More hereditary factors that increase the risk of cancer

In an individual, mutations occur in various of its tissues and organs. The so-called “somatic mutations” occur in those cells that do not have descendants and, therefore, are not transmitted to the following generations.

These mutations are the consequence of a large number of factors, such as age and smoking. They are the main cause of cancer and are also involved in other diseases.

A study led by Fran Supek, from the Barcelona Biomedical Research Institute (IRB Barcelona), and Ben Lehner, from the Center for Genomic Regulation (CRG) in Barcelona, ​​has revealed the inherited genetic traits that predispose individuals to the appearance of certain types of somatic mutations in their tissues.

People with higher mutation rates in an organ are more likely to accumulate mutations in essential cancer genes that can increase the risk of tumor formation.

In previous studies, researchers have described hereditary mechanisms that predispose individuals to cancer, even though many tumors do not have a clear genetic explanation. It is conceivable that cancer risk is the result of changes in the spectrum of different types of somatic mutations, a common cause of cancer.

“In this comprehensive study we tested whether the different types of DNA changes observed in tumors were associated with inherited variants in many different genes. We developed a methodology that has allowed us to identify 42 genes that are related to 15 different cellular mechanisms and that affect to the risk of different types of somatic mutations. This could help explain cancer predisposition risks,” explains Dr. Mischan Vali Pour, who led the study while a Ph.D. student in the laboratories of Dr. Lehner and Dr. Supek.

“While some examples of genes responsible for changing patterns of somatic mutations were previously known (such as the BRCA genes, which predispose to breast and ovarian cancer, and the Lynch syndrome genes, which predispose to colon cancer), now we found many other genes that can similarly affect the accumulation of somatic mutations,” explains Dr. Fran Supek.

Future work based on this study could contribute to assessing the hereditary risk of a patient developing a specific type of cancer and, therefore, to personalizing their prevention program and/or detecting the disease in its early stages. In addition, cancer treatments could be personalized through somatic mutational signatures, as another recent IRB Barcelona study has shown.

Genomic instability and cancer risk

Most of the mechanisms involved in the generation of mutations are related to defects in the repair of damaged DNA. This results in a phenomenon known as ‘genomic instability’, which reduces the time needed for the 2 to 10 mutations in cancer-driving genes that are typically required for tumor development to appear.

In addition, each of the identified mechanisms causes different types of mutations or does so in different areas of the genome and may therefore be related to cancer that arises in specific organs.

Artist’s rendering of cancer cells and DNA chain. (Illustration: Amazings/NCYT)

Statistical and machine learning methods

To make these predictions, the researchers developed a methodology based on statistical genomics and a machine learning model – the so-called “Autoencoder” neural network – with the ability to find patterns in complex data. The study analyzed 11,000 genome sequences from cancer patients of European descent.

One of the limitations of the study is the great variability of hereditary factors related to somatic mutations and the relatively low prevalence of each of these factors separately. The number of available genomic sequences limits the ability to detect links between genes and mutations. Access to larger numbers of genomic data from cancer patients of non-European descent could lead to new findings.

“As more genetic data becomes available, it is likely that other genetic factors will be found that predispose to cancer mutagenesis. As for the ‘rare’ genetic variants we have considered here, although each of Although they are present in only a few individuals, they are, taken together, quite important in shaping cancer genomes and possibly in cancer risk,” concludes Dr. Ben Lehner.

The study is titled “The impact of rare germline variants on human somatic mutation processes”. And it has been published in the academic journal Nature Communications. The investigation received funding from the insurance company AXA and other entities. (Source: IRB Barcelona)