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

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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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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