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Clinical Value of Mitochondrial Mutations in Colorectal Cancer

From the Institut National de Santé et de la Recherche Médicale (INSERM) U490, Laboratoire de Toxicologie Moléculaire; Pôle de Cancérologie, Hôpital Européen Georges Pompidou, Paris; Centre Hospitalier Universitaire (CHU) Dijon, Service d'Anatomo-Pathologie; INSERM Equipe Mixte INSERM (EMI) 0106, CHU, Registre Bourguignon des Tumeurs; Centre de Pathologie, Rue Nicolas Bornier; Centre Georges François Leclerc, Service d'Anatomo-Pathologie, Dijon, France

Address reprint requests to Pierre Laurent-Puig, INSERM U490 Laboratoire de Toxicologie Moléculaire, 45 Rue des Saints Pères, 75006 Paris, France; e-mail: pierre.laurent-puig{at}biomedicale.univ-paris5.fr

PURPOSE: 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.

PATIENTS AND 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).

CONCLUSION: 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.

Supported by L'Association de Recherche Contre le Cancer (ARC No. 3329); La Société Nationale Française de Gastroentérologie; La Region Ile de France, La Fondation de France, Paris, France.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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