Integrative multi-omics approach for stratification of tumor recurrence risk groups of Hepatocellular Carcinoma patients

Abstract

Postoperative tumor recurrence is one of the major concerns associated with the poor prognosis of HCC patients. There is yet to elucidate a standard surveillance system for HCC recurrence risk owing to complexity of this malignancy. Generation of multi-omics data from patients facilitate the identification of robust signatures for various diseases. Thus, the current study is an attempt to develop the prognostic models employing multi-omics data to significantly (p-value <0.05) stratify the recurrence high-risk (median Recurrence Free Survival time (RFS) =<12 months) and low-risk groups (median RFS >12 months). First, we identified key 90RNA, 50miRNA and 50 methylation features and developed prognostic models; attained reasonable performance (C-Index >0.70, HR >2.5), on training and validation datasets. Subsequently, we developed a prognostic (PI) model by integrating the four multi-omics features (SUZ12, hsa-mir-3936, cg18465072, and cg22852503), that are biologically inter-linked with each other. This model achieved reasonable performance on training and validation dataset, i.e. C-Index 0.72, HR of 2.37 (1.61 - 3.50), p-value of 6.72E-06, Brier score 0.19 on training dataset, and C-Index 0.72 (95% CI: 0.63 - 0.80), HR of 2.37 (95% CI: 1.61 - 3.50), p-value of 0.015, Brier score 0.19 on validation dataset. Eventually, Drugbank data was investigated to elucidate therapeutic potential of these signatures. We have identified nine potential drugs against three genes (CA9, IL1A, KCNJ15) that are positively correlated with the tumor recurrence. We anticipate these results from our study will help researchers and clinicians to improve the HCC recurrence surveillance, eventually outcome of patients.

Cellular, Molecular and Proteomic Characteristics of Early Hepatocellular Carcinoma

“…Having said that, detection of HCC at very early stages is still a challenging task. Recent sophisticated omics techniques have been applied for HCC and have reported possible prognostic models based on molecular signatures, but with low sensitivity and accuracy [ 17 , 18 , 19 ]. Consequently, the necessity of the development of more accurate and sensitive tools guiding early diagnosis and prognostic assessments in HCC patients remains.…”

“…Previous evidence indicated the possibility of the use of multi-omics techniques prior to the establisment of more accurate diagnostic tools in HCC [ 17 , 18 ]. Our aim was to determine useful markers to predict the development of HCC at very early stages in cirrhotic patients.…”

Identification of NAA40 as a Potential Prognostic Marker for Aggressive Liver Cancer Subtypes

“…Molecular signatures in cancer have multiple potential uses including improved diagnosis, prognosis, and patient stratification for treatment. A number of studies in recent years have aimed toward identifying molecular signatures for LIHC, for examples see (51)(52)(53)(54). In general, such studies improve their potency through the inclusion of multiple variates generated by one or more -omic technological platforms.…”

“…Using NAA40 expression as a univariate prognostic survival marker for the TCGA LIHC cohort revealed prognostic ability (HR=1.67; p=0.003) that is similar or better than other candidate genes when examined by themselves [e.g. FCN3, CLEC1B, and PRC1 in ( 54 )] although not as good as multi-variant classifiers [e.g., ( 51 , 53 )]. Further work is needed to validate the prognostic ability of NAA40 in multiple independent LIHC and to examine whether it can be integrated with other multi-variate predictive and prognostic signatures.…”

Development and Verification of an Immune-Related Gene Pairs Prognostic Signature in Hepatocellular Carcinoma

“…Therefore, it is extremely crucial to determine the sensitivity of different patient subsets to treatment response. Individualized treatment for different patient subgroups will help to enhance the prognosis of patients (Gan et al, 2020;Zhou et al, 2020;Kaur et al, 2021). Novel signature related to tumor immune infiltration may be a sword for identifying new molecular targets and improving patient prognosis.…”