Mitochondrial DNA mutations in colorectal cancer a prognostic and a predictive factor of response to adjuvant chemotherapy

Abstract

9614 Background:Mitochondrial DNA (mtDNA) mutations have been reported in 10% to 70% of colorectal cancers (CRC). Conflicting data on frequency and localization of mtDNA mutations in CRC have been published. Furthermore no data were available on prognostic value of mtDNA mutations. Methods:The aim of this study was to 1) characterize mtDNA mutations in CRC patients 2) search for an association between these mtDNA mutations and tumor phenotype 3) investigate their prognostic value and their role in response to chemotherapy (CT).First, the entire mtDNA was sequenced in normal and tumoral tissues from 11 CRC patients. Then, a 400 bp fragment of the D-Loop was sequenced from tumor mtDNA on a based-population series of 365 colorectal cancer patients treated between 1998 and 2000. Results:Among the 11 patients in whom the entire mtDNA was analyzed, 6 exhibited mtDNA somatic mutations in the D-Loop region, mainly in the D310 repeat (6/8). In the second screening D-Loop mutation was found in 141 of the 365 patients (39%) studied. No association between mtDNA mutation and age, gender, tumor location, tumor stage and tumor MSI status was found. 3-year survival rate of patients without D-Loop mutation was significantly higher than that of patients with D-Loop mutation (62% vs 53%, p= 0.05). In a Cox model, after adjustement for age, tumor stage and tumor MSI status, the RR of death in patients without D-Loop mutation was 0.7 (p<0.04) when compared with those with D-Loop mutation. In the subgroup of stage III colon cancer patients, the presence of a tumor D-Loop mutation was associated with a poor prognosis (3-year survival rate : 42% vs 70%, p<0.02) and was predictive of no response to 5FU-based adjuvant CT. The 3-year survival rate of patients with D-Loop mutation was not improved by CT (41% vs 50%, NS) as it was observed in patients without D-Loop mutation (81% vs 45.5%, p=0.01). Conclusions:the presence of tumor mtDNA mutations, are a prognostic marker and seems to be a relevant predictive factor of no response to adjuvant chemotherapy in patients with stage III colon cancer. These results provide a rationale to evaluate an intensification of adjuvant CT in this setting. No significant financial relationships to disclose.