Abstract
Methods for predicting individual responsiveness to targeted chemotherapy are urgently needed, considering the frequent resistance and extremely high cost. A chemosensitive single-nucleotide polymorphism (SNP) discovery schema is presented that utilizes (i) genome-wide SNP screening with a human SNP array and an in vitro chemosensitivity assay in 118 colorectal cancers, (ii) clinical association analysis in the other 98 patients who had received chemotherapy for metastatic cancer, and (iii) biological utility assessment using cell viability assays of transfected colorectal cancer (CRC) cells. Nine SNPs related to bevacizumab and cetuximab regimen sensitivity were chosen during screening. Overall responses for bevacizumab regimens revealed that patients carrying the TT genotype at ANXA11 rs1049550 or at least one G allele at LINS1 rs11247226 seemed greater chemosensitive than those carrying at least one C allele or the AA genotype, respectively (P < 0.05). For cetuximab regimens, patients carrying the GG genotype at DFNB31 rs2274159 or LIFR rs3729740 seemed greater chemosensitive than those carrying at least one A allele (P = 0.025 and P = 0.07). Cytotoxicity analyses showed that all RKO and HCT116 CRC clones transfected with the G allele at LIFR rs3729740 and the C allele at ISX rs361863 were more sensitive to cetuximab regimens than those with the A and T allele, respectively (P ≤ 0.001-0.024). Chemosensitive SNP markers were identified using a novel three-step process. The candidate marker LIFR rs3729740 and possibly ISX rs361863 will hopefully predict responsive patients to cetuximab regimens, although further validation is needed in large cohorts.
Highlights
More than 50% of patients with colorectal cancer (CRC) exhibit recurrence or metastasis, commonly designated as metastatic CRC, regardless of curative operations [1]
Screening procedures and subjects A 3-step process of genome-wide single-nucleotide polymorphism (SNP) screening, clinical association analysis, and biological utility assessment was used for chemosensitive SNP discovery
For Hardy–Weinberg equilibrium (HWE) and clinical association analyses, a separate cohort of 460 healthy controls and 98 evaluable patients with targeted chemotherapy who were a different cohort from the first step were included for genotyping the selected SNPs during GWAS screening, using their genomic DNA
Summary
More than 50% of patients with colorectal cancer (CRC) exhibit recurrence or metastasis, commonly designated as metastatic CRC, regardless of curative operations [1]. Numerous treatment regimens for such patients have been developed to achieve a significant improvement in the response rate and survival time. 2 biologically targeted agents, bevacizumab (Avastin; Genentech Inc.) and cetuximab (Erbitux; ImClone Systems Inc.), have. Bevacizumab is a humanized monoclonal antibody targeting the proangiogenic VEGF-A. Cetuximab is a chimeric monoclonal antibody that binds to and subsequently blocks the activity of epidermal growth factor receptor (EGFR). Targeted chemotherapy clearly benefits a significant proportion of patients with metastatic CRC whereas other patients gain very little or even no benefit. Health economics have limited the ordinary use of targeted regimens. Efficient predictive biomarkers are urgently required to enhance the responsiveness and cost-effectiveness of such therapies
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