New genetic variations discovered in KRAS wild‐type cetuximab resistant chinese colorectal cancer patients

Abstract

To perform a comprehensive genomic analysis of colorectal cancer (CRC) tumor to detect genetic variants and identify novel resistant mutations associated with cetuximab‐resistance in CRC patients. A retrospective study was performed using whole exome sequencing (WES) to identify common genetic factors from 22 cetuximab‐sensitive and 10 cetuximab‐resistant patients. In all 10 cetuximab‐resistant patients, we discovered there are 37 significantly mutated genes (SMGs). CYP4A11 was the most frequently mutated gene in cetuximab‐resistant patients. BCAS1 and GOLGA6L1 were found to be among the second group of frequently mutated genes with a frequency of 60%. After cosine similarity analysis, three mutational signatures (signature a, b, and c) were found in all CRC tumors, similar to signature 1, 5, and 6 in COSMIC, respectively. Gene ontology analysis was performed on SMGs and found 12 enriched GO terms. Four genes are enriched in six specific Kyoto Encyclopedia of Genes and Genomes pathway groups, including the metabolism of xenobiotics by cytochrome P450, steroid hormone biosynthesis, retinol metabolism, and drug metabolism. Our data supports a network composed of SMGs and cellular signaling pathways that have been positively linked to the mechanisms of cetuximab resistance. These involve DNA damage repair, angiogenesis, invasion, drug metabolism, and the CRC tumor microenvironment. There is a SMG, OR9G1 correlated with survival rates of KRAS wild‐type colon adenocarcinoma patients. These findings support further investigation using WES in a prospective clinical study of cetuximab resistance CRC, to further identify, confirm, and extend the clinical significance of these and other potentially important new candidate predictive biomarkers of cetuximab response.

Differential Expression Analysis Revealing CLCA1 to Be a Prognostic and Diagnostic Biomarker for Colorectal Cancer

“…GO analysis indicated that negative regulation of growth, bicarbonate transport, and transporter activity ( 38 – 40 ) were closely related to the development and growth of cancer; some KEGG pathways, such as nitrogen metabolism and retinol metabolism, were also linked to the pathogenesis of CRC. Nitrogen is an essential biomolecule in humans and regulates cellular metabolism, and retinol is a form of vitamin A closely related to immune functions ( 41 , 42 ). Based on the results of the GO and KEGG enrichment analyses, the DEGs were closely associated with CRC occurrence and development.…”

Establishment of a Novel Combined Nomogram for Predicting the Risk of Progression Related to Castration Resistance in Patients With Prostate Cancer

“…For cancer patients, the expression level of BCAS1 affects prognosis variously among different tumor types ( McFarlane et al, 2018 ; Zhang et al, 2019 ). Even BCAS1 is associated with drug resistance in cancer patients during treatment ( Jing et al, 2020 ). More importantly, BCAS1 can be used as an accurate marker in the urine cell-free DNA analysis for early prostate cancer diagnosis ( Casadio et al, 2013 ).…”

Multi-Omics Analysis to Identify Driving Factors in Colorectal Cancer

“…We analyzed the similarity between these three mutation signatures and COSMIC signatures through R package maftools. The result illustrated that these mutation signatures were similar to signature 6, 1 and 10 in COSMIC, with cosine similarity 0.961, 0.924 and 0.977 respectively (Supplementary Table 2), of which, COSMIC signature 6 and signature 1 are associated with KRAS Wild-Type Cetuximab Resistant CRC [16].…”