Translational study identifies XPF and MUS81 as predictive biomarkers for oxaliplatin-based peri-operative chemotherapy in patients with esophageal adenocarcinoma.
T P MacGregorR CarterR S GilliesJ M FindlayC KartsonakiFrancesc Castro GinerN SahgalL M WangR ChettyN D MaynardJ B CazierF BuffaP J McHughIan P M TomlinsonM R MiddletonR A SharmaPublished in: Scientific reports (2018)
Oxaliplatin-based chemotherapy is used to treat patients with esophageal adenocarcinoma (EAC), but no biomarkers are currently available for patient selection. We performed a prospective, clinical trial to identify potential biomarkers associated with clinical outcomes. Tumor tissue was obtained from 38 patients with resectable EAC before and after 2 cycles of oxaliplatin-fluorouracil chemotherapy. Pre-treatment mRNA expression of 280 DNA repair (DNAR) genes was tested for association with histopathological regression at surgery, disease-free survival (DFS) and overall survival (OS). High expression of 13 DNA damage repair genes was associated with DFS less than one year (P < 0.05); expression of 11 DNAR genes were associated with worse OS (P < 0.05). From clinical associations with outcomes, two genes, ERCC1 and EME1, were identified as candidate biomarkers. In cell lines in vitro, we showed the mechanism of action related to repair of oxaliplatin-induced DNA damage by depletion and knockout of protein binding partners of the candidate biomarkers, XPF and MUS81 respectively. In clinical samples from the clinical trial, pre-treatment XPF protein levels were associated with pathological response, and MUS81 protein was associated with 1-year DFS. XPF and MUS81 merit further validation in prospective clinical trials as biomarkers that may predict clinical response of EAC to oxaliplatin-based chemotherapy.
Keyphrases
- dna damage
- dna repair
- clinical trial
- locally advanced
- genome wide
- free survival
- binding protein
- squamous cell carcinoma
- poor prognosis
- rectal cancer
- oxidative stress
- bioinformatics analysis
- phase ii
- genome wide identification
- protein protein
- minimally invasive
- dna methylation
- radiation therapy
- gene expression
- type diabetes
- adipose tissue
- coronary artery disease
- endothelial cells
- hepatitis c virus
- insulin resistance
- coronary artery bypass
- transcription factor
- weight loss
- wild type
- stress induced