Fewer mutations in kids' cancer

There are substantial differences between the adult and childhood forms of cancer, according to the first pediatric cancer genome sequence, published online Thursday by Science.

The most common type of childhood brain cancer has five- to ten-fold fewer cancer-linked mutations in the genome than adult tumors, and these differences could extend to other cancer types, the researchers report.

Brain scan of six-year-old girl with a medulloblastoma Wikimedia Commons, Reytan

"It was a surprise," said Victor Velculescu, an oncologist at the Johns Hopkins Kimmel Cancer Center and senior author on the paper. "People think cancers are all alike."

And this could be good news, he noted: The presence of fewer mutations in pediatric tumors suggests it may be easier to develop therapies to treat childhood cancer than adult cancer.

Despite the many researchers dedicated to cancer, relatively little is known about the childhood version of the disease. "Pediatric cancers, in large part, have been neglected, both in the war on cancer as well as recent cancer genetic efforts," Velculescu said.

"We understand the genetic landscape of far more adult tumors than pediatric tumors," agreed William Polkinghorn, an oncologist at the Memorial Sloan-Kettering Cancer Center, who was not involved in the research, in an email to The Scientist.

Part of that neglect is due to the difficulty of amassing samples because of the small number of pediatric cancer patients, said Polkinghorn.

But with the help of numerous hospitals contributing samples, Velculescu and his team -- who previously sequenced the genomes of adult pancreatic, brain, breast and colon cancers -- collected 22 samples of medulloblastoma, the most common type of brain tumor in children. They compared each sequence with normal DNA from the corresponding patient to identify tumor-specific mutations. On average, each tumor had 11 mutations, 5 to 10 times fewer than adult brain, breast, and colorectal tumors.

The discovery may be a benefit for designing future therapies: Fewer mutations causing uncontrolled cell growth means fewer errors to try and fix. "The hope is that there are some potentially simpler approaches [to childhood cancers] available in the future, as opposed to adult cancers which appear to be more complex," said Velculescu.

Overall, the team identified 225 mutations, including alterations in the Hedgehog and Wnt pathways, which have been previously shown to play a role in medulloblastomas. "It reinforces the idea that these cancers probably arise through a misregulation of normally occurring developmental pathways in the brain, processes that are quite different from common adult cancer," said Velculescu.

Notably, however, the two genes most commonly mutated were not previously linked to medulloblastomas: histone methyltransferase genes MLL2 and MLL3, epigenetic genes responsible for chromatin remodeling and transcriptional regulation. The researchers plan to next investigate the downstream genes that are regulated by MLL2 and MLL3 and how they might play a role in the cancer.

Some of the pathways identified could be potential targets for therapy, said Velculescu -- but, he cautioned, "more research still needs to be done."

Parsons, D.W., et al., "The Genetic Landscape of the Childhood Cancer Medulloblastoma," Science, published online 16 December 2010.


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