Classification of clear cell renal cell carcinoma based on PKM alternative splicing
Journal article, 2020
Clear cell renal cell carcinoma (ccRCC) accounts for 70–80% of kidney cancer diagnoses and displays high molecular and histologic heterogeneity. Hence, it is necessary to reveal the underlying molecular mechanisms involved in progression of ccRCC to better stratify the patients and design effective treatment strategies. Here, we analyzed the survival outcome of ccRCC patients as a consequence of the differential expression of four transcript isoforms of the pyruvate kinase muscle type (PKM). We first extracted a classification biomarker consisting of eight gene pairs whose within-sample relative expression orderings (REOs) could be used to robustly classify the patients into two groups with distinct molecular characteristics and survival outcomes. Next, we validated our findings in a validation cohort and an independent Japanese ccRCC cohort. We finally performed drug repositioning analysis based on transcriptomic expression profiles of drug-perturbed cancer cell lines and proposed that paracetamol, nizatidine, dimethadione and conessine can be repurposed to treat the patients in one of the subtype of ccRCC whereas chenodeoxycholic acid, fenoterol and hexylcaine can be repurposed to treat the patients in the other subtype.
Drug repositioning
Transcriptomics
Systems biology
Biomarker
Alternative splicing
Bioinformatics
Cancer research
PKM
Author
Xiangyu Li
Royal Institute of Technology (KTH)
Beste Turanli
Istanbul Medeniyet University
Kajetan Juszczak
Royal Institute of Technology (KTH)
Woonghee Kim
Royal Institute of Technology (KTH)
Muhammad Arif
Royal Institute of Technology (KTH)
Yusuke Sato
University of Tokyo
Institute for the Advanced Study of Human Biology
Seishi Ogawa
Karolinska Institutet
Institute for the Advanced Study of Human Biology
Hasan Turkez
Erzurum Technical University
Jens B Nielsen
Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology
Jan Borén
Sahlgrenska University Hospital
Mathias Uhlen
Royal Institute of Technology (KTH)
C. Zhang
Zhengzhou University
Royal Institute of Technology (KTH)
Adil Mardinoglu
King's College London
Royal Institute of Technology (KTH)
Heliyon
24058440 (eISSN)
Vol. 6 2 e03440Subject Categories
Hematology
Urology and Nephrology
Cancer and Oncology
DOI
10.1016/j.heliyon.2020.e03440