A study by Yale researchers found two novel genetic mutations which could be responsible for causing a particularly aggressive form of ovarian and uterine cancer.

The study, led by Yale researcher Alessandro Santin  and Rockefeller University President Richard Lifton, was published online Oct. 10 in the Early Edition of the Proceedings of the National Academy of Sciences (PNAS) journal. Carcinosarcomas, a rare type of tumor that can appear in certain gynecologic cancers, display characteristics of both epithelial cancers and sarcomas. Before the study was published, carcinosarcoma tumors were known to acquire the traits of both cancer types through a process known as epithelial-mesenchymal transition, but the composition of these tumors, as well as the impetus for this transition, was a mystery until now.

“We have established unequivocally that the common genetic origin of this tumor is epithelial,” Santin said.

The team first conducted whole-exome sequencing on the genomes of 54 uterine and ovarian cancer patients to pinpoint the mutations typical for uterine and ovarian carcinosarcomas. In addition to finding known oncogenes, or previously-studied genetic culprits in cancer, the researchers found mutations in two histone core genes, which are responsible for the tightening and loosening of DNA and are unlikely to be mutated by random chance.

After consistently detecting these unexpected histone mutations and using different methods of analyzing the data, the team ran another experiment to confirm the active presence of these mutations, Santin said.

“We have been able to validate our discovery using other methods, other technology, to show that these mutations are playing a major biological role in these cells,” Santin said.

According to the study, researchers created a plasmid with the specific mutations and transfected tumor cells that had not undergone epithelial-mesenchymal transition to see if they would if they possessed the histone core gene mutations.

The transfected tumor cells appeared more metastatic and moved more quickly, typical of epithelial-mesenchymal transition cells, Santin said.

In addition to their rarity, uterine and ovarian carcinosarcomas are unique among cancers, according to Matthew Powell, the director of the Division of Gynecologic Oncology at the Washington University School of Medicine in St. Louis School.

“It’s a rather bizarre tumor in that it has traditional cell types that come from the uterus but can also make the appearance of a cancer that comes from someplace else,” Powell said.

It took a team of 47 researchers from around the globe, as well as experts in genetics, gynecologic oