Mitochondrial DNA damage in non-melanoma skin cancer

Abstract

Mitochondrial DNA (mtDNA) damage, predominantly encompassing point mutations, has been reported in a variety of cancers. Here we present in human skin, the first detailed study of the distribution of multiple forms of mtDNA damage in nonmelanoma skin cancer (NMSC) compared to histologically normal perilesional dermis and epidermis. We present the first entire spectrum of deletions found between different types of skin tumours and perilesional skin. In addition, we provide the first quantitative data for the incidence of the common deletion as well as the first report of specific tandem duplications in tumours from any tissue. Importantly, this work shows that there are clear differences in the distribution of deletions between the tumour and the histologically normal perilesional skin. Furthermore, DNA sequencing of four mutation 'hotspot' regions of the mitochondrial genome identified a previously unreported somatic heteroplasmic mutation in an SCC patient. In addition, 81 unreported and reported homoplasmic single base changes were identified in the other NMSC patients. Unlike the distribution of deletions and the heteroplasmic mutation, these homoplasmic mutations were present in both tumour and perilesional skin, which suggests that for some genetic studies the traditional use of histologically normal perilesional skin from NMSC patients may be limited. Currently, it is unclear whether mtDNA damage has a direct link to skin cancer or it may simply reflect an underlying nuclear DNA instability.

Association of decreased mitochondrial DNA content with ovarian cancer progression

“…Detection of many mtDNA alterations in the premalignant or preinvasive lesions indicated that mtDNA alterations could be an early genetic event in tumorigenesis (Chen et al, 2002;Ha et al, 2002;Durham et al, 2003). Mitochondrial DNA copy number was suggested to be increased by a feedback mechanism that compensates for the defective respiratory system owing to mutated mtDNA .…”

Ultraviolet radiation exposure accelerates the accumulation of the aging‐dependent T414G mitochondrial DNA mutation in human skin

“…None of the patients used had a mitochondrial disease. Epidermis and dermis were separated using 0.25% dispase at 4 ° C overnight (Durham et al ., 2003) and DNA was extracted using a Qiagen DNeasy (Crawley, UK) tissue extraction kit. Fibroblasts were isolated by explanting dermal skin and the outgrowing dermal fibroblasts were harvested once they approached confluence within the first 75 cm 2 flask.…”

Real-time PCR analysis of a 3895 bp mitochondrial DNA deletion in nonmelanoma skin cancer and its use as a quantitative marker for sunlight exposure in human skin

“…Therefore, one might suggest that prolonged UVR exposure could either directly (by inducing base substitutions as opposed to deletions) or indirectly (by induction of free radicals) affect these 12 bp repeat structurally labile sites through opening a 'bubble' of singlestranded DNA that would enhance the recombination event, thereby eliciting an increase in mtDNA deletions. In this respect, it is of interest to note that investigation of the 3895 bp deletion in the same NMSC samples which were used in a previous study of the 4977 bp common deletion (Durham et al, 2003), showed a comparatively greater frequency of occurrence of the 3895 bp deletion. As these tumours were excised from body sites that are usually exposed to the sun, it is interesting to speculate that the 3895 bp deletion may be a more sensitive marker of cumulative sun exposure than the 4977 bp common deletion.…”

“…There are no significant age differences between the usually and occasionally sun-exposed groups (P ¼ 0.1134): two-tailed t-test (Welch correction). For all perilesional skin samples, epidermis and dermis were separated using 0.25% dispase at 41C overnight (Durham et al, 2003) and DNA was extracted using a Qiagen, DNeasy tissue extraction kit. None of the patients used for this study suffered from a mitochondrial myopathy or had a mtDNA associated neurodegenerative disease.…”