Clinical value of mitochondrial mutations in colorectal cancer.
OBJECTIVE
Prognostic factors that could select high-risk recurrence colorectal cancer patients and predict chemosensitivity are needed. Since mutations of mitochondrial DNA (mtDNA) have been described in different types of cancers and since they may play a role in response to anticancer agents, we investigated in a population-based series of colorectal cancer patients the clinical value of mtDNA mutations.


METHODS
The displacement loop (D-loop) region of mtDNA was sequenced on a series of 365 patients recorded in the Digestive Cancer Registry of Côte-d'Or (France) between 1998 and 2000. Clinicopathologic characteristics were correlated to the presence of a D-loop mutation. Survival rates were compared with the log-rank test. A multivariate survival analysis was performed.


RESULTS
D-loop mutations were found in 38.3% of the tumors. The 3-year survival rate was 53.5% in patients with D-loop mutation versus 62.1% in patients without (P = .05). After adjustment for age, stage, and microsatellite instability status, the relative risk of death in patients with D-loop mutation was 1.40 (95% CI, 1.02 to 1.93; P = .034) as compared with those without. In stage III colon cancers, adjuvant chemotherapy was beneficial only for patients without D-loop mutation (3-year survival, 78.3% v 45.4%, P < .02). In those with D-loop mutation who received adjuvant chemotherapy, the relative risk of death was 4.30 (95% CI, 1.23 to 15.00; P < .02).


CONCLUSIONS
The D-loop region is a hotspot for somatic mutations in colorectal tumors. Moreover, presence of tumor D-loop mutation appears to be a factor of poor prognosis in colorectal patients and a factor of resistance to fluorouracil-based adjuvant chemotherapy in stage III colon cancers.
Lièvre
Astrid
A
INSERM U490 Laboratoire de Toxicologie Moléculaire, 45 Rue des Saints Pères, 75006 Paris, France.
Chapusot
Caroline
C
Bouvier
Anne-Marie
AM
Zinzindohoué
Franck
F
Piard
Françoise
F
Roignot
Patrick
P
Arnould
Laurent
L
Beaune
Philippe
P
Faivre
Jean
J
Laurent-Puig
Pierre
P
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000032:analysis*; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D016001:Confidence Intervals; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D015999:Multivariate Analysis; D009154:Mutation; D010597:Pharmacogenetics; D016133:Polymerase Chain Reaction / Q000379:methods; D011379:Prognosis; D016016:Proportional Hazards Models; D012016:Reference Values; D012494:Sampling Studies; D012680:Sensitivity and Specificity; D016019:Survival Analysis; D046509:Tissue Culture Techniques; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; D004272:DNA, Mitochondrial