Carcinogenesis Advance Access published online on January 10, 2006
Carcinogenesis, doi:10.1093/carcin/bgi326
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1 School of Biological Sciences, University of Wales Swansea, Swansea, SA2 8PP, UK
* To whom correspondence should be addressed. It has previously been demonstrated that mitochondrial DNA (mtDNA) mutations within the ND2 gene of histologically normal parotid salivary gland tissue of smokers may be molecular biomarkers for smoking induced mtDNA damage. Oral squamous cell carcinoma (SCC) is strongly related to cigarette smoking, therefore we used PCR and direct sequencing to establish whether mtDNA mutations were also present in oral SCC which could be used as additional biomarkers for smoking-associated DNA damage. In addition to searching for mutations in the ND2 gene, the mitochondrial D-Loop was also analysed. Three mutation hotspots were observed in the D-Loop at nucleotides (nt) 146, 152 and 186, two of which (nts 146 and 152) have also been implicated in oesophageal squamous cell carcinoma, another smoking related cancer. The mutation hotspot observed at nt 186 has not previously been reported in other tumours. Furthermore, we show that the mutations previously reported within the ND2 gene in normal parotid tissue of smokers were not evident in these samples, but that a mutation hotspot occurs at nucleotide 4917 in oral SCC. We also show that D-Loop mutations occur predominantly in male smokers and female non-smokers and that this association with gender is statistically significant (P=0.003). We conclude that the mtDNA mutation hotspots found in this study, in particular nt 186, are potential biomarkers for oral SCC. However, due to gender specific differences in occurrence in smokers and non-smokers and a lack of environmental smoking history, in general, it is difficult to associate these mutations with mtDNA damage induced by smoking. If the mutations observed in the subset of male patients are smoking induced then, given our previous findings, mutation hotspots in the ND2 gene may be tissue specific suggesting the causative mutagens for mtDNA damage within these tissues are likely to be different.
Received May 20, 2005
Revised November 9, 2005
Accepted December 20, 2005
CANCER BIOLOGY
Mitochondrial DNA mutations in oral squamous cell carcinoma
S. L. Prior 1,
A. P. Griffiths 2,
J. M. Baxter 1,
P. W. Baxter 3,
S. C. Hodder 3,
K. C. Silvester 3,
and
P. D. Lewis 4 *
2 Department of Histopathology, Morriston Hospital, Swansea, SA6 6NL, UK
3 Maxillofacial Surgery, Morriston Hospital, Swansea, SA6 6NL, UK
4 South West Wales Cancer Institute, Singleton Hospital, Swansea, SA2 8QA, UK
P. D. Lewis, E-mail: p.d.lewis{at}swansea.ac.uk
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