Researchers uncover complex genetic secrets of cancer risk

In a landmark multi-country study, Australian researchers have transformed our understanding of the genes that affect our risk of cancer. The researchers uncovered numerous new genetic risk factors for the bone and soft-tissue cancer, sarcoma – and, in a world first for any cancer, they showed that carrying several of these genetic mutations markedly increases an individual’s cancer risk. The findings have immediate implications for how sarcomas and other cancers are treated.

In a landmark study of over 1000 sarcoma patients, the researchers uncovered numerous new genetic risk factors for the cancer – and, in a world first for any cancer type, they showed that carrying two or more of these rare mutations increases an individual’s cancer risk.

Sarcomas are cancers of connective tissues that disproportionately affect the young. They are one of the three leading causes of disease-related death among children and young adults in Australia, and sarcoma survivors are at higher risk of developing a second cancer.

The new findings relating to cancer risk were uncovered through the International Sarcoma Kindred Study (ISKS), an Australian-led international consortium that is exploring the genetic basis of sarcoma in over 1000 individuals – the largest study ever conducted in this disease.

The ISKS team used a ‘gene panel’ of 72 genes to detect mutations in each study participant. They identified mutations in a number of new genes that significantly increase the risk of developing sarcoma, including in the genes ERCC2, ATR, BRCA2 and ATM.

Importantly, in individuals carrying mutations in two genes, the risk of developing sarcoma was measurably higher than in those with a mutation in only one gene. And in carriers of three or more mutations, the risk was greater still.

“This is the first time – in any cancer – that anyone has quantified the effect of multiple rare genetic mutations on cancer risk,” says Professor David Thomas (Head of The Kinghorn Cancer Centre and the Cancer Division of the Garvan Institute of Medical Research), who led the study.

“Until now, we’ve been limited to single-gene thinking, so we tell patients, for instance, that carrying a BRCA1 mutation means their breast cancer risk is higher, or that their risk of sarcoma and other cancers is higher if they’ve got a particular mutation in the p53 gene.

“The study shows us that the landscape of cancer risk is far more complex than that. We can now see that the risk for developing sarcoma is increased through the combined effect of multiple genes, and that the more mutations someone carries, the earlier the onset of cancer.

“These previously invisible effects are at least as large as the impact of mutations in the p53 gene itself, which is currently the strongest known genetic cause of sarcoma.”

Dr Mandy Ballinger (Garvan), who co-ordinates the ISKS globally, says the study will radically change how sarcoma risk is understood.

“It’s well accepted for a few cancers – like breast cancer and bowel cancer – that cancer risk is substantially determined by the genes we inherit from our parents. Our study brings sarcoma into that select group.

“About half the study participants carried at least one of these apparently cancer-promoting mutations, and almost a quarter carried more than one, which really underscores that sarcoma risk is inherited to a large extent from one’s parents.”

“We’ve never been able to identify these at-risk individuals, and their families, before. Now we can,” adds Prof Thomas. “That means we can manage risk better, and help those people to get the care they need, when they need it.”

Garvan Institute www.garvan.org.au/news/news/beyond-single-gene-thinking-garvan-researchers-uncover-complex-genetic-secrets-of-cancer-risk