Young and ill: role of genetics in cancer  Heredity research in AYAs may identify cause

19 November 2024

It is rare for people to develop cancer before the age of forty. However, this makes scientific research into this group of individuals challenging, explain genetic researcher Richarda de Voer and internist-oncologist Suzanne Kaal from Radboud university medical center. 'We find common ground in the quest for the best care for young adults with cancer.' 

Every year, about 4,000 young adults aged 18 to 39 are diagnosed with cancer. They are referred to as AYAs—adolescents and young adults—and constitute a rare group. For comparison, in 2023, over 128,000 people in the Netherlands were diagnosed with cancer. 

Despite their rarity, there is enormous diversity among AYAs, says Suzanne Kaal. She is an internist-oncologist at Radboudumc, specializing in sarcomas, which are cancers of soft tissues or bones. Bone sarcomas are more common in AYAs. 'Among young AYAs, we still see a remnant of tumors that often occur in childhood, such as brain tumors and leukemia. After that, you see specific AYA cancers like testicular cancer, thyroid cancer, and melanomas. From age thirty onward, we see more AYAs with breast or colorectal cancer.' 

It is well known that an unhealthy lifestyle increases the risk of cancer, but AYAs are still too young for this to be a significant factor. So, what causes cancer in young adults? 'If only we knew,' sighs Kaal. 'This is one of the major research questions we have. It seems that chance plays an important role.'  

Internist oncologist Suzanne Kaal.

Genetic Research 

Some AYAs undergo genetic testing, which may reveal a genetic predisposition. Richarda de Voer is one of the molecular geneticists involved in these analyses. 'Not all AYAs are genetically tested. We suspect that about 10 to 20 percent of AYAs have a hereditary predisposition, but we don’t know the exact percentage.' 

Not yet, because De Voer is currently researching this. Within the Dutch Cancer Society (KWF)-funded GERMAYA project, she collects tissue samples from all individuals aged 18 to 30 who developed cancer. She examines how often a hereditary component is present for each type of cancer. Earlier research by De Voer showed that about 60 percent of AYAs under 25 with colorectal cancer have a genetic tumor risk syndrome. 'The percentage may not be as high for all types of cancer, but we want to map it out in terms of treatment and subsequent care.' 

Family Members 

This is also important for patients, explains De Voer. Individuals with a hereditary predisposition are at higher risk for new tumors. 'If we know someone has a genetic tumor risk syndrome, we may be able to detect new tumors earlier or even prevent them. We also learn more about the appropriate treatment for that patient. Lastly, we can test close family members. If they also have that hereditary predisposition, we can monitor them, so we can detect, treat, or even prevent potential cancers earlier.' This might involve preventive measures like the removal of breasts or ovaries. 

300 Involved Genes

In cases where there is suspicion of a hereditary predisposition, genetic testing can be conducted. This involves examining the DNA from white blood cells to see if there is a genetic predisposition to develop cancer. Richarda de Voer states, 'We currently know about 300 genes involved for all cancers. For someone with breast cancer, we look for changes in the BRCA1 gene, as we know it increases the risk of cancer.' 

Sometimes, geneticists find no cause in the initial analysis but suspect that heredity may still play a role. In such cases, they investigate all genes in the DNA. 'We do this for individuals who have developed different types of cancer. There may still be a genetic tumor risk syndrome at play. We want to know, as this hereditary condition can also increase cancer risk in family members.' 

But what if this analysis also yields no leads? It could be due to chance, or we may still not know what is going on. Developments in genetics are ongoing, according to De Voer. The standard research method, whole exome sequencing, maps out the genes that code for proteins, excluding the DNA in between. However, the number of tests using a newer technique, long read whole genome sequencing, is increasing. This method accurately maps the entire DNA. Currently, it is not yet standard for patients but is used only in research settings. 'If we can apply this technique more broadly, I believe we can provide more patients with the correct diagnosis, as the understanding of hereditary material becomes more complete.' 

Bloom Syndrome: Exceptionally uncommon

There’s rare, and then there’s very rare. Bloom syndrome falls into the latter category. Individuals with this diagnosis have changes in the BLM gene, which prevents their DNA from being repaired properly. These patients have an 80 percent chance of developing cancer before the age of forty, with an average life expectancy of just 36 years. Richarda de Voer is particularly interested in this condition because chemotherapy and radiation may increase the risk of new tumors. 'If we better understand what goes wrong in the DNA, we can seek a much more targeted treatment, such as immunotherapy. Moreover, we might be able to apply this diagnostics and research to other rare forms of cancer.'

Researcher Richarda de Voer.

Nijmegen: The Cradle of AYA Clinics

For all AYAs, whether or not they have a genetic predisposition, a diagnosis has a tremendous impact. Young adults face different issues than older patients. Suzanne Kaal notes, 'Think about questions regarding work, family, mortgage, sexuality, and fertility. These also deserve attention, alongside the medical treatment.' This is why, in 2009, she started the AYA outpatient clinic, alongside Winette van der Graaf, who now works at the Antoni van Leeuwenhoek Hospital. 'It was truly pioneering.' 

Today, AYA clinics can be found throughout the Netherlands. This allows AYAs to receive care and support tailored to their life stage. Kaal adds, 'But we also conduct research. We look very specifically at quality of life, based on work, lifestyle, and late effects. Many patients ask at diagnosis, 'What can I do myself?' This often leads to discussions about nutrition and exercise. We know how important a healthy lifestyle is during and after treatment. We also receive many questions about work. Our clinical occupational physician, Desiree Dona, investigates if and how people can continue working during treatment and how they experience it.' 

This supportive care enhances quality of life, even after treatment. 'If someone stays active during illness and we can prevent weight gain, we achieve significant benefits in terms of quality of life and also a lower risk of cardiovascular diseases. That’s why AYAs who have undergone intensive pre-treatment with chemotherapy and/or radiation are referred to the AYA-LATER clinic, focussed on Long-Term Effects. With this care, we can provide patient-centered advice and investigate whether this leads to health benefits.'

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