy correlated with chemotherapy outcome. Chromosome 2q and 8p gains before treatment were associated with chemotherapy responses. lcWGS identified all amplifications found by prior targeted tumour tissue sequencing in cases with detectable ctDNA as well as finding additional changes. SCNA profiles changed during chemotherapy, indicating that cancer cell populations evolved during treatment; however, no recurrent SCNA changes were acquired at progression. Tracking the evolution of OGA cancer cell populations in ctDNA is feasible during chemotherapy. The observation of genetic evolution warrants investigation in larger series and with higher resolution techniques to reveal potential genetic predictors of response and drivers of chemotherapy resistance. The presence of liver metastasis is a potential biomarker for the selection of patients with high ctDNA content for such studies. View Full-Text
Keywords: oesophagogastric adenocarcinoma; circulating tumour DNA; somatic copy number aberration; liquid biopsy oesophagogastric adenocarcinoma; circulating tumour DNA; somatic copy number aberration; liquid biopsy
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Davidson, M.; Barber, L.J.; Woolston, A.; Cafferkey, C.; Mansukhani, S.; Griffiths, B.; Moorcraft, S.-Y.; Rana, I.; Begum, R.; Assiotis, I.; Matthews, N.; Rao, S.; Watkins, D.; Chau, I.; Cunningham, D.; Starling, N.; Gerlinger, M. Detecting and Tracking Circulating Tumour DNA Copy Number Profiles during First Line Chemotherapy in Oesophagogastric Adenocarcinoma. Cancers 2019, 11, 736.

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