p53 gene mutation, microsatellite instability and adjuvant chemotherapy: impact on survival of 388 patients with Dukes' C colon carcinoma.
Two common genetic alterations in colon carcinoma, p53 mutation and microsatellite instability (MSI), were investigated to determine their prognostic importance for cancer-specific survival and response to adjuvant chemotherapy in patients with Dukes' C colon cancer. The p53 tumour suppressor gene encodes for a nuclear phosphoprotein involved in cellular response to DNA damage, while MSI is a characteristic feature of tumours with defective DNA mismatch repair. The cellular response mechanisms to DNA-damaging agents in tumours with mutant p53 or MSI may as a consequence differ, and this might translate into different outcomes following adjuvant chemotherapy. A consecutive series of 388 Dukes' C colon carcinomas with 5-year median follow-up was analysed for p53 mutation and for MSI (in proximal/transverse carcinomas only) using polymerase chain reaction single-strand conformation polymorphism. The incidence of p53 mutation was 28% in all carcinomas while that of MSI in proximal/transverse carcinomas was 19%. One hundred and thirty-three patients (34%) received adjuvant chemotherapy (5-fluorouracil/levamisole) with curative intent. The presence of p53 mutation did not predict for survival in either the treated or untreated groups. The presence of MSI in the proximal/transverse colon carcinoma group was associated with significantly better 5-year survival: 58 versus 32% (p = 0.015, log rank test). This was largely due to better survival observed in the MSI subgroup that received adjuvant chemotherapy (p = 0.017, log rank test). Further work in prospective, randomised clinical trials investigating the effects of adjuvant therapy should consider incorporating MSI status in order to determine whether this is an independent predictive factor for survival and/or response to adjuvant chemotherapy.
Elsaleh
H
H
Department of Surgery, University of Western Australia, Nedlands, Australia. helsaleh@cyllene.uwa.edu.au
Powell
B
B
Soontrapornchai
P
P
Joseph
D
D
Goria
F
F
Spry
N
N
Iacopetta
B
B
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics* / Q000556:secondary; D017024:Chemotherapy, Adjuvant; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D007978:Levamisole / Q000008:administration & dosage; D008297:Male; D018895:Microsatellite Repeats; D009154:Mutation; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction / Q000379:methods; D018807:Polymorphism, Single-Stranded Conformational; D011237:Predictive Value of Tests; D011379:Prognosis; D016019:Survival Analysis; D016896:Treatment Outcome
D007978:Levamisole; D005472:Fluorouracil