Cancer driver interception allows for counteracting tumors even before the very first stages of the disease. It enables taking action during cancer prodromal stage by targeting the factors that drive cancer development, first and foremost genome instability.
Transformation of normal cells into cancer cells is a process lasting years or decades. It can take place also in healthy and totally asymptomatic people, completely unaware to have to deal with several factors that actively drive this transformation.
Actually, it is possible to interrupt carcinogenesis at any point before the development of an invasive cancer. This approach corresponds to the so-called cancer driver interception, and can be implemented since the totally asymptomatic phase known as the prodromal stage.
Cancer prodromal stage and genome instability
Cancer prodromal stage is the period, lasting several years, during which cells progressively accumulate mutations in clinically healthy individuals showing no cancer symptoms.
In fact, cancer has its roots in our genes, and lifelong exposure to cancer risk factors promotes genome alterations which make cells grow abnormally, invade tissues and organs, and spread to other body parts.
However, not all mutations are created equal. In particular, when discussing the relationship between DNA mutations and cancer, it is mandatory to differentiate between germline mutations and somatic mutations.
Germline mutations are hereditary mutations that have been associated with the risk of cancer development; they occur in germ cells (the ones that will give rise to sperm or eggs) and are passed onto every cell of the offspring. BRCA 1 and 2 mutations stand as examples of germline mutations associated with breast cancer susceptibility.
In contrast, somatic mutations are acquired, non-heritable, changes in DNA sequence in cells other than germ cells. They occur after conception, cannot be passed onto offspring, and develop in specific tissues (e.g. breast or lung).
Only a limited percentage of cancers have a clear hereditary component, and even in those cases in which cancer susceptibility is clearly inherited, acquired mutations are needed for cancer to develop. In particular, the progressive accumulation of somatic mutations can lead to cancer and is indicative of genome (or genomic, or genetic) instability.
Contrary to germline mutations, genome instability is not a marker of the risk of cancer; rather, it is indicative of the cancer prodromal stage. Researchers already gave proof of concept that genome instability analysis is useful to assess the cancer prodromal stage. And, fortunately, genome instability is preventable and actionable.
Genome instability as an actionable cancer driver
Evidence indicates that genome instability is an actionable cancer driver that can be managed by both drugs and lifestyle.
Certain drugs are associated with a reduction in genome instability. For instance, when a patient with Barrett’s esophagus starts taking NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) their somatic copy number alterations rate drops by an order of magnitude.
Also, genome integrity has been shown to be highly sensitive to nutrient status, with optimal nutrient levels differing among individuals. As a consequence, nutrigenetics and nutrigenomics are interesting tools to avoid genomic instability through a simple approach based on lifestyle.
As explained by Silvia Soligon, Bioscience Institute‘s consultant, «biomarkers of genome integrity can be utilized to establish recommended daily intakes for nutrients; in turn, optimizing nutrient intake plays a significant role in stabilizing the genome». Soligon is a Ph.D. in Genetics and Biomolecular Sciences with a Specializing Master in Nutrition Science and Applied Dietetics.
«For example, in smokers, carotenoid consumption correlates to lung cancer incidence, and β-carotene supplements are associated with a significant increase in mortality; cell cultures studies suggest that any concentration of non-vitamin A carotenoids tends to decrease DNA damage, whereas high concentrations of provitamin A carotenoids such as β-carotene tend to increase it.
Vitamin B3 deficiency impairs the function of critical DNA repair enzymes (in particular, PARP proteins), and folate deficiency (especially if combined with suboptimal vitamin B6 and B12 levels) may lead to DNA breaks.
In the presence of oxidative stress, vitamin C correlates with various markers of genome stability. Meanwhile, vitamin D and selenium concentrations are critical in the maintenance of genome stability too, possibly protecting against chromosomal aberrations. Cells supplemented with selenium showed reduced DNA breakage, and vitamin D could counteract oxidative stress.
Also, food components can help to increase the capability of the cells to repair DNA damage, which is among the factors enabling genome stability maintenance.
For instance, resveratrol, which is a polyphenol present in fruits and other vegetable foods (for example in grapes, berries, and peanuts) may activate Sirt1 (sirtuin 1), a DNA damage repair-activating enzyme. In mice with reduced Sirt1, resveratrol treatment was associated with reduced cancer development».
How to intercept genome instability
Thanks to advanced methods for genome analysis, today we can assess the prodromal, totally asymptomatic, stage of most solid cancers, and intercept genome instability when we are totally healthy.
HELIXAFE, Bioscience Institute’s five-test program enabling the interception of genomic instability drivers and cancer prodromal stage assessment, allows for identifying mutations that promote genome instability and obtaining a trend of stability for solid cancer associated mutations.
Both somatic and germline mutations are monitored. The mutation rate in blood cfDNA (cell-free DNA; that is, outside the cell) is analyzed by means of Multi Biomarker Next Generation Sequencing (NGS) and a sophisticated management software.
NGS is an innovative DNA sequencing technology that allows for simultaneously sequencing a high number of small DNA, with a very high coverage of a region of interest. This is especially important for identifying mutations associated with cancer that are present at low fractions.
Based on the HELIXAFE algorithm, if there are no mutations in cfDNA, or if mutations in cfDNA are also detected in white blood cells’ DNA (germline control), all that is needed is to schedule the next check-up in one year; in fact, the presence of a mutation in the germline control means that it is an inherited (not acquired) mutation, not indicative of genome instability.
