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Sequencing IDs Causative, Druggable Genes in Infantile Myofibromatosis


An exome sequencing study evaluating nine different families affected by autosomal-dominant infantile myofibromatosis has identified two candidate disease-causing genes that may be amenable to treatment with approved drugs.

John Martignetti, associate professor of genetics and genomic sciences at Mount Sinai Hospital, said that the next steps are to do functional studies on cell lines to understand the mutations' impact as well as how the indicated drugs affect the cells.

"That will help us define the next steps, including thinking about potential therapy," he told Clinical Sequencing News.

The study was published online in the American Journal of Human Genetics last month.

Infantile myofibromatosis is an autosomal dominant, genetically heterogeneous disease with limited treatment options. The disease causes tumors to grow in the skin, muscle, and bone. These tumors are "benign in the sense that they don't metastasize," explained Martignetti, but "can be locally destructive," depending on where they grow.

For instance, if the tumors grow in the bone, they can cause damage to it as well as cause extreme pain. They can also grow in organs, and children will often present with tumors growing near the mandible that will then grow inwards toward the skull, he said.

The only way to treat the disease is through surgery. While chemotherapy has been tried in the past, it has had mixed results, so identifying a genomic alteration that drugs could effectively target could have important consequences for how the disease is treated and managed, Martignetti said.

The researchers performed exome sequencing in 32 affected individuals from nine unrelated families on the Illumina HiSeq 2000 to an average coverage of 74x.

They identified two missense variants in the gene PDGFRB in eight members of eight different families. Sanger sequencing of all family members concluded that the variants segregated with disease status. In the ninth family without PDGFRB mutations, the researchers instead identified a germline mutation that segregated by disease to the NOTCH3 gene.

The finding of the NOTCH3 mutation was somewhat surprising, said Martignetti, because the family's disease did not appear to be clinically different from the other eight families.

"It was very difficult to distinguish why the NOTCH3 family had the NOTCH3 mutation as opposed to the PDGFRB mutation," Martignetti said.

Closer evaluation of the pathway involved, however, found that the two genes act on the same pathway. Specifically, activated forms of the NOTCH3 receptor or NOTCH3 ligand induction have been shown to up-regulate PDGFRB expression, the authors found.

The PDGFRB gene is involved in a signaling pathway impacting cell proliferation, differentiation, survival, and migration. The NOTCH3 gene is also involved in signaling, and in particular, plays a role in development and determining cell fate.

"NOTCH3 can be an upstream activator of PDGFRB," said Martinetti. "So it looks like we've actually identified the cascade of signals, and these would be the first two members of that cascade."

Both mutations can also potentially be targeted with approved drugs, Martignetti said. Both Pfizer's Sutent (sunitinib) and Novartis' Gleevec (imatinib) act within the platelet derived growth factor (PDGF) pathway to inhibit cell growth.

Sutent is currently approved for the treatment of advanced kidney cancer, pancreatic neuroendocrine tumors, and gastrointestinal stromal tumors.

Gleevec is approved for certain forms of chronic myeloid leukemia and acute lymphoblastic leukemia, myelodyplastic and myeloproliferative diseases associated with PDGFR gene rearrangements, and certain gastrointestinal stromal tumors, among other indications.

"We know the two genes, the three mutations shared by the families, and now we've got to get in there and understand what those mutations do to the protein, and what do they do to the signaling pathways," Martignetti said.

The researchers have established cell lines from the patients and are trying to determine how the mutations affect the downstream signaling pathways and whether they are activating-mutations and how they activate, he said.

Additionally, the team is looking at other patients with the disease. Aside from studying patients with a familial history of the disease, Martignetti said that the team also wants to analyze patients with a de novo form to see whether the same genes are involved.

Martignetti said that a better understanding of infantile myofibromatosis could also lead to a better understanding of cancer in general. For instance, he said, understanding what happens to cause the tumors to form in the first place could shed light on cancer development. Additionally, sometimes the tumors actually regress, so understanding why that happens could point to new ways to treat other tumors.

"Once these tumors form, why do they regress? Is the cell able to regain control, or is there some kind of upstream signaling pathway and then the cells revert back to normal?" he said. "Understanding that might teach us something about regression."