Circulating tumor DNA profiling by next generation sequencing reveals heterogeneity of crizotinib resistance mechanisms in a gastric cancer patient with MET amplification
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Juan Du1,*, Xue Wu2,*, Xiaoling Tong2, Xiaonan Wang3, Jia Wei1, Yang Yang1, Zhili Chang3, Yu Mao3, Yang W Shao2, Baorui Liu1
1The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu, 210008, China
2Geneseeq Technology Inc., Toronto, Ontario, M5G1L7, Canada
3Nanjing Geneseeq Technology Inc., Sino-Danish Life Science Park, Nanjing, Jiangsu, 210032, China
*These authors contributed equally to this work
Baorui Liu, email: firstname.lastname@example.org
Yang W Shao, email: email@example.com
Keywords: circulating tumor DNA, next generation sequencing, MET, crizotinib, drug resistance
Received: April 19, 2016 Accepted: February 04, 2017 Published: February 17, 2017
Crizotinib has been used to counter MET gene amplification in a number of different human malignancies. Transient response to crizotinib in MET-amplified gastric cancer has been reported, but the mechanisms of resistance are not well studied. Here, we reported a stage IV gastric cancer patient with high levels of MET amplification. The implementation of crizotinib treatment led to significant symptomatic improvement in the first 2 months, but was followed by rapid disease progression. Periodic mutation profiling of patient’s circulating tumor DNA (ctDNA) by next generation sequencing (NGS) revealed a number of genetic alterations including re-occurrence of MET amplification, multiple secondary MET mutations, a dramatic increase of FGFR2 gene relative copy number as well as mutations in other downstream and bypassing elements, which may collectively related to the patient’s cancer progression. Our results illustrate the complex and heterogeneous molecular mechanisms for crizotinib resistance in this patient, and demonstrate the great potential of ctDNA profiling for treatment decision-making and prognosis in clinical practice.
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