However, if mutations in cfDNA are not detected in the germline control, that means they are somatic, acquired mutations. In such a case, germline mutations in cancer susceptibility genes should also be tested, looking for genes that can promote cancer development in the presence of somatic mutations.
In the end, patients are referred to a counseling session with a cancer specialist.
Genetic instability can be further analyzed by HELIDX, a non-invasive screening assay for early detection of solid cancer.
The five-test HELIXAFE program for cancer driver interception
The first level HELIXAFE prevention program for cancer driver interception is meant to identify mutations responsible for genome instability. This test is called HELIXBALANCE, and analyzed genes include factors involved in DNA damage and/or repair, chromatin remodeling or DNA methylation, β-catenin/WNT signaling, and cell cycle control – which all play a role in maintaining genome stability.
If no mutation is detected, individuals are sent to genetic counseling to plan the next check-up, whereas if one, or more mutations are detected in the cfDNA but not in white blood cells, individuals are sent to genetic counseling to plan a second level prevention program.
There are 4 possible second level cancer interception programs.
-
- HELIXMOKER is specifically designed for smokers and highly pollution-exposed subjects; it analyzes 11 genes and 169 hotspots directly involved in respiratory system cancers.
- HELIXCOLON monitors for a total of 14 genes and 245 hotspots involved in colon cancer.
- HELIXGYN is a lifeline for women exposed to hormone therapies or who are at a high risk for breast or ovarian cancer because of BRCA 1 or 2 mutations, which analyzes 11 genes and 157 hotspots.
- HELIXPAN is appropriate for people at a low risk for solid cancer; it allows for the identification of tissues and organs needing targeted prevention from somatic mutations linked to genome instability by monitoring 50 genes and 2800 solid cancer associated mutations. If detected mutations are in lung, colon or breast-associated genes, an additional analysis with one of the three more specific programs (HELIXMOKER, HELIXCOLON or HELIXGYN) looking for low-frequency somatic mutations is recommended.
How to request HELIXAFE
In the past, cancer prevention was achieved by means of the analysis of familial susceptibility, and test results needed to be interpreted, potentially resulting as non-informative; the analysis and monitoring of mutation rates are instead objective parameters.
Aging is the most important cancer risk factor, but the disease can occur at all ages, and it is never too soon or too late to start prevention by evaluating genomic instability to intercept the most important cancer driver.
For further information about HELIXAFE, please visit Bioscience Institute webpage, or contact us at info@bioinst.com. Our biologists will answer your questions with no commitment on your part.
References
- Alborelli et al. Cell-free DNA analysis in healthy individuals by next-generation sequencing: a proof of concept and technical validation study. Cell Death Dis.. 2019 Jul 11;10(7):534. doi: 10.1038/s41419-019-1770-3
- Alix-Panabières C and Pantel K. Clinical Applications of Circulating Tumor Cells and Circulating Tumor DNA as Liquid Biopsy. Cancer Discov. 2016 May;6(5):479-91. doi: 10.1158/2159- 8290.CD-15-1483
- Ciccia A and Elledge SJ. The DNA Damage Response: Making it safe to play with knives. Mol Cell. Mol Cell. 2010 Oct 22; 40(2): 179–204. doi: 10.1016/j.molcel.2010.09.019
- Ferguson LR et al. Genomic instability in human cancer: Molecular insights and opportunities for therapeutic attack and prevention through diet and nutrition. Semin Cancer Biol . 2015 Dec;35 Suppl(Suppl):S5-S24. doi: 10.1016/j.semcancer.2015.03.005
- Nair-Shalliker V et al. Does vitamin D protect against DNA damage? Mutat Res 2012;733:50–7. doi: 10.1016/j. mrfmmm.2012.02.005
- Niedernhofer LJ et al. Nuclear Genomic Instability and Aging. Annu Rev Biochem. 2018 Jun 20;87:295-322. doi: 10.1146/ annurev-biochem-062917-012239
- Omenn GS et al. Risk factors for lung cancer and for intervention effects in CARET, the Beta- Carotene and Retinol Efficacy Trial. J Natl Cancer Inst 1996;88:1550–9. doi: 10.1093/jnci/88.21.1550
- Risuleo G. Efficacy, Safety and Toxicity. Chapter 33 – Resveratrol: Multiple Activities on the Biological Functionality of the Cell. (2016) Pages 453-464. doi: 10.1016/B978-0-12-802147-7.00033-4
- Sethi S et al. Clinical advances in molecular biomarkers for cancer diagnosis and therapy. Int J Mol Sci. 2013 Jul 16;14(7):14771-84. doi: 10.3390/ijms140714771
- Sram RJ et al. Vitamin C for DNA damage prevention. Mutat Res 2012;733:39–49. doi: 10.1016/j.mrfmmm.2011.12.001
- Tomasetti C et al. Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention. Science. 2017 Mar 24;355(6331):1330-1334. doi: 10.1126/ science.aaf9011
- van Ommen B et al. The Micronutrient Genomics Project: a community-driven knowledge base for micronutrient research. Genes Nutr 2010;5:285–96. doi: 10.1007/s12263-010-0192-8
- Volik S et al. Cell-free DNA (cfDNA): Clinical Significance and Utility in Cancer Shaped By Emerging Technologies. Mol Cancer Res. 2016 Oct;14(10):898-908. doi: 10.1158/1541-7786.MCR-16-0044
