Development and validation of a robust multigene signature as an aid to predict early relapse in stage I-III clear cell and papillary renal cell cancer

Abstract

Background and objectives:Multi-gene signature can be used as prognostic indicator in many types of cancer, but the association with early-relapse in patients with stage I-III clear cell and papillary renal cell cancer (RCC) is unknown. We aim to establish a mRNAs signature for improving prediction of early-relapse in patients with stage I-III clear cell and papillary RCC. Methods: The data of 610 patients with stage I-III RCC from The Cancer Genome Atlas (TCGA) and 270 patients from Fudan University Shanghai Cancer Center (FUSCC) were extracted. Propensity score matching analysis, linear models for microarray data VOOM method, least absolute shrinkage and selection operation Cox regression modeling analysis was conducted in turn for selecting multi-mRNA signature. Survival differences were assessed by Kaplan-Meier estimate and compared using log-rank test. Multivariable Cox regression and time-dependent receiver operating characteristic curves were used to evaluate the association of mRNAs signature with relapse-free survival (RFS). Results: Seventeen mRNAs were identified to constitute the early-relapse signature. Among patients with stage I-III RCC, those with high-risk score calculated from 17 mRNAs signature showed shorter RFS than those with low-risk score, both in TCGA discovery and internal validation sets, and in FUSCC discovery and internal validation sets (all p < 0.05). In multivariable Cox regression analysis, the 17 mRNAs signature remained an independent prognostic factor both in TCGA discovery (HR 2.43, 95%CI 1.98-2.96) and internal validation sets (HR 1.66, 95%CI 1.19-2.30), and FUSCC discovery (HR 1.28, 95%CI 1.13-1.43) and internal validation sets (HR 1.65, 95%CI 1.11-2.48). Additionally, the 17 mRNAs signature achieved a higher accuracy for RFS estimation beyond clinical indicator. Conclusion: The 17 mRNAs signature could classify stage I-III RCC patients into low-or high-risk of early-relapse, and will help to guide interventions to optimize survival outcomes.

Development and Validation of an Individualized Immune-Related Gene Pairs Prognostic Signature in Papillary Renal Cell Carcinoma

“…Some researchers have developed several signatures on the prognosis of PRCC at the molecular level, including mRNA, lncRNA, alternative splicing, mutation and etc., ( Cao et al, 2020 ; Duan and Zhang, 2019 ; Zhang C. et al, 2019 ; Zuo et al, 2018 ). Previous study reported a five-gene signature to predict overall survival of patients with PRCC ( Gao et al, 2019 ).…”

Influence of gene expression on survival of clear cell renal cell carcinoma

“…This is similar to what we have seen in our other studies using the TCGA gene expression and methylation data. 92,93 Strengths of our study include a multistage design that consisted of two discovery independent discovery datasets and a validation dataset; the use of NanoString platform that allows for accurate and reproducible measurement of RNA from FFPE samples; selection of candidate genes based on a thorough literature search [9][10][11][12][13][14][15][16][17][18][19] ; and validation of the role of identified genes previously implicated in ccRCC and are potential targets for novel cancer therapies. Indeed, inhibitors of some of these genes are already in early phase I trials.…”

“…Candidate ccRCC-related genes were selected based on previous published literature., [9][10][11][12][13][14][15][16][17][18][19] including our review article 19 and pathways described in the Cancer Genome Anatomy project. A total of 388 candidate genes were evaluated in the discovery sets.…”

“…Therefore, the identification of reliable biomarkers for ccRCC progression is greatly needed. We and others reported candidate biomarkers, such as long non-coding RNAs, 9 gene expression signatures, [10][11][12][13][14][15] epigenetics 16 for ccRCC progression and/or survival. [17][18][19] However, there is currently no clinically accepted molecular biomarker for ccRCC progression.…”

Development and validation of an individualized immune-related gene pairs prognostic signature in papillary renal cell carcinoma

“…Some researchers have developed several signatures on the prognosis of PRCC at the molecular level, including mRNA, lncRNA, alternative splicing, mutation and etc. [22][23][24][25]. However, these signatures have not yet reached a robust high accuracy rate, and have not considered the important impact of tumor immunology on the prognosis and treatment of PRCC.…”