Tag Archives: genome maintenance

Understanding Cancer Mutations Makes Testing and Prevention Necessary – Same for Aging

Did you know that there are only 138 mutations that play the major role in making a cell cancerous? Well, 138 found so far, however, the number of these driver mutations inside the genes won’t grow significantly, at least that’s not anticipated. Obviously there are thousands of mutations in cancer cells, but not all of them give the selective grow advantage. This beautifully written review of cancer genetics tells us what the researchers all over the world have learned about differences in normal and cancer genomes. Sequencing technologies are becoming less and less expensive and hopefully very soon we will see sequencing as part of routine clinical testing. Although we are not there yet. The authors of the article provide this outline:

1. Most human cancers are caused by two to eight sequential alterations that develop over the course of 20 to 30 years.

2. Each of these alterations directly or indirectly increases the ratio of cell birth to cell death; that is, each alteration causes a selective growth advantage to the cell in which it resides.

3. The evidence to date suggests that there are ~140 genes whose intragenic mutations contribute to cancer (so-called Mut-driver genes). There are probably other genes (Epi-driver genes) that are altered by epigenetic mechanisms and cause a selective growth advantage, but the definitive identification of these genes has been challenging.

4. The known driver genes function through a dozen signaling pathways that regulate three core cellular processes: cell fate determination, cell survival, and genome maintenance.

5. Every individual tumor, even of the same histopathologic subtype as another tumor, is distinct with respect to its genetic alterations, but the pathways affected in different tumors are similar.

6. Genetic heterogeneity among the cells of an individual tumor always exists and can impact the response to therapeutics.

7. In the future, the most appropriate management plan for a patient with cancer will be informed by an assessment of the components of the patient’s germline genome and the genome of his or her tumor.

8. The information from cancer genome studies can also be exploited to improve methods for prevention and early detection of cancer, which will be essential to reduce cancer morbidity and mortality.

Those 138 mut-driver genes (oncogenes and tumor suppressor genes) can be classified into one or more of 12 pathways. And these pathways can be grouped into three large groups: cell survival, cell fate and genome maintenance. All these things go wrong during aging. The majority of the listed pathways play a role in aging. Naturally, cell senescence is seen as an anti-cancer strategy of the cell. And it works well until it doesn’t. The relationship between these  two processes is not understood completely and more research is definitely needed to answer the question what happens over time. What distorts the balance?

cancer pathways

Cancer is truly an age-related disease. Aging brings decline in DNA repair efficiency and other mechanisms of genome stability maintenance. I think that if we figure out a way how to keep those mechanisms intact, working as good as they do at the age of 16, for example, there’s a good chance we will eradicate cancer, at least the solid tumors. This will be a huge step in increasing human longevity.

I wholeheartedly agree with the authors of the article on the following matter:

“plan A” should be prevention and early detection, and “plan B” (therapy for advanced cancers) should be necessary only when plan A fails. To make plan A viable, government and philanthropic organizations must dedicate a much greater fraction of their resources to this cause, with long-term considerations in mind. We believe that cancer deaths can be reduced by more than 75% in the coming decades (152), but that this reduction will only come about if greater efforts are made toward early detection and prevention.

This idea of prevention is valid not only for cancer, but for aging in general. In my opinion, if we develop the tests, that will definitely include cancer testing, we will be able to see what is happening, what is going wrong on molecular level, and we won’t wait until 90% of the organ is non-functional, until Alzheimer’s have consumed the personality of our loved one, until we feel we can no longer walk up three staircases. We will fight the disease in its infancy, and we will fight aging to remain youthful for as long as we choose to be.

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Jan Vijg – Aging of the genome

Watch Dr. Jan Vijg’s plenary talk about genetics and epigenetics of aging.

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New Study on the Somatic Mutations that Accumulate with Age

I would like to bring your attention to Dr. Jan Vijg who is leading several important research studies involving the role of non-cancerous mutations in aging.

Previous scientific reports of premature aging in mutant mice with greatly increased rates of mitochondrial DNA (mtDNA) appeared to confirm that accumulation of mtDNA mutations is a key mechanism of normal aging. Now, in a dramatic turnaround, a new study by Vijg and his team report that levels of mutations in tissues of aged normal mice are much lower than in the mutator mice, ruling out the causal role in normal aging!

Jan Vijg, Chair at the Department of Genetics at Albert Einstein College of Medicine and formerly the Director of the Buck Institute for Aging Research, has been focusing on genome instability and the mechanisms through which this may cause human disease and aging. Genome instability is generally considered as a cause of cancer and could play a general role in the overall etiology of human aging and disease.

The possible connection between damage to the genome and aging was supported in the discovery that heritable defects in genome maintenance are often associated with premature aging, as for example in Werner Syndrome and Hutchinson Gilford Progeria Syndrome. The DNA repair defects present in these conditions and other defects have been engineered in mice and shown to cause premature aging in these animals.

Members of the Vijg lab generated transgenic mouse and fruit fly strains harboring plasmids containing the bacterial lacZ gene. These plasmids were recovered from genomic DNA and subsequently transferred into E. coli to positively select for colonies representing a mutant lacZ-plasmid. In this way it was demonstrated that as predicted, the frequency of mutations increases with age in most tissues and cell types. Both the rate of mutation accumulation and the mutation spectra were shown to be tissue-specific. Vijg also demonstrated in a mouse model for increased oxidative stress that mutation accumulation correlates with cancer in a tissue-specific manner. Similar studies in the fruit fly lacZ-plasmid model are currently underway.

The key types of mutation that are a focus at the Vijg labs are genome rearrangements. This type of mutation is caused by errors made during the repair of DNA double strand breaks, which are highly toxic. They accumulate during aging and in some tissues comprise a major fraction of the mutation spectrum. Genome rearrangements are currently emerging as a major causal factor in the non-cancer, degenerative component of the aging process.

Based on previous observations that genetic defects in genome maintenance are associated with multiple symptoms of premature aging, Vijg is also studying the mechanistic basis of the possible causal role of Genotoxic Stress in aging. This is caused by exposure to toxic agents, including the sun’s ultraviolet rays, background ionizing radiation, chemicals in food and the environment, and highly reactive molecules produced within cells during metabolism.

In his research, characterization at the phenotypic level showed that only mutations in select genome maintenance pathways, e.g., nucleotide excision repair, double-strand break repair, lead to premature aging. Other pathways, most notably DNA mismatch repair, are associated with cancer but do not elevate the frequency of non-cancer, degenerative symptoms in aging. It was found that both cellular responses to DNA damage, cellular senescence and increased levels of genome rearrangements were critical in the etiology of the observed premature aging phenotypes.

The overall main focus of these studies is to extend the concept of genome maintenance to healthy human aging. This research is important as it should lead to new intervention strategies aimed at improving late-life health and reducing mortality rates.

Read more about Dr. Vijg and his research on the role of non-cancer mutations in aging.

Maria Konovalenko
SCIENCE FOR LIFE EXTENSION FOUNDATION
http:/mariakonovalenko.wordpress.com/
maria.konovalenko@gmail.com

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