Discovery could pave way to new treatment for rare jaw tumor

May 26, 2014 by Patricia Waldron, Stanford University Medical Center
Discovery could pave way to new treatment for rare jaw tumor
(From left) Researchers Robert West, Andrew McClary, Robert Sweeney and Jonathan Pollack and their colleagues found two genes that are linked with a majority of cases of a rare type of jaw tumor.

(Medical Xpress)—Researchers at the Stanford University School of Medicine have identified the mutations underlying a rare, understudied type of jaw tumor called ameloblastoma.

In a paper published online May 25 in Nature Genetics, the researchers identify mutations in two genes that are associated with 80 percent of ameloblastoma cases. The Food and Drug Administration has already approved drugs for other cancers caused by these mutations. Now, the paper's authors are pursuing funding for a pilot study to use one of these drugs to treat ameloblastoma.

Doctors diagnose about 300 to 600 cases of ameloblastoma in the United States each year. Neither drugs nor radiation have been successful at eradicating the cancer, leaving surgery as the only option. Though the tumors are considered benign, surgeons must cut away large margins around the growths to try to ensure that it will not reoccur. Because the operation removes a portion of the jaw as well as arteries and facial nerves, the patients require extensive reconstructive surgeries and rehabilitation to regain the ability to smile and chew.

"They require quite a disfiguring surgery to treat," said Andrew McClary, MD, chief pathology resident at Stanford Hospital & Clinics. Patients often lose a large section of their jaw, he said. McClary shares lead authorship of the paper with postdoctoral scholars Robert Sweeney, MD, and Benjamin Myers, PhD, and with research assistant Jewison Biscocho.

The quest to find underlying mutations

McClary first became interested in this rare disease when he examined a slide from a patient's tumor. He often uses a mnemonic trick to remember a disease by associating its name with the gene mutations that cause it. But he found that ameloblastomas had no known gene abnormalities.

To find the underlying mutations causing these tumors, McClary worked with colleagues at the University of British Columbia in Vancouver, the Cleveland Clinic in Ohio and the Oregon Health Sciences University in Portland to collect tumor samples. Because the disease is so rare, they only had older bits of tissue that had been preserved for microscopy work, not genetic studies.

Fortunately, the researchers still were able to sequence the mRNA—copies of genes that tell the cell how to make specific proteins—even when the mRNA was old and degraded. The researchers then embarked on what McClary called a "fishing expedition" to find the mRNAs with the mutations that caused the tumors.

By sequencing all the mRNAs in two ameloblastoma samples, they identified two genes that carried mutations involved in growth and development, called SMO and BRAF. They then sequenced these genes in additional tissue samples to confirm their presence in other ameloblastomas. SMO mutations were most often found in the upper jaw, while BRAF mutations occurred predominantly in the lower jaw.

"These genes are essential for delivering signals of growth and development, particularly in developing organs," said Robert West, MD, PhD, associate professor of pathology at Stanford and a senior author of the study. "But it's increasingly apparent that they are often mutated in cancers."

Possible therapies

Perhaps most promising, researchers found that there are already FDA-approved drugs for cancers with mutations in the same developmental pathway. A drug called vemurafenib is toxic to ameloblastoma cell cultures that harbor a BRAF mutation, they found. This drug is effective against melanomas that carry the same mutant gene. Researchers also found that a compound called arsenic trioxide, an approved anti-leukemia drug, is effective at blocking the mutant SMO protein.

In April, West and McClary began collaborating with Dimitrios Colevas, MD, associate professor of oncology at Stanford, to plan a small to assess whether vemurafenib can shrink ameloblastoma tumors that have a BRAF mutation.

In future work, the researchers plan to conduct more fishing expeditions to look for these mutations in other types of tumors, cysts and lesions in the jaw.

"These are findings you can hang your hat on," said West. "It really opens up a number of different avenues of research where we can confidently go forward and make a lot of molecular inroads into a set of tumors and lesions in the mouth that previously we haven't known much about, or been able to do much but excise them."

The work also has implications for future studies of tooth development. If these specific genes cause unbridled growth when they accumulate , then they likely play an important role in the formation of teeth in the embryo, the researchers say.

Reaching out to patients

Throughout this project, McClary has engaged with an ameloblastoma Facebook group to hear members' stories and to learn what a patient goes through during the initial surgery and subsequent facial reconstruction. He plans to conduct a webinar with the group, and can't wait to share his findings with them.

"It's a great motivator," he said about his involvement with the group. "Our face is a special place. I couldn't imagine not smiling."

Explore further: Finnish team of researchers finds a mutation in a tumor of the jaw

More information: Paper:

Related Stories

Finnish team of researchers finds a mutation in a tumor of the jaw

April 24, 2014
A Finnish team of researchers was the first in the world to discover a gene mutation in ameloblastoma, which is a tumour of the jaw.

Study finds targetable mutation in rare brain tumor

January 12, 2014
A team led by investigators from Massachusetts General Hospital (MGH), Brigham and Women's Hospital (BWH) and the Broad Institute has found that a gene mutation associated with several types of cancer also may be responsible ...

Recurrent but rare mutations might underlie cancer growth

February 26, 2014
A potential new gene mutation that might drive lung cancer development and growth has been identified by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard ...

Studies identify cell-signaling pathway alterations responsible for melanoma drug resistance

November 22, 2013
Genomic profiling of treatment-resistant, BRAF-mutated melanomas revealed multiple gene alterations, mostly involving a cell-signaling pathway called the MAPK pathway, and more potent forms of existing drugs and drugs targeting ...

New molecular targets identified in some hard-to-treat melanomas

December 17, 2013
Two novel BRAF fusions were identified in melanomas previously considered to be negative for molecular targets, and melanomas with these fusions were found to be potentially sensitive to anticancer drugs called MEK inhibitors, ...

Scientists identify genetic blueprint for cancerous tumors of the appendix

May 12, 2014
Using next generation DNA sequencing, Dartmouth scientists have identified potentially actionable mutations in cancers of the appendix. Their study, "Molecular Profiling of Appendiceal Epithelial Tumors Using Massively Parallel ...

Recommended for you

Epigenetics study helps focus search for autism risk factors

January 16, 2018
Scientists have long tried to pin down the causes of autism spectrum disorder. Recent studies have expanded the search for genetic links from identifying genes toward epigenetics, the study of factors that control gene expression ...

Group recreates DNA of man who died in 1827 despite having no body to work with

January 16, 2018
An international team of researchers led by a group with deCODE Genetics, a biopharmaceutical company in Iceland, has partly recreated the DNA of a man who died in 1827, despite having no body to take tissue samples from. ...

Study advances gene therapy for glaucoma

January 16, 2018
While testing genes to treat glaucoma by reducing pressure inside the eye, University of Wisconsin-Madison scientists stumbled onto a problem: They had trouble getting efficient gene delivery to the cells that act like drains ...

The surprising role of gene architecture in cell fate decisions

January 16, 2018
Scientists read the code of life—the genome—as a sequence of letters, but now researchers have also started exploring its three-dimensional organisation. In a paper published in Nature Genetics, an interdisciplinary research ...

How incurable mitochondrial diseases strike previously unaffected families

January 15, 2018
Researchers have shown for the first time how children can inherit a severe - potentially fatal - mitochondrial disease from a healthy mother. The study, led by researchers from the MRC Mitochondrial Biology Unit at the University ...

Genes that aid spinal cord healing in lamprey also present in humans

January 15, 2018
Many of the genes involved in natural repair of the injured spinal cord of the lamprey are also active in the repair of the peripheral nervous system in mammals, according to a study by a collaborative group of scientists ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.