Clinical Value of Mitochondrial Mutations in Colorectal Cancer

Lièvre, Astrid; Chapusot, Caroline; Bouvier, Anne–Marie; Zinzindohoué, Franck; Piard, F; Roignot, Patrick; Arnould́, Laurent; Beaune, Philippe; Faivre, Jean; Laurent‐Puig, Pierre

doi:10.1200/jco.2005.07.044

Cited by 138 publications

(150 citation statements)

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“…Mitochondria is known to play a pivotal role in apoptosis (Green and Kroemer, 2004), and it was suggested that mtDNA determines the cellular response to some cancer therapeutic agents through a mechanism that could be an apoptosis modulation (Singh et al, 1999;Hail et al, 2001). We recently found that D-Loop mutations were associated with poor prognosis and absence of benefit from adjuvant 5FU chemotherapy in colon cancers (Lievre et al, 2005). Given these results, as all patients in our study received a neoadjuvant chemotherapy with 5FU -cisplatin, we investigated the association between DLoop mutations and response to this treatment.…”

Section: Discussionmentioning

confidence: 95%

“…Polymerase chain reaction (PCR) amplification of the D-Loop was performed on a Gen Amp PCR System 9700 (Applied Biosystems, Foster City, CA, USA) using primers F47: 5 0 -CGC ACG GAC TAC AAC CAC GAC-3 0 (forward) and R15: 5 0 -CTG TGG GGG GTG TCT TTG GG (reverse) as described previously (Lievre et al, 2005). The 2467 bp PCR products (nucleotide positions: 14679 -577) were then purified using G-50 Sephadex superfine (Amersham Biosciences, Orsay, France) on Multiscreen support (Millipore, Bedford, MA, USA).…”

Section: Displacement-loop Amplificationmentioning

confidence: 99%

“…The D310 repeat sequencing was performed on a Gene Amp PCR System 9700 (Applied Biosystems) using a Big Dye Terminator cycle sequencing kit (Applied Biosystems) as described previously (Lievre et al, 2005). Sequences were analysed on an ABI Prism s 3900 DNA Analyser automated sequencer (Applied Biosystems).…”

Section: Direct Sequencing Of the D310 Repeatmentioning

confidence: 99%

“…Its role in apoptosis supports this hypothesis (Zamzami and Kroemer, 2001) and it was shown that mtDNA mutations may lead to a dysregulation of oxidative phosphorylation that can enhance production of the carcinogenic ROS. Over last years, somatic mtDNA mutations have been reported in many human tumours (Polyak et al, 1998;Maximo et al, 2000;Richard et al, 2000;Yeh et al, 2000;Hibi et al, 2001b;Sanchez-Cespedes et al, 2001;Kirches et al, 2001;Liu et al, 2001;Lievre et al, 2005), including head and neck squamous cell carcinoma (HNSCC) that were found mutated in small series in 37 -77% of the cases (Fliss et al, 2000;Sanchez-Cespedes et al, 2001;Ha et al, 2002;Tan et al, 2003;Poetsch et al, 2004). Although mutations may occur throughout the mitochondrial genome, the vast majority of them have been described in the noncoding region of the D-Loop and particularly in a mononucleotide repeat named D310 (C-tract, nucleotide position: 303 -315) that has emerged as a mutational hotspot in HNSCC (Fliss et al, 2000;Sanchez-Cespedes et al, 2001;Ha et al, 2002;Tan et al, 2003;Poetsch et al, 2004).…”

mentioning

confidence: 99%

“…Identification of new genetic alterations associated with HNSCC is important since they may allow to better understand the molecular mechanisms involved in head and neck carcinogenesis and serve as a molecular marker that may be used in evaluating the tumorigenic potential of head and neck lesions in individuals at high risk of cancer. Recently, we found that D-Loop mutations were linked to prognosis and lack of benefit from 5 fluorouracil (5FU)-based adjuvant chemotherapy in colorectal carcinomas (Lievre et al, 2005). Neoadjuvant chemotherapy have been recently developed in new treatment strategies of locally advanced HNSCC and has been shown to be curative in complete clinical responder patients with a cancer of the pharyngolarynx (Laccourreye et al, 2001).…”

