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Nature – Genome studies unlock childhood-cancer clues

Nature – Genome studies unlock childhood-cancer clues

Researchers have combed through the genomes of more than 1,700 tumours, representing more than 20 different kinds of childhood cancer, to unearth potential drug targets and a better understanding of how cancer arises in the youngest patients.

 

The work, published by two teams on 28 February in Nature1,2, is part of a growing movement to harness genomics against childhood cancers. Around the world, researchers are banding together to share genomics data, techniques and cell lines that can be used to study these diseases.

 

The efforts are generating a long list of genetic alterations that might be important in triggering cancer. But it will take considerable work to determine which of these genetic clues are pointing to the best drug targets. “It’s not just a matter of picking through genomics data,” says Susan Weiner, founder of the Children’s Cause for Cancer Advocacy in Washington DC. “There’s also the question of the validity of the targets.”

 

“In children we see cancers sometimes before babies are born.”

In some ways, this job is easier to do for paediatric cancers than for adult cancers: childhood tumours tend to have accumulated fewer mutations, making it easier to distinguish the genetic changes that actually drive tumour growth.

 

But paediatric cancers tend to be rare, which means there are fewer patients to enrol in clinical trials, fewer tumours to sequence and fewer pharmaceutical companies interested in creating drugs for a comparatively small market. “We are playing catch-up with drugs in development in adults,” says Weiner.

Collaborating against cancer

To boost their ability to pick out important genetic mutations, two groups of researchers combined their data across many different tumours. One team, led by scientists at the German Cancer Research Center in Heidelberg, Germany, studied 961 tumours representing 24 different types of cancer1. The other, led by computational biologist Jinghui Zhang of St Jude Children’s Research Hospital in Memphis, Tennessee, analysed 1,699 tumours across 6 forms of cancer2. The samples included blood cancers, such as leukaemias, and solid tumours, such as those found in the brain and bones.

 

Each study identified more than 140 genes that might help drive tumour growth. Only 45% of the genes identified by the St Jude analysis matched potential cancer drivers found in analyses of adult tumours. The other study estimated that about half of its hits could be useful drug targets.

 

A surprising number of childhood tumours showed signs of a possible defect in DNA repair, similar to the effects seen in adult cancers with mutations in the genes BRCA1 and BRCA2. In adults, such cancers are increasingly being treated with a class of drugs called PARP inhibitors, which target cells with abnormal DNA repair. The latest studies suggest that these drugs might also work for some children.

 

The findings could lead to tests for detecting other genes important in childhood cancer, which researchers could then use to select appropriate treatments. At present, these tests often screen for mutations found in adult cancers, and so might not include mutations particular to childhood tumours. “There’s no gene panel that was developed specifically for paediatric cancers,” says Zhang.

Future targets

But it is still a long road from identifying mutations to developing effective drugs.

 

On 20 February, hundreds of researchers, advocates and regulators met in Washington DC to discuss how to home in on the most promising targets. The meeting, organized by the Friends of Cancer Research, a think tank and lobbying group in the city, was spurred by a law enacted in 2017 that gives the US Food and Drug Administration the power to require drug manufacturers to test some new cancer drugs in children — even if the treatments had been developed to tackle adult cancers. But to do so, the experimental drug in question must have a molecular target deemed to be of “significant relevance” to childhood cancers.

 

Determining the meaning of that phrase could be tricky, says Katherine Janeway, a paediatric oncologist at the Dana-Farber Cancer Institute in Boston, Massachusetts. “There is a huge amount that we don’t know about what molecular targets are relevant in children with cancer,” she says.

 

But building up a solid foundation in genomics is a helpful start, says Scott Armstrong, a paediatric oncologist also at Dana-Farber. And multiple labs are trying to learn how such mutations could contribute to cancer. One large-scale project at the Broad Institute of MIT and Harvard in Cambridge, Massachusetts, for example, is using genome-editing tools to systematically study gene function in paediatric cancer cells.

 

“Those screens are going to be very informative, but they’re not going to be the end of the story,” Armstrong says. “They’re going to be more the beginning of understanding what’s going on.”

 

https://www.nature.com/articles/d41586-018-02359-6