The Secrets of Our DNA
How Genetic Susceptibility Determines Cancer Risk
Introduction: When Our Genes Make Us Vulnerable
Imagine our genetic material as a vast library containing all the instruction manuals for our body's functioning. What would happen if some of these manuals had printing errors that caused cells to behave abnormally? This analogy helps us understand the basic concepts of cancer molecular biology and how our genetic susceptibility can predispose us to developing this disease.
Cancer is essentially a genetic disease characterized by the progressive accumulation of alterations in our DNA that allow cells to grow uncontrollably, evade programmed cell death mechanisms, and even invade other tissues. While some of these alterations are acquired during our lifetime through exposure to environmental factors (such as tobacco or ultraviolet radiation), others are inherited and have been part of our genetic heritage since conception 5 .
Genetic susceptibility explains why two people exposed to the same environmental risk factors can have very different probabilities of developing cancer. Understanding these mechanisms not only satisfies our scientific curiosity but opens the door to prevention strategies, early detection, and personalized treatments that are revolutionizing modern oncology.
Fundamentals of Genetic Susceptibility to Cancer
Molecular Mechanisms of Cancer Susceptibility
Genome Guardians
Tumor Suppressor Genes
Our cells possess a sophisticated DNA surveillance and repair system. Tumor suppressor genes act as genome guardians, preventing uncontrolled cell proliferation.
The best-known example is the TP53 gene, known as "the guardian of the genome," which detects DNA damage and can stop the cell cycle to allow repair or induce programmed cell death (apoptosis) if the damage is irreparable 8 .
Oncogenic Accelerators
Oncogenes
While tumor suppressor genes act as brakes, oncogenes act as accelerators of cell growth.
Under normal conditions, these genes (called proto-oncogenes) participate in regulating cell division and differentiation. However, when they undergo mutations that permanently activate them, they drive the uncontrolled cell growth characteristic of cancer.
Cellular Mechanics
DNA Repair Genes
Our DNA suffers thousands of daily lesions from environmental factors and normal cellular processes. DNA repair genes encode proteins that act as specialized mechanics that correct these damages.
A crucial example are genes involved in the mismatch repair system (MMR), such as MLH1, MSH2, MSH6 and PMS2 3 .
Subtle Variations
Polymorphisms
Not all genetic variations that affect our cancer risk are dramatic mutations. Single nucleotide polymorphisms (SNPs) are minor variations in a single letter of our genetic code that can subtly modify protein function.
These genetic differences explain why some people metabolize environmental carcinogens differently 2 5 .
Case Study: Deciphering Genetic Susceptibility in Colorectal Cancer in Colombian Population
Context and Study Objectives
In 2025, a team of Colombian researchers conducted a pioneering study published in Frontiers in Oncology that perfectly illustrates how modern technologies are revolutionizing our understanding of genetic susceptibility to cancer 3 .
Colorectal cancer (CRC) represents a significant health problem in Colombia, with approximately 11,163 new cases and 5,640 annual deaths according to GLOBOCAN data. About 30-35% of patients have family history of the disease, suggesting a strong genetic component even in cases not associated with classic hereditary syndromes.
Methodology Step by Step
Participant Selection
100 Colombian patients with histopathologically confirmed diagnosis of colorectal cancer.
DNA Extraction and Preparation
DNA extracted from peripheral blood using the Quick-DNA 96 plus kit.
Whole Exome Sequencing
Library preparation with 250 ng of DNA using MGIEasy FS DNA Library Prep Kit.
Sequencing
Using the DNBSeqG400 platform, with minimum coverage of 50x.
Bioinformatic Analysis
Reads mapped against hg19 reference genome using BWA aligner.
Variant Classification
Variants classified according to ACMG guidelines.
Functional Validation
Minigene assay used to evaluate effect on mRNA splicing.
AI Analysis
Implementation of BoostDM method to identify germline cancer driver variants.
Results and Analysis
Researchers discovered that 12% of patients carried pathogenic or likely pathogenic variants in cancer susceptibility genes according to ACMG criteria. When they applied the BoostDM artificial intelligence algorithm, they identified cancer driver variants in 65% of cases.
| Variant Category | Percentage of Patients | Most Frequently Affected Genes |
|---|---|---|
| Pathogenic (P) | 8% | APC, MLH1, MSH2 |
| Likely Pathogenic (LP) | 4% | CHEK2, MUTYH |
| Total P/LP | 12% | - |
| Prediction Method | Average AUC (complete dataset) | Average AUC (panel genes) |
|---|---|---|
| BoostDM | 0.788 | 0.803 |
| AlphaMissense | Not reported | Not reported |
This experiment is fundamental because it demonstrates that even in understudied populations like Latin Americans, the integration of advanced technologies (massive sequencing and artificial intelligence) allows identifying genetic susceptibilities that would otherwise go unnoticed, opening the door to personalized prevention strategies based on individual genetic profile.
