Germline variants are present in every single cell of our body. By contrast, somatic mutations occur in individual body cells during an organism's lifetime and only affect the tissue that is derived from that cell. They can be driven by external factors like UV light or tobacco smoking. "The main finding of our study is that a person's genetic background can influence the changes we see in the genome of their cancer cells," says the author.
"Cancer is a disease of the somatic genome, caused by mutations that arise during our lifetime," says the group leader. "But in a certain number of patients, at least 5 to 10%, the reason for cancer is due to inherited mutations. In our study we identified several genetic factors that promote the somatic evolution of cancer cells."
On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumor evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously.
Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition.
The group identified germline mutations in the gene MBD4 as a driver for an overabundance of somatic mutations in cancer genomes. MBD4 influences a mutational process that occurs naturally during ageing and is described as clock-like, because of the rhythm with which somatic mutations occur during our lifetime. In the presence of a mutated MBD4 gene, the clock-like mutational process runs at a much faster pace.
Finding germline variants that influence cancer development is key for future medical applications. "Our methodology can be used to identify genetic factors that increase the pace at which somatic mutations are acquired," says the author. In the future, patients with an identified genetic risk could be counselled and offered regular screenings so that a pre-cancerous lesion is discovered as early as possible.
How our genetic background influences cancer development
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