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Clinicopathological significance of mitochondrial D-Loop mutations in head and neck carcinoma

et al. 2006

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Mitochondrial DNA mutations have been reported in several types of tumours, including head and neck squamous cell carcinoma (HNSCC). The noncoding region of the Displacement-Loop (D-Loop) has emerged as a mutational hotspot and we recently found that they were associated with prognosis and response to 5 fluorouracil (5FU) in colon cancers. In order to evaluate the frequence of D-Loop mutations in a large series of HNSCC and establish correlations with clinicopathologic parameters, we sequenced the D-Loop of 109 HNSCC before a treatment by neoadjuvant 5FU-cisplatin-based chemotherapy and surgery. Then, we correlated these mutations with prognosis and response to chemotherapy. A D-Loop mutation was identified in 21% of the tumors, the majority of them were located in a C-tract (D310). The prevalence of D310 mutations increased significantly with the number of cytosines in the matched normal tissue sequence (P ¼ 0.02). Hypopharyngeal cancer was significantly more frequent (P ¼ 0.03) and tobacco consumption more important (P ¼ 0.01) in the group of patients with D-Loop mutation. The presence of D-Loop mutation was not associated with prognosis or with response to neoadjuvant chemotherapy. These results suggest that D-Loop mutations should be considered as a cancer biomarker that may be useful for the early detection of HNSCC in individuals at risk of this cancer.

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Section: Discussionmentioning

confidence: 95%

Section: Displacement-loop Amplificationmentioning

confidence: 99%

Section: Direct Sequencing Of the D310 Repeatmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Clinicopathological significance of mitochondrial D-Loop mutations in head and neck carcinoma

et al. 2006

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Mitochondrial DNA Copy Number Alterations in Human Cancers

2012

Encyclopedia of Life Sciences

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Mitochondria are cytoplasmic organelles that participate in adenosine triphosphate (ATP) production through respiration and oxidative phosphorylation (OXPHOS), free radical formation and execution of apoptosis. Perturbation of mitochondrial function has been proposed as one vital hallmark of cancer cells. Besides plenty of germline and polymorphic sequence variations accumulated in both coding and noncoding regions of the mitochondrial genome ( mitochondrial deoxyribonucleic acid (DNA); mtDNA), increased or reduced mtDNA copy number has also been increasingly described in a plethora of primary human malignancies. Altered mtDNA quantity may act as an important player in the multistep carcinogenesis of at least some types of human cancer by fuelling tumour initiation and/or advancement. In addition, mtDNA content turnover in bodily liquids from cancer patients could be exploited as a novel molecular tool for early cancer screening and diagnosis. Key Concepts: Disruption of mitochondrial function and the oxidative phosphorylation system may lead to cancer occurrence and development. MtDNA copy number changes have been frequently observed in a wide range of human malignancies. Aberrant mtDNA quantity is correlated with many key clinicopathological features of cancer patients. Alterations in mtDNA copy number have potential to affect cancer cell behaviours in vitro and in vivo . mtDNA content alterations could be considered as a novel biomarker for early cancer detection and diagnosis.

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Generation, function, and prognostic utility of somatic mitochondrial DNA mutations in cancer

Kulawiec¹,

Salk²,

Ericson³

et al. 2010

Environ and Mol Mutagen

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Exciting new studies are increasingly strengthening the link between mitochondrial mutagenesis and tumor progression. Here we provide a comprehensive review and meta-analysis of studies reporting on mitochondrial DNA mutations in common human cancers. We discuss possible mechanisms by which mitochondrial DNA mutations may influence carcinogenesis, outline important caveats for interpreting the detected mutations--particularly differentiating causality from association--and suggest how new mutational assays may help resolve fundamental controversies in the field and delineate the origin and expansion of neoplastic cell lineages. Finally, we discuss the potential clinical utility of mtDNA mutations for improving the sensitivity of early cancer diagnosis, rapidly detecting cancer recurrence, and predicting the disease outcome.

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Clinical Value of Mitochondrial Mutations in Colorectal Cancer

Abstract: 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.

Cited by 138 publications

References 27 publications

Clinicopathological significance of mitochondrial D-Loop mutations in head and neck carcinoma

Clinicopathological significance of mitochondrial D-Loop mutations in head and neck carcinoma

Mitochondrial DNA Copy Number Alterations in Human Cancers

Generation, function, and prognostic utility of somatic mitochondrial DNA mutations in cancer

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