Prospective study of telomere length and the risk of skin cancer.
Han J, Quresh AA, Prescott J et al.
J Invest Dermatol, 2009, 129, 415-421
Skin ageing has long been associated with exposure to UV rays, pollution and smoking. The damage caused is thought to be mediated through the production of free radicals in the skin and long-term consequences of oxidative stress, causing cumulative damage to collagen and elastin, and changes in the skin's outward appearance. However, there must also be other contributing factors to skin damage, as protected skin will also eventually show signs of ageing. Recent discoveries in this latter area are beginning to unravel how this 'internal' ageing may occur and these mechanisms may involve sirtuins, fibroblast senescence and telomere length.
Telomeres are long hexameric repeats at the ends of chromosomes. Murine studies and studies in yeast have demonstrated that telomeres play a critical role in maintaining structural integrity of chromosomes following replication in mitosis by preventing fusion of chromosomal ends, nucleolytic decay, end-to-end fusion and atypical recombination. However, at each cell division, DNA polymerases fail to complete a full replication of the telomeres, resulting in cumulative erosion of these tail ends of the chromosomes by approximately 30-200bp after each mitotic division, and this has been likened to a 'biological clock' of ageing reflecting the number of divisions a cell may have undergone. When telomeres shorten to a critical length, the cells undergo apoptosis, senescence or become genomically unstable.
Shorter telomere length has been linked to an increase risk of some cancers [1,2] and, in fact, UVB exposure creates a high frequency of pyrimidine dimers in telomeric regions. UVA-induced cellular oxidative stress on the other hand, may lead to telomere shortening. Both of these events can be potentially carcinogenic. This paper investigates whether telomere length is related to the risk of skin cancers: melanoma, basal cell carcinoma or squamous cell carcinoma. Women aged between 43 and 68 years were studied (mean age 58.7 years), blood draws were taken to determine telomere length in peripheral blood leukocytes (PBL) using realtime PCR and a record was taken of risk factors likely to be associated with skin cancer. The data showed an inverse correlation between telomere length and smoking and age, while there was a positive correlation between the number of moles on arms and telomere length. No correlation was found between sun exposure and telomere length. With respect to skin cancer, shorter telomere length was associated with a decreased risk of melanoma and an increased risk of basal cell carcinoma. No association was observed between telomere length and squamous cell carcinoma.
This study used real-time PCR and DNA derived from PBL to determine relative telomere length. The authors comment that the observed correlation with age and cigarette smoking confirms that real-time PCR provides a biologically meaningful measure of telomere length, and is consistent with previous findings [3,4]. This is currently the most economical and versatile high throughput method of determining telomere length, although the values are not an actual kilobase pair length as compared to the data provided by Southern blots. PBLs can be used as a valid measure of skin telomere length and this was reported by Friedrich in 2000 .
The data presented in this study give conflicting results that could result from the diversity of the skin cells in the epidermis and the differing roles and functions orchestrated by the cell types. Telomere shortening plays conflicting roles in cancer development. The most common theme is that progressive loss of telomeric repeats with each cell division limits the total number of times a cell can divide, which results in a DNA damage response being triggered when telomeres reach a critical length, and causing senescence or apoptosis. However, this would not explain the findings that shorter telomere length is associated with a reduced risk of melanoma and clearly more work needs to be done to confirm these findings.
[1.] Wu X, Amos CI, Zhu Y et al. Telomere dysfunction: a potential cancer predisposition factor. J Natl Cancer Inst, 2003, 95, 1211-1218.
[2.] Widmann TA, Herrmann M, Taha N et al. Short telomeres in aggressive non-Hodgkin's lymphoma as a risk factor in lymphomagenesis. Exp Hematol, 2007, 35, 939-946.
[3.] Frenck RW Jr, Blackburn EH, Shannon KM. The rate of telomere sequence loss in human leukocytes varies with age. Proc Natl Acad Sci USA, 1998, 95, 5607-5610.
[4.] Valdes AM, Andrew T, Gardner JP et al. Obesity, cigarette smoking, and telomere length in women. Lancet, 2005, 366, 662-664.
[5.] Friedrich U, Griese E, Schwab M et al. Telomere length in different tissues of elderly patients. Mech Ageing Dev, 2000, 119, 89-99.
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|Article Type:||Clinical report|
|Date:||Mar 1, 2009|
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