PMID- 36076047
OWN - NLM
STAT- MEDLINE
DCOM- 20221027
LR  - 20221028
IS  - 1617-4623 (Electronic)
IS  - 1617-4615 (Print)
IS  - 1617-4623 (Linking)
VI  - 297
IP  - 6
DP  - 2022 Nov
TI  - Epigenetic inactivation of DNA repair genes as promising prognostic and 
      predictive biomarkers in urothelial bladder carcinoma patients.
PG  - 1671-1687
LID - 10.1007/s00438-022-01950-x [doi]
AB  - We sought to examine epigenetic inactivation of DNA damage repair (DDR) genes as 
      prognostic and predictive biomarkers for urothelial bladder cancer (UBC) as there 
      are currently no reliable prognostic biomarkers that identify UBC patients who 
      would benefit from chemotherapy. Genome-wide DNA methylome using the cancer 
      genome atlas-bladder cancer (TCGA-BLCA) datasets (primary tumors = 374 and normal 
      tissues = 37) was performed for 154 DDR genes. The most two significant 
      differentially methylated genes, Retinoblastoma binding protein 8 (RBBP8) and 
      MutS homologue 4 (MSH4), between primary tumors and normal tissues of TCGA-BLCA 
      were validated by methylation-specific PCR (MSP) in UBC (n = 70) compared to 
      normal tissues (n = 30). RBBP8 and MSH4 expression was measured using qRT-PCR. We 
      developed a predictive model for therapeutic response based on the RBBP8- and 
      MSH4-methylation along with patients' clinical features. Then, we assessed the 
      prognostic significance of RBBP8 and MSH4. RBBP8- and MSH4 methylation and 
      corresponding gene downregulation significantly associated with muscle-invasive 
      phenotype, prolonged progression-free survival (PFS) and increased susceptibility 
      to cisplatin chemotherapy in UBC. Promoter methylation of RBBP8 and MSH4 was 
      positively correlated with each other and with their corresponding gene 
      repression. The best machine-learning classification model predicted UBC 
      patients' response to cisplatin-based chemotherapy with an accuracy of 
      90.05 +/- 4.5%. Epigenetic inactivation of RBBP8 and MSH4 in UBC could sensitize 
      patients to DNA-damaging agents. A predictive machine-learning modeling approach 
      based on the clinical features along with RBBP8- and MSH4-methylation might be a 
      promising tool for stratification of UBC responders from nonresponders to 
      chemotherapy.
CI  - (c) 2022. The Author(s).
FAU - Mohanad, Marwa
AU  - Mohanad M
AUID- ORCID: 0000-0002-3827-9647
AD  - Biochemistry Department, College of Pharmaceutical Sciences and Drug 
      Manufacturing, Misr University for Science and Technology, 6th of October, Giza, 
      Egypt. marwamohanad@gmail.com.
FAU - Yousef, Hend F
AU  - Yousef HF
AD  - Tissue Culture and Cytogenetics Unit, Pathology Department, National Cancer 
      Institute, Cairo University, Cairo, Egypt.
FAU - Bahnassy, Abeer A
AU  - Bahnassy AA
AD  - Tissue Culture and Cytogenetics Unit, Pathology Department, National Cancer 
      Institute, Cairo University, Cairo, Egypt.
LA  - eng
PT  - Journal Article
DEP - 20220908
PL  - Germany
TA  - Mol Genet Genomics
JT  - Molecular genetics and genomics : MGG
JID - 101093320
RN  - Q20Q21Q62J (Cisplatin)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Retinoblastoma Binding Proteins)
SB  - IM
MH  - Humans
MH  - *Urinary Bladder Neoplasms/drug therapy/genetics/pathology
MH  - Cisplatin/pharmacology/therapeutic use
MH  - Prognosis
MH  - Urinary Bladder/metabolism/pathology
MH  - Biomarkers, Tumor/genetics/metabolism
MH  - Epigenesis, Genetic
MH  - DNA Repair/genetics
MH  - Retinoblastoma Binding Proteins/genetics/metabolism
MH  - *Carcinoma/drug therapy/genetics/metabolism
MH  - DNA Methylation/genetics
PMC - PMC9596572
OTO - NOTNLM
OT  - CtIP/RBBP8
OT  - Epigenetic inactivation
OT  - MSH4
OT  - Machine-learning predictions of response
OT  - Prognosis
OT  - Urothelial bladder carcinoma
COIS- All authors declare no conflict of interest to disclosure.
EDAT- 2022/09/09 06:00
MHDA- 2022/10/28 06:00
PMCR- 2022/09/08
CRDT- 2022/09/08 23:29
PHST- 2021/06/23 00:00 [received]
PHST- 2022/08/27 00:00 [accepted]
PHST- 2022/09/09 06:00 [pubmed]
PHST- 2022/10/28 06:00 [medline]
PHST- 2022/09/08 23:29 [entrez]
PHST- 2022/09/08 00:00 [pmc-release]
AID - 10.1007/s00438-022-01950-x [pii]
AID - 1950 [pii]
AID - 10.1007/s00438-022-01950-x [doi]
PST - ppublish
SO  - Mol Genet Genomics. 2022 Nov;297(6):1671-1687. doi: 10.1007/s00438-022-01950-x. 
      Epub 2022 Sep 8.