Mutational status of plasma exosomal KRAS predicts outcome in patients with metastatic colorectal cancer

Abstract

Liquid biopsy has become a useful alternative in metastatic colorectal cancer (mCRC) patients when tissue biopsy of metastatic sites is not feasible. In this study we aimed to investigate the clinical utility of circulating exosomes DNA in the management of mCRC patients. Exosomes level and KRAS mutational status in exosomal DNA was assesed in 70 mCRC patients and 29 CRC primary tumor and were analysed at different disease steps evaluating serial blood samples (240 blood samples). There was a significant correlation between the extension of disease and exosomes level and the resection of primary localized tumor was correlated with a decrease of KRAS G12V/ D copies and fractional abundance in metastatic disease. CEA expression and liver metastasis correlated with a higher number of KRAS G12V/D copies/ml and a higher fractional abundance; in the subgroup of mCRC patients eligible for surgery, the size of tumor and the radiological response were related to exosomes level but only the size was related to the number of KRAS WT copies; both KRAS wild-type and mutated levels were identified as a prognostic factor related to OS. Finally, we found that 91% of mutated mCRC patients became wild type after the first line chemotherapy but this status reverted in mutated one at progression in 80% of cases. In a prospective cohort of mCRC patients, we show how longitudinal monitoring using exosome-based liquid biopsy provides clinical information relevant to therapeutic stratification.

Roles of Exosome Genomic DNA in Colorectal Cancer

“…In CRC, KRAS and BRAF mutation was detected from the serum exosomes of CRC patients with higher sensitivity and specificity ( Hao et al, 2017 ; Lucchetti et al, 2021 ). In addition, it has been reported that transforming growth factor receptor 2 (TGFR2) is a part of the key signal pathway in colon epithelial cells.…”

“…The author also confirmed that KRAS mutation disappeared rapidly after the first chemotherapy cycle. However, it is necessary to closely monitor secondary drug resistance after anti-EGFR treatment to stop this treatment as soon as possible ( Lucchetti et al, 2021 ). Therefore, exosome gDNA can be used as an innovative tool to monitor the diagnosis, drug resistance, and prognosis of CRC patients during treatment.…”

COPS3 Promotes Proliferation, Invasion, and EMT of Colorectal Cancer Cells by MEK/ERK Pathway

“…CRC is a common gastrointestinal malignancy occurring in the colon [ 18 ]. CRC inchoate symptom is more not apparent and often already was in progress period when seeing a doctor, right now commonly used remedial measure [ 2 ]. To improve the resection rate, reduce the recurrence rate, and improve the survival rate, the treatment of intermediate and advanced CRC is based on surgery, supplemented by chemotherapy, immunotherapy, traditional Chinese medicine, and other supportive therapies [ 18 ].…”

“…Colorectal cancer (CRC), as one of the most aggressive cancers with poor prognosis, causes a large number of deaths worldwide and affects millions of people every year [ 1 , 2 ]. CRC mainly affects the distal rectum, sigmoid colon, and descending colon [ 3 ].…”

Biological Features of Extracellular Vesicles and Challenges

“…Mutations of EV-derived DNA reliably reflect the mutational state in the tumor of origin (García-Silva et al, 2020). For example, EGFR mutation was presented in plasma exosomes from lung cancer (Krug et al, 2018;Purcell et al, 2021) and cerebrospinal fluid EVs from glioblastoma (Figueroa et al, 2017), and KRAS mutation was presented in plasma exosomes from pancreatic cancer (Allenson et al, 2017) and colorectal cancer (Lucchetti et al, 2021). Some EV-derived DNA is tissuespecific.…”