DNA methylation profiling reveals new potential subtype-specific gene markers for early-stage renal cell carcinoma in Caucasian population

Alvaro Filbert Liko, Edward Ciputra, Nathaniel Alvin Sanjaya, Priskila Cherisca Thenaka, David Agustriawan

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Quant. Biol. ›› 2022, Vol. 10 ›› Issue (1) : 79-93. DOI: 10.15302/J-QB-021-0279
RESEARCH ARTICLE

DNA methylation profiling reveals new potential subtype-specific gene markers for early-stage renal cell carcinoma in Caucasian population

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Abstract

Background: Renal cell carcinoma (RCC) is among the top adult cancers worldwide, with a challenging management due to lack of early diagnosis, therapy resistance, and diverse molecular background. Aberrant DNA methylation has been associated with RCC development due to transcription deregulation. We discovered potential DNA methylation-based biomarkers for stage I RCC in Caucasian population from The Cancer Genome Atlas (TCGA) database.

Methods: Patients’ clinical, methylation beta-value, and mRNA expression data were retrieved. Differential methylation and expression analysis were conducted to obtain differentially methylated CpG-gene pairs. Inversely correlated CpG-gene pairs between their expression and methylation levels were selected using Pearson’s correlation test and then screened for any recorded somatic mutations. Their biomarker capacities were analyzed using the Kaplan-Meier and receiver operating characteristic analysis, followed by protein network and functional enrichment analysis.

Results: We obtained differentially methylated CpGs in clear cell (KIRC) and papillary RCC (KIRP) but not chromophobe RCC (KICH). Six inversely correlated CpG-gene pairs with no reported cancer-associated mutations were selected. Prognostic values were found in ATXN1 and RFTN1 for KIRC, along with GRAMD1B and TM4SF19 for KIRP, while diagnostic values were found in VIM and RFTN1 for KIRC, along with TNFAIP6 and TM4SF19 for KIRP. Both subtypes showed enrichment of immune and metabolism-related pathways.

Conclusion: We discovered novel potential DNA methylation-based prognostic and diagnostic markers for early-stage RCC in Caucasian population. Validation by wet laboratory analysis and adjustments for confounding variables might be needed, considering our study limitation to specific race.

Author summary

Renal cell carcinoma (RCC) is strongly associated with epigenetic aberrations, including DNA methylation. The lack of early diagnosis, however, leads to unexplored epigenetic landscape in stage I RCC. Herein, we identified novel, methylation-driven, and subtype-specific gene markers of three early-stage RCC subtypes (KIRC, KIRP, KICH) with potential prognostic and diagnostic values, from TCGA database. Strikingly, stage I KIRC displays total hypomethylation, while KICH displays insignificant methylation aberration. Importantly, the identified genes (ATXN1, RFTN1, VIM, HLA-B, TM4SF19, TNFAIP6, GRAMD1B) correlate with immune infiltration and altered metabolism as the main hallmarks of RCC, which may contribute to better understanding of early-stage RCC.

Graphical abstract

Keywords

biomarker / chromophobe renal cell carcinoma / clear cell renal cell carcinoma / DNA methylation / papillary renal cell carcinoma / TCGA

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Alvaro Filbert Liko, Edward Ciputra, Nathaniel Alvin Sanjaya, Priskila Cherisca Thenaka, David Agustriawan. DNA methylation profiling reveals new potential subtype-specific gene markers for early-stage renal cell carcinoma in Caucasian population. Quant. Biol., 2022, 10(1): 79‒93 https://doi.org/10.15302/J-QB-021-0279

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ABBREVIATIONS

AJCC American Joint Committee on cancer
ATG2A Autophagy-related 2A
ATG2B Autophagy-related 2B
ATXN1 Ataxin-1
AUC Area under the curve
CASR Calcium sensing receptor
CDC42 Cell division control protein 42 homolog
CDC42BPG CDC42 binding protein kinase gamma
CHI3L2 Chitinase 3-like 2
CI Confidence interval
COSMIC Catalogue of somatic mutations in cancer
CPNE7 Copine 7
CRC Colorectal cancer
DNA Deoxyribonucleic acid
DMRs Differentially methylated regions
DEGs Differentially expressed genes
ECM Extracellular matrix
EGR3 Early growth response 3
EWAS Epigenome wide association study
FDR False discovery rate
Glut-4 Glucose transporter 4
GO Gene ontology
GRAM Glucosyltransferases, rab-like GTPase activators and myotubularins
GRAMD1B GRAM domain containing 1B
HIF-α Hypoxia inducible factor-alpha
HLA-B Human leukocyte antigen B
HR Hazard ratio
HTRA4 HtrA serine peptidase 4
ICGC International cancer genome consortium
JAK/STAT Janus kinase/signal transducers and activators of transcription
KEGG Kyoto Encyclopedia of Genes and Genomes
KICH Chromophobe renal cell carcinoma
KIRC Clear cell renal cell carcinoma
KIRP Papillary renal cell carcinoma
LEPROTL1 Leptin receptor overlapping transcript like 1
MEK1 Mitogen-activated protein 2 kinase 1
MMP-9 Matrix metalloproteinase 9
mRNA Messenger ribonucleic acid
OS Overall survival
PI3K Phosphoinositide 3-kinase
PTX3 Pentraxin 3
RAC1 Rac family small GTPase 1
RCC Renal cell carcinoma
RFTN1 Raftlin-1
RIN1 Ras and Rab interactor 1
ROC Receiver operating characteristic
SCA1 Spinocerebellar ataxia type 1
SIM1 Single-minded homolog 1
SMEK1 Suppressor of MEK1
STRING Search tool for the retrieval of interacting genes/proteins
TCGA The Cancer Genome Atlas
TLR6 Toll-like receptor 6
TM4SF19 Transmembrane 4 L six family member 19
TNFAIP6 Tumor necrosis factor-alpha induced protein 6
TP53 Tumor suppressor protein 53
TRPM8 Transient receptor potential cation channel subfamily melastatin member 8
TSS Transcription start site
VHL Von Hippel-Lindau
VIM Vimentin

SUPPLEMENTARY MATERIALS

The supplementary materials can be found online with this article at https://doi.org/10.15302/J-QB-021-0279.

ACKNOWLEDGEMENTS

This research was funded by an internal grant from Indonesia International Institute for Life Sciences (No. 001/SK/WRII-IBSII/I/2020). Unconditional in-kind support was provided by our colleague Stefanus Bernard for helping us with the bioinformatics coding.

COMPLIANCE WITH ETHICS GUIDELINES

The authors Alvaro Filbert Liko, Edward Ciputra, Nathaniel Alvin Sanjaya, Priskila Cherisca Thenaka and David Agustriawan declare no competing financial interests. All procedures performed in studies were in accordance with the ethical standards of the institution or practice at which the studies were conducted, and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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