The Scientist's Toolkit: Investigating Genetic Susceptibility to Cancer
Modern research in genetic susceptibility to cancer depends on a sophisticated set of technological tools that allow everything from reading our DNA sequence to predicting the functional impact of its variations.
| Tool or Reagent | Main Function | Application Example |
|---|---|---|
| Next-generation sequencing (NGS) | Massive sequencing of multiple genes simultaneously | Cancer susceptibility gene panels 3 |
| Whole-genome amplification | Amplification of complete DNA from small amounts | Study of scarce or valuable samples |
| CRISPR/Cas9 systems | Precise genetic editing | Functional validation of variants in cell models |
| Immunohistochemistry | Detection of protein expression in tissues | Analysis of repair protein loss (MLH1, MSH2) 8 |
| DNA methylation analysis | Detection of epigenetic alterations | Identification of epigenetic silencing of suppressor genes 8 |
| Tissue microarrays | Multiplex analysis of multiple samples | Biomarker validation in large cohorts 8 |
| Artificial intelligence platforms | Prediction of functional impact of variants | Variant classification like BoostDM and AlphaMissense 3 |
| Minigene assays | Evaluation of variant effect on splicing | Validation of intronic variants of uncertain significance 3 |
| Circulating tumor DNA analysis | Non-invasive detection of genetic alterations | Monitoring therapeutic response and resistance 4 |
Sequencing Technologies
Advanced NGS platforms enable comprehensive genomic analysis at unprecedented speed and accuracy.
AI and Machine Learning
Advanced algorithms help interpret complex genetic data and predict variant pathogenicity.
Functional Validation
CRISPR and other gene editing tools allow researchers to test the functional impact of genetic variants.
Implications and Future of Genetic Susceptibility Research
Towards Precision Medicine in Oncology
Knowledge about our individual genetic susceptibility to cancer is driving the transition toward a precision medicine model. As Dr. Lillian Siu of the Princess Margaret Cancer Centre explained, "we are entering a new era to attack the 'unattackable' with a new generation of specific molecules for mutations" 4 .
Future Advances:
- Specific mutation inhibitors: Beyond KRASG12C inhibitors (sotorasib and adagrasib), inhibitors for KRASG12D, KRASG12V, and even pan-KRAS and pan-RAS inhibitors are being developed 4 .
- Personalized immunotherapies: Therapeutic vaccines based on neoantigens derived from each patient's specific tumor mutations.
- Advanced cell therapies: Development of CAR-T cell therapies with Boolean logic that require the presence of two specific target antigens to activate 4 .
Early Detection and Stratified Prevention
Knowledge of genetic susceptibility allows implementing intensive early detection strategies in high-risk populations. For example, people with mutations in DNA repair genes (MLH1, MSH2) can benefit from more frequent colonoscopies starting at earlier ages 3 .
Prevention Strategies:
- Chemoprevention: Use of non-steroidal anti-inflammatory drugs (such as aspirin) in Lynch syndrome has been shown to reduce the incidence of colorectal cancer by up to 63% 3 .
- Lifestyle modifications: Personalized recommendations based on genetic risk profiles.
- Enhanced surveillance: Tailored screening protocols for high-risk individuals.
Ethical and Social Challenges
Advances in knowledge about genetic susceptibility to cancer present important ethical and social challenges that we must address as a society:
Confidentiality
Protecting genetic information from misuse by insurers or employers
Informed Consent
Ensuring patients understand implications of genetic testing
Equitable Access
Ensuring advances benefit all populations, not just those with resources
Conclusion: Our Genetic Heritage as a Tool for Empowerment
The revolution in our understanding of genetic susceptibility to cancer is transforming oncology from a reactive specialty (treating advanced disease) to a proactive discipline (identifying risks and implementing personalized prevention and early detection strategies).
As we have seen, each of us carries in our cells a unique genetic heritage that influences our individual risk of developing cancer. Reading and interpreting this information encoded in our DNA allows us to make informed decisions about our health, empowering us to actively participate in our prevention.
The future of oncology will not be dominated by one-size-fits-all treatments, but by personalized strategies based on our individual genetic profile, where artificial intelligence will help interpret the complexity of our genome and advanced therapies will specifically attack each tumor's weak points.
While we face ethical and access challenges, one thing is clear: understanding the basic concepts of cancer molecular biology and our genetic susceptibility is not just material for scientists, but essential knowledge for anyone who wants to take control of their health in the 21st century.
