Inherited genetic variation shapes how tumors evolve after DNA damage, according to a study published in Nature. The research reveals that modest inherited differences influence not only overall cancer risk but also which mutations become established in tumor cells, the number of genetic alterations required to initiate the disease, and the biological pathways tumors follow as they grow.
How Inherited Genetics Dictate Tumor Evolution
Not everyone who smokes develops lung cancer, and some non-smokers receive a diagnosis. Similarly, sunlight exposure does not trigger skin cancer in everyone. According to Dr. Avishay Spitzer, a physician-scientist and medical oncology resident at Tel Aviv Sourasky Medical Center (Ichilov) specializing in computational cancer genomics, healthy tissues naturally accumulate mutations over time. However, most cells carrying these changes fail to form tumors.
Researchers examined this phenomenon by exposing four groups of mice with different genetic backgrounds to a single injection of diethylnitrosamine (DEN), a carcinogen found in tobacco smoke and some processed foods, as reported by Euronews. Even under identical environmental conditions, tumors developed at drastically different rates across the groups, ranging from 25 weeks in the most susceptible group to 78 weeks in the most resistant group.
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The study analyzed a total of 581 liver tumors, finding that 95% of them activated the same biological pathway, known as MAPK, despite utilizing different underlying mutations.
Mutation Types, DNA Repair, and Driver Mutations
Susceptibility to cancer was not determined purely by the raw count of mutations. Two groups accumulated more DNA changes than the group that developed tumors the fastest, pointing to the critical importance of mutation type and genetic background.
The research identified distinct differences in DNA repair capabilities. Two groups exhibited lower activity of the Mgmt gene, which counteracts damage caused by the carcinogen. Furthermore, genetic background influenced how many driver mutations were necessary to initiate cancer. The most susceptible group generally required only a single driver mutation, whereas the other three groups typically needed at least two.
Genome Duplication and Telomere Stability
Another major differentiator among the groups involved whole-genome duplication, a process that destabilizes cells and allows tumors to gather further genetic abnormalities. According to the study’s findings, whole-genome duplication appeared in 37% of tumors within the most resistant group. These specific tumors carried BRAF mutations and later showed abnormal chromosome counts.
Mice in this resistant cohort also possessed shorter telomeres, which protect chromosome ends. Researchers connected telomere damage to genome duplication, noting that similar mechanisms occur in human tumors where whole-genome duplication often correlates with a poorer prognosis.
Future Implications for Personalized Oncology
Current disease progression and treatment response tests do not adequately account for the interaction between tumor mutations and an individual’s inherited genetic background. Spitzer stated that integrating a patient’s complete inherited genome with a tumor’s genetic profile could eventually transform diagnostics and treatment selection.
However, Spitzer emphasized that clinical application remains distant, noting that extensive further studies are required to confirm these findings across diverse human populations before translating them into direct patient care.
Frequently Asked Questions
Does inherited genetics determine whether someone will get cancer?
According to the study published in Nature, inherited genetic variation influences cancer risk, the number of alterations required to initiate a tumor, and how a tumor evolves, though environmental factors also play a critical role.
What is the MAPK pathway in cancer development?
The MAPK pathway regulates cell division, growth, and survival. The research found that 95% of the analyzed tumors activated this pathway, though they did so through different mutations such as BRAF, HRAS, EGFR, or KRAS.
Can these findings be applied to human cancer treatment immediately?
No. Researchers stress that clinical application requires much more study to confirm whether these animal-model findings apply across diverse human populations.
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