Identification of potential pharmacogenomic markers of clinical efficacy of 5-fluorouracil in colorectal cancer.
Although adjuvant chemotherapy has significantly increased overall survival in resected Stage III colorectal cancer, disease recurrence is still high (30-40%). 20-25% of Stage II patients also develop recurrent disease. Thus, high-risk patients may benefit from chemotherapy. As patient response to standard chemotherapy varies, the study of molecular differences in the expression of pharmacologically relevant genes may help clinicians to understand variability and tailor therapy. The expression of 5-fluorouracil (5-FU) pathway genes in tumors from 53 Stages II-III colorectal cancer patients who underwent 5-FU adjuvant chemotherapy was investigated by reverse transcription quantitative real-time polymerase chain reaction. Patients were dichotomized into high- and low-mRNA expression level groups using median values of gene mRNA levels. Then, a threshold analysis to identify a cut-off distinguishing recurrent- or nonrecurrent-disease was used. A high degree of interpatient variation in relative tumor expression of study genes was observed. Multiple gene correlations were found, which suggest possible coregulation mechanisms. No statistically significant relationship between experimental data and baseline clinical/pathological characteristics or clinical outcome was observed using gene expression median values. Threshold analysis indicated significant inverse relationships between deoxyuridine triphosphatase (DUT), ferrodoxin reductase (FDXR) or tumor protein p53 (TP53) and disease-free survival (DFS) in the entire case series and between DUT or NM23-H1 and DFS in Stage III patients: higher gene expression was associated with shorter DFS. This study provides data on relationships between expression of 5-FU pathway genes and clinical outcome of colorectal cancer patients undergoing 5-FU adjuvant chemotherapy and underscores the predictive role of specific genes. Validation in an independent case series is warranted.
Nobili
Stefania
S
Department of Pharmacology, University of Florence, Florence, Italy.
Napoli
Cristina
C
Landini
Ida
I
Morganti
Maria
M
Cianchi
Fabio
F
Valanzano
Rosa
R
Tonelli
Francesco
F
Cortesini
Camillo
C
Mazzei
Teresita
T
Mini
Enrico
E
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008875:Middle Aged; D054778:NM23 Nucleoside Diphosphate Kinases / Q000235:genetics / Q000378:metabolism; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010597:Pharmacogenetics; D011379:Prognosis; D011755:Pyrophosphatases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D054778:NM23 Nucleoside Diphosphate Kinases; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C517938:NME1 protein, human; D011755:Pyrophosphatases; C020020:dUTP pyrophosphatase; D005472:Fluorouracil