DPYD, TYMS, TYMP, TK1, and TK2 genetic expressions as response markers in locally advanced rectal cancer patients treated with fluoropyrimidine-based chemoradiotherapy.
This study is to investigate multiple chemotherapeutic agent- and radiation-related genetic biomarkers in locally advanced rectal cancer (LARC) patients following fluoropyrimidine-based concurrent chemoradiotherapy (CCRT) for response prediction. We initially selected 6 fluoropyrimidine metabolism-related genes (DPYD, ORPT, TYMS, TYMP, TK1, and TK2) and 3 radiotherapy response-related genes (GLUT1, HIF-1α, and HIF-2α) as targets for gene expression identification in 60 LARC cancer specimens. Subsequently, a high-sensitivity weighted enzymatic chip array was designed and constructed to predict responses following CCRT. After CCRT, 39 of 60 (65%) LARC patients were classified as responders (pathological tumor regression grade 2 ~ 4). Using a panel of multiple genetic biomarkers (chip), including DPYD, TYMS, TYMP, TK1, and TK2, at a cutoff value for 3 positive genes, a sensitivity of 89.7% and a specificity of 81% were obtained (AUC: 0.915; 95% CI: 0.840-0.991). Negative chip results were significantly correlated to poor CCRT responses (TRG 0-1) (P = 0.014, hazard ratio: 22.704, 95% CI: 3.055-235.448 in multivariate analysis). Disease-free survival analysis showed significantly better survival rate in patients with positive chip results (P = 0.0001). We suggest that a chip including DPYD, TYMS, TYMP, TK1, and TK2 genes is a potential tool to predict response in LARC following fluoropyrimidine-based CCRT.
Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan ; Department of Radiation Oncology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan ; Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
Ming-Yii
MY
Huang
Department of Medical Research, Fooyin University Hospital, Pingtung County 928, Taiwan.
Chan-Han
CH
Wu
Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan ; Department of Radiation Oncology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
Chun-Ming
CM
Huang
Department of Medical Research, Fooyin University Hospital, Pingtung County 928, Taiwan.
Fu-Yen
FY
Chung
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan ; Division of Gastrointestinal and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan ; Department of Surgery, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung 812, Taiwan.
Ching-Wen
CW
Huang
Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan ; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan ; Division of General Surgery Medicine, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan.
Hsiang-Lin
HL
Tsai
Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
Chin-Fan
CF
Chen
Department of Medical Research, Fooyin University Hospital, Pingtung County 928, Taiwan.
Shiu-Ru
SR
Lin
Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan ; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan ; Division of Gastrointestinal and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan ; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan ; Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan ; Department of Genomic Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
Jaw-Yuan
JY
Wang
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000096:biosynthesis; D059248:Chemoradiotherapy; D003131:Combined Modality Therapy; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000096:biosynthesis*; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D011379:Prognosis; D012004:Rectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D013937:Thymidine Kinase / Q000096:biosynthesis*; D013939:Thymidine Phosphorylase / Q000096:biosynthesis*; D013940:Thymidylate Synthase / Q000096:biosynthesis*
D014408:Biomarkers, Tumor; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; C543750:TYMP protein, human; D013939:Thymidine Phosphorylase; C105339:thymidine kinase 2; D013937:Thymidine Kinase; C092717:thymidine kinase 1