Altered genes that increase cancer risk

The results of a recent study reveal the type of cancer susceptibility genes and suggest additional mechanisms of action to those already known.

About a hundred so-called cancer susceptibility genes (CPGs) are known. Those who have inherited certain altered variants of one of these genes are more likely to develop cancer. “But these hundreds of genes explain only 10% of cancers. The vast majority of other cases may be due to mutations that we don’t know about,” explains Solip Park, head of the computational cancer genomics group at the National Center for Cancer Research (CNIO) in Spain. The discovery of these other altered variants helps in early detection and development of treatments that counteract their effect.

To find them, Park, Seulki Song of the CNIO and their colleagues narrowed the search to a group with an easily identifiable genetic profile: people who carry genes whose changes lead to an inherited disease. These are monogenic diseases (caused by a change in a single gene), such as muscular dystrophy or Gaucher disease, in which fat accumulates in different cells.

Park, Song and their colleagues from several institutions in Seoul, South Korea, identified 103 genes in which changes that cause monogenetic diseases often coexist with other changes that predispose to cancer.

The study found that people with inherited monogenetic mutations in these 103 genes also had more cancer-linked mutations than controls (a group of healthy people). Some of these mutations are associated with specific types of cancer, such as renal cell carcinoma, B-cell non-Hodgkin lymphoma, breast adenocarcinoma, and medulloblastoma; others with a tendency toward cancer in general.

Thus, the study authors concluded that these 103 genes, whose mutations can cause Mendelian diseases, may also behave as cancer susceptibility genes, according to Park.

Solip Park. (Photo: Laura M. Lombardia. CNIO)

In their study, the study authors also analyzed how defective variants of these genes contribute to tumor progression and cause other diseases. Based on the data collected, various mechanisms of action are involved, for example, disturbances in cellular metabolism or immune response. Some mechanisms have not yet been examined in cancer, so the study authors emphasize the need to study them in more depth.

They analyzed the PAH gene in more detail (known for the fact that some of its mutations cause the rare hereditary disease phenylketonuria, which impedes the absorption of proteins and aspartame). They selected it because it had the largest number of variants that can cause different types of cancer, and found an association with squamous cell lung cancer, liver tumors, and other diseases and delays. in growth.

“Our study shows for the first time how genes associated with a number of inherited monogenic diseases can increase the risk of developing cancer. Likewise, it reveals the mechanisms of tumor formation caused by new and previously unknown cancer susceptibility genes,” says Solip Park.

The study authors note the need to continue studying the role of these 103 genes in cancer development, the clinical significance of which has so far been limited to other inherited diseases. In particular, the association of each variant with different types of cancer remains to be clarified.

However, based on the results, it would be beneficial for people with the changes causing the monogenic diseases being studied to participate in already existing cancer prevention programs.

The study is titled, “Systematic analysis of gene variants associated with Mendelian diseases identifies new classes of cancer susceptibility genes.” And it was published in the academic journal Genome Medicine. (Source: CNIO)