Abstract
There is increasing evidence suggesting that short telomeres and subsequent genomic instability contribute to malignant transformation. Telomere shortening has been described as a mechanism to explain genetic anticipation in dyskeratosis congenita and Li-Fraumeni syndrome. Since genetic anticipation has been observed in familial breast cancer, we aimed to study telomere length in familial breast cancer patients and hypothesized that genetic defects causing this disease would affect telomere maintenance resulting in shortened telomeres. Here, we first investigated age anticipation in mother-daughter pairs with breast cancer in 623 breast cancer families, classified as BRCA1, BRCA2, and BRCAX. Moreover, we analyzed telomere length in DNA from peripheral blood leukocytes by quantitative PCR in a set of 198 hereditary breast cancer patients, and compared them with 267 control samples and 71 sporadic breast cancer patients. Changes in telomere length in mother-daughter pairs from breast cancer families and controls were also evaluated to address differences through generations. We demonstrated that short telomeres characterize hereditary but not sporadic breast cancer. We have defined a group of BRCAX families with short telomeres, suggesting that telomere maintenance genes might be susceptibility genes for breast cancer. Significantly, we described that progressive telomere shortening is associated with earlier onset of breast cancer in successive generations of affected families. Our results provide evidence that telomere shortening is associated with earlier age of cancer onset in successive generations, suggesting that it might be a mechanism of genetic anticipation in hereditary breast cancer.
Highlights
Genetic anticipation is the observation of progressively earlier age of onset or an increase of severity of clinical features of a genetic disorder as it is passed on to the generation
The fact that accelerated telomere shortening accompanies different premature aging syndromes and seems to be associated with increased risk of cancer development prompted us to analyze the role of telomere length in hereditary breast cancer
In this study we found that telomeres of peripheral blood cells from familial breast cancer patients were significantly shorter than those from the control population
Summary
Genetic anticipation is the observation of progressively earlier age of onset or an increase of severity of clinical features of a genetic disorder as it is passed on to the generation. The molecular mechanisms underlying anticipation are largely unknown, but it has been typically associated to trinucleotide repeat expansions in several genetic diseases [1,2]. Telomere shortening has been more recently described as another mechanism of anticipation, being associated with early onset and severity of disease in genetic disorders, such as dyskeratosis congenita [12,13], a disease characterized by cutaneous abnormalities, bone marrow failure and an increased predisposition to cancer, and in the Li-Fraumeni Syndrome [7,8]. Telomeres shorten with each cell cycle and there is increasing evidence suggesting that short telomeres and subsequent genomic instability contribute to malignant transformation
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