Cancer Study Reveals Insights to Causes and Inherited Risk

In a largest-to-date genomics study of brain cancer, researchers have uncovered treasure trove of information about genetics underlying the most common form of brain cancer – glioma. They were able to identify mutations that increase susceptibility, and assess more specific associations with developing one or the other of the two main glioma subtypes.

Scientists at The Institute of Cancer Research, London (UK), along with colleagues in Europe and the US, led the international study of over 30,000 people to search for inherited mutations that increase risk. They carried out 2 new genome-wide studies and combined the results with 6 previous studies in a meta-analysis – involving in total 12,496 people with glioma and 18,190 without. The large cohort enabled them to detect 13 previously undiscovered genetic changes that increased risk of glioma. These were found to affect a variety of cell functions, including nerve cell division, DNA repair, cell cycle control, protein production, and inflammation.

One of the 13 mutations increases risk by as much as 1/3 and the others by at least 15% each, suggesting that they could be used as markers in a screening panel to identify people at substantially increased risk of developing the disease. Gliomas account for around 40% of all brain tumors but there is currently no reliable way of detecting the disease early and current treatments are not very effective. The study could lead to enabling doctors to monitor those most at risk and diagnose the disease earlier.

The team also found that different sets of genes influence a person’s risk of developing the two subtypes of glioma – glioblastoma (particularly aggressive type with an average survival of 10–15 months after diagnosis) and non-glioblastoma tumors. For example, a mutation in the gene HEATR3 increases the risk of glioblastoma by 18%, but has a much lower effect on risk of developing non-glioblastoma.

In addition to new mutations, the team generated stronger evidence for roles of mutations they had previously identified as being associated with glioma and other cancers – including p53, EGFR, and the genes TERT and RTEL1 which function to protect the ends of chromosomes. This brought to 26 the total number of genetic mutations they associated with glioma risk.

Study co-leader Prof. Richard Houlston of ICR said: “It’s been exciting to have been involved in such a gigantic study including cases of brain cancer from all over the world. We’ve uncovered a treasure trove of new information about the genetic causes of glioma brain cancers.” This “allows us to start thinking about ways of identifying people at high inherited risk, and will open up a search for new treatments that exploit our new knowledge of the biology of the disease,” he said, “The changes in the way we think about glioma could be quite fundamental. So for example, what we thought of as two related sub-types of the disease turn out to have quite different genetic causes which may require different approaches to treatment.”

Prof. Paul Workman, chief executive of ICR, said: “The genetics of glioma had been poorly understood, but this huge and excellent new study at a stroke gives us the same kind of knowledge of the disease as we have with other, more intensely studied cancers.”

The study, by Melin BS et al, was published March 27, 2017, in the journal Nature Genetics.