Garvan Breakthrough magazine - Feb 2018

Calculating cancer risk

It is always tragic when cancer is diagnosed in a young person. Now, thanks to whole genome sequencing, medical research is better able to predict an individual’s level of risk and offer management strategies

multiple genetic factors as being significant in contributing to cancer risk, as enabled by whole genome sequencing. “We’re approaching the point where we can look across all the genes and start to get a picture of the contribution of more than one variant to somebody’s risk – not only rare variants, but also the more common ones – and add all of those risks together and come up with a single risk score,” says Ballinger. Thus, the greater the number of harmful gene variants a person has, the greater their risk of developing cancer at a young age. The challenge for researchers is to pin down exactly what they are, how they work together and, ultimately, what we can do about it.

At 28 years old, Hugh* was like any other person his age and living life to the full, with a young family, burgeoning career and enjoying living abroad in Australia. He had seen the GP about a lump on the side of his tongue, who prescribed antibiotics and then antivirals to no effect. Then came the evening of Monday 10 March, 2014. With wife Alice away sitting an exam, Hugh was eating dinner with his 18-month-old son when a crust of bread caught on the lump. “It was so painful I fell to my knees,” he recalls. “I called my neighbours and asked them to care for Henry while I took myself to hospital.” By Wednesday, Hugh was undergoing a biopsy. “The doctor said, ‘Don’t worry, it’s not going to be cancer.’ ‘I thought, pfft – cancer? Are you serious?’ But then on the Monday the doctor called and said, ‘You need to come in tomorrow.’ My heart stopped. I started thinking, I’m going to die, and about Alice and Henry and I just went into tears on the phone.” Within a fortnight, Hugh was undergoing surgery to remove the tumour and nearby lymph nodes, followed by six weeks of daily radiotherapy. Though Hugh is unfortunately not alone in his experience of cancer, his relative youth places him in a minority, with the average age of cancer diagnoses in the Australian population at around 65 years. This raises the question, how and why does cancer arise in young people? “We tend to think of cancer as a disease of ageing, where genetic changes accumulate over time,” says Dr Mandy Ballinger, Group Leader – Genetic Cancer Risk in Garvan’s Cancer Division. “If you are diagnosed with cancer at a younger age, it means you have a head start, which is generally a genetic predisposition. A number of papers have shown that the younger a person is diagnosed with cancer, the greater the likelihood that there are heritable factors at play.” Certain genes are now well established in increasing cancer risk, such as variants in BRCA1 and BRCA2 and their relationship to breast and ovarian cancer, or in TP53 as the basis of Li-Fraumeni syndrome, which is associated with early-onset cancer in a number of organs. Increasingly, however, research is recognising the combined impact of

The greater the number of harmful gene variants a person has, the greater their risk of developing cancer at a young age

This is the objective of the Genetic Cancer Risk in the Young study (RiSC), which Ballinger leads, and in which Hugh is a member of the cohort. The project sequences the whole genomes of people who have been diagnosed with cancer between the ages of 16 and 40, and analyses them for known cancer-causing features. “Ultimately, we want to identify the entire set of genetic variants that affect the risk of developing cancer,” says Ballinger. Over time, the unfolding medical stories of the cohort bring a wealth of clinical information to complement the genomic, with the potential to both validate and expand our understanding of genetic cancer risk. This paves the way for better monitoring, earlier detection and, as a result, improved outcomes for patients. Among risk-management strategies, whole-body magnetic resonance imaging (MRI) is emerging as one of the most promising. In a major finding last year, Ballinger and colleagues validated this approach in Li-Fraumeni syndrome,

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