Qualitative Transcriptional Signature For Predicting Pathological Response And Prognosis Of Colorectal Cancer To FOLFOXTherapy

Colorectal cancer(CRC)is oneofthe most common malignant tumors.About 20%of CRC patients have distant metastases at the time of initial diagnosis,and 50% of those without metastases develop distant metastases within 3 years after the initial diagnosis.FOLFOX(a combination of 5-Fluorouracil,Leucovorin and Oxaliplatin)is the first-line chemotherapy regimen for metastatic colorectal cancer.However,about half of CRC patients show resistance to FOLFOX chemotherapy.Therefore,there is an urgent need to build signatures for predicting the pathological response to FOLFOX chemotherapy.There are somepublished signatures for predicting Pathological Response of colorectal cancer to FOLFOX chemotherapy.However,these signatures have two main problems.On the one hand,CRC researchers often divide patients into responders and non-responders according to the Response Evaluation Criteria in Solid Tumors(RECIST)when the signatureswere built.However,such a classification method for response is still controversial.On the other hand,these signatures mainly use the gene expression value within signature directly.However,due to factors such as batch effects,cancer cell proportion,RNA partial degradation and amplification bias,such signatures are less reproducible in colorectal cancer samples from different laboratories.Our laboratory found that the relative expression orderings(REOs)within samples is highly robust to these factors,and has strong clinical applicability.In view of the above problems and the advantages of the REOs,this study will be expounded from the following three aspects:1.Analysis of the association between RECIST classification and prognosis in metastatic CRCFirstly,245 metastatic CRC samples from the GSE104645 and GSE72970 datasets with different chemotherapy regimens were collected.Then,these samples were divided into four groups according to their chemotherapy regimens in each dataset,including not only FOLFOX group but also FOLOFX + Bevacizumab combination group,FOLFIRI group and FOLFIRI + Bevacizumab combination group.In these groups,we compared progression-free survival(PFS)among CRC patients with different RECIST response levels.Results showed that RECIST response in colorectal cancer patients was significantly correlated with their PFS,but a significantly better PFS in patients who were classified as responders(CR/PR)than those classified as non-responders(SD/PD)were not observed,and there was a similar PFS between PR and SD.2.Signatures for predicting pathological responseand prognosis to FOLFOX chemotherapy in metastatic CRCsBased on the qualitative transcriptome characteristics of 96 metastatic CRC samples from the training dataset,a signature consistinga set of 5 gene pairs for predicting pathological response of metastatic CRC to FOLFOX therapy(5-GPS)was build.Then,the signature was validated in CRC datasets from different laboratories.For 96 CRC samples from the training dataset,the sensitivity,specificity,F-score,accuracy,and AUC values of the signature are 0.89,0.92,0.90,0.90,and 0.94,respectively.In 25 CRC samples with FOLFOX response information,the sensitivity,specificity,accuracy,and AUC of our marker can reach 0.85,0.80,0.84,and 0.82,respectively.In other three CRC groups which accepted FOLFOX chemotherapy and had PFS information,the responders predicted by our signature have significantly better PFS than the predicted non-responders.In addition,in asynchronous CRC,synchronous CRC,right colon cancer,left colon cancer,and rectal cancer,the responders predicted by our signature also have significantly better PFS than the predicted non-responders.So,5-GPS is also a prognosis signature.The protein-protein interaction network shows that the genes in 5-GPS can play a role in FOLFOX chemotherapy through some commonly used genes.Through gene co-expression network analysis and enrichment analysis,we found that co-expression gene were mainly enrichment in functional pathways related to genetic information processing,suchas Mismatch repair ? Nucleotide excision repair ? Homologous recombination and RNA degradation.And,these pathways are associated with tumor progression,chemotherapy and prognosis of CRC,according to recent study.3.Comparison with published CRC chemotherapy signaturesBy comparing our FOLFOX signature with two published FOLFOX signatures,the 27-probes signature and the 15-probes signature,we found that all three signatures performed well in their corresponding training datasets.In 25 CRC samples with FOLFOX chemotherapy response information,the AUC of our signature can reach0.82,but the AUC of the 27-probes signature and the 15-probes signature can only reach 0.60 and 0.54.Similar results were observed in 52 colorectal cancer samples with prognostic survival information.Since the FOLFOX chemotherapy regimen is one of the 5-FU based chemotherapy regimens,we also tested the ability of four 5-FU based chemotherapy response signatures to predict FOLFOX chemotherapy response information in metastatic CRC.The results show that these four 5-FU based signatures are not suitable for predicting the pathological response of FOLFOX chemotherapy in metastatic CRC.