Germline Telomere Length Dynamics and Mutagen Sensitivity Studies in a Family with Acute Reactions to Sun Exposure: Involvement of Three Generations.

Most cancers are the result of an interaction between germline genetic susceptibility and exposure to environmental carcinogens. We studied chromosomal aberrations, telomeric associations, telomere signal intensity by fluorescence in situ hybridization, p53 germline mutation, bleomycin (Bleo) and 4-nitroquinoline-1-oxide (4NQO) sensitivity, and chromosome-specific telomere signals in T and B lymphocytes in a Caucasian family involving three generations and 13 family members. This family was chosen because eight of its members are extremely sensitive to sunlight and burn easily even upon short exposure. The family members have shown: (a) hypersensitivity either to Bleo or 4NQO mutagens, with values much higher than 1.00 breaks/cell (b/c) for Bleo and 0.40 b/c for 4NQO; (b) an increased rate of telomeric associations; (c) variable amounts of telomeric DNA not common for the person's age; (d) the presence of intron 7 polymorphism in the proband and no significant effect on N-methyl-N'-nitosoguanidine (MNNG)-induced p53 expression in two key family members; and (e) an incidence of epithelial malignancies in two family members. Seven additional members showed polymorphism of telomeric signals in the short arm of two homologous chromosome 17s, where the p53 gene is localized. A 78-year-old grandmother, who had developed colon cancer, was predicted to have metastatic cancer based on the telomeric DNA amount in her lymphocytes (2.90%); she subsequently developed metastatic lesions within a year and died. Based on these observations, we conclude that telomere erosion is the initial cause of genomic instability/susceptibility which, in turn, may be causal for the reproductive complications, premature aging phenotypes and, in some cases, predisposition to cancer development.

Telomere dynamics, aneuploidy, stem cells, and cancer (review).

The real cause of genetic instability, which is the hall-mark of most cancers, is poorly understood. Specific gene mutations and acquired aneuploidy have been implicated as the root causes of genetic instability. Here we propose and cite evidence for the hypothesis that genetic instability of cancer cells is caused by telomere dynamics, erosion and/or amplification of the TTAGGG repeat sequences present at chromosomal termini. Since telomeres determine the domain of individual chromosomes within a nucleus and protect them from internal and external challenges, their erosion will destabilize the cell karyotype. Our hypothesis predicts that telomere dynamics provides the single unifying mechanism playing a major role in speciation, aging and cancer development. It was found that metastatic cancers of different histologic phenotypes, as well as mammalian taxa with active speciation and larger numbers of species exhibit amplification of their telomeric DNA as compared to non-metastatic counterpart cancers and taxa with only a limited number of species. The dynamic nature of this DNA can be found not only in the cancer cells but also in the peripheral lymphocytes of cancer patients. Human syndromes such as Down, Turner, Bloom, Werner, Fanconi, ataxia and many others, show aneuploidy and also are prone to develop various malignancies and premature aging. We have found that of all these syndromes have a reduced amount of telomeric DNA associated with specific mitotic catastrophes as compared to cells of age- and sex-matched normal individuals. From these and additional data generated by our group concerning speciation, aging and cancer karyotypes, we conclude that aneuploidy, which is responsible for birth defects, cancer initiation and is a major player in natural speciation, is a consequence of telomere dynamics. Because telomere reduction is linked to the aging process, which is a risk factor for cancer development in the human population, our hypothesis offers a unifying mechanism for the initiation of both hematologic and solid cancers, as well as for the origin of new species.