Genetic Characteristics Associated With Drug Resistance in Lung Cancer and Colorectal Cancer Using Whole Exome Sequencing of Cell-Free DNA

Abstract

Circulating cell-free DNA (cfDNA) can be used to characterize tumor genomes through next-generation sequencing (NGS)-based approaches. We aim to identify novel genetic alterations associated with drug resistance in lung cancer and colorectal cancer patients who were treated with EGFR-targeted therapy and cytotoxic chemotherapy through whole exome sequencing (WES) of cfDNA. A cohort of 18 lung cancer patients was treated with EGFR TKI or cytotoxic chemotherapy, and a cohort of 37 colorectal cancer patients was treated with EGFR monoclonal antibody or cytotoxic chemotherapy alone. Serum samples were drawn before and after development of drug resistance, and the genetic mutational profile was analyzed with WES data. For 110 paired cfDNA and matched germline DNA WES samples, mean coverage of 138x (range, 52–208.4x) and 47x (range, 30.5–125.1x) was achieved, respectively. After excluding synonymous variants, mutants identified in more than two patients at the time of acquired resistance were selected. Seven genes in lung cancer and 16 genes in colorectal cancer were found, namely, APC, TP53, KRAS, SMAD4, and EGFR. In addition, the GPR155 I357S mutation in lung cancer and ADAMTS20 S1597P and TTN R7415H mutations in colorectal cancer were frequently detected at the time of acquired resistance, indicating that these mutations have an important function in acquired resistance to chemotherapy. Our data suggest that novel genetic variants associated with drug resistance can be identified using cfDNA WES. Further validation is necessary, but these candidate genes are promising therapeutic targets for overcoming drug resistance in lung cancer and colorectal cancer.

Response and resistance to BRAFV600E inhibition in gliomas: Roadblocks ahead?

“…The most pressing concern at present is resistance to targeted therapy as a cause of treatment failure, morbidity, and mortality. In many human cancers, important progress has been made using genomic and transcriptomic profiling of paired clinical samples to track the tumor evolution during and after targeted treatment ( 92 , 93 ). Yet, re-biopsy at time of relapse is not a standard of care in patients with relapsed gliomas and data are limited.…”

Exploring the Role of Circulating Cell-Free RNA in the Development of Colorectal Cancer

“…With the usage of high-sensitivity detection and quantification techniques, in clinical research and practice, circulating cell-free DNA (cfDNA) has been increasingly applied in the detection of resistance mutations and oncogenic driver mutations [ 20 , 21 , 22 , 55 ]. For instance, mutations in APC , KRAS , TP53 , and SMAD4 have been reported as key drivers of progression and metastasis in CRC [ 56 ]. Besides this, the number of resistance mechanisms to anti-EGFR therapies in CRC patients has been previously reported, including mutations of BRAF , MEK, and the EGFR extracellular domain (ECD) and the amplification of ERBB2 , MET , KRAS, and NRAS , which could benefit from the inclusion of targeted therapies in standard protocols, emphasizing the importance of personalized medicine [ 20 , 21 , 22 ].…”

Evolution of the Membrane Transport Protein Domain

“…However, on the contrary, Gpr155 was upregulated in UVR-induced mouse melanomas [ 12 ]. Moreover, the GPR155 I357S mutation was associated with the acquired resistance to chemotherapy in lung cancer patients [ 13 ]. Moreover, GPR155 was studied in several other experiments.…”