Comprehensive Analysis of Genomic Mutation Signature and Tumor Mutation Burden for Prognosis of Intrahepatic Cholangiocarcinoma

Abstract

Background: The intrahepatic cholangiocarcinoma (iCCA) is highly lethal malignancy of biliary tract cancer. Analysis of somatic mutational profiling could help to reveal new prognostic markers and actionable targets for treatment. We aim to explore the impact of genomic mutation signature and tumor mutation burden (TMB) on prognosis of iCCA patients. Methods: The whole-exome sequencing and corresponding clinical data were collected from ICGC portal and cBioPortal database to detect the mutation prognostic genes and TMB values. To identify the hub prognostic mutant signature, Cox regression and Lasso feature selection were conducted. We built a mutation related signature (MRS) through multivariate Cox regression. The predictive performance of MRS and TMB were assessed using Kaplan-Meier (KM) analysis and receiver operating characteristic (ROC). We performed a functional enrichment pathway analysis with gene set enrichment analysis (GSEA) for mutated genes were conducted. Moreover, on the base of MRS, TMB and TNM stage, a nomogram was constructed to visualize the prognosis of iCCA patients.Results: The mutation landscape illustrated the distributions of mutation frequencies and types on iCCA, and revealed a list of most frequent mutation genes (such as Tp53, KRAS, ARID1A, IDH1). We obtain a 6- gene signature using the Lasso and Cox method. The AUC of MRS in 1, 3, 5-year OS prediction were 0.759, 0.732, 0.728, respectively. Moreover, Kaplan-Meier analysis showed a significant difference on the prognosis of iCCA with high and low MRS score (P <0.001). Interestingly, GSEA was utilized to show several signaling pathways including MAPK signaling pathway, PI3K-AKT signaling pathway and proteoglycans in cancer. On the other hand, survival analysis indicated that TMB was significantly associated with prognosis. And GSEA indicated that samples with high MRS or TMB upregulated signaling pathways involved in tumor signaling and immune system. At last, we constructed a predictive nomogram (included MRS, TMB and TNM stage) with satisfactory performance in survival prediction. Conclusions: The mutation genes signature and TMB were associated with prognosis in patients with iCCA. Our study provides a valuable prognostic predictor for further uncovering molecular pathogenesis in iCCA.

Evaluation of the potential diagnostic role of the Lnc-MIAT, miR-29a-3p, and FOXO3a ceRNA networks as non-invasive circulatory biomarkers in ductal carcinoma breast cancer

“…High-Capacity cDNA revers-transcription kit (Smobio, Taiwan) was used for cDNA synthesis. Speci c primers were designed for MIAT, GAPDH using oligo primer analysis software (version 0.7.0), a speci c primer for FOXO3a was used from primer bank Harvard (Gen Bank Accession: NM_001455); and primers of miRNA29a-3p and, U6 are taken from (22). The primer sequences are shown in Table 2.…”

“…Additionally, miRNA-29a-3p expression levels have been discovered to be abnormally low in a variety of human malignancies, including papillary thyroid carcinoma (PTC), hepatocellular carcinoma, and gastric cancer [22]. Previous research found that miRNA-29a-3p is involved in the progression of BC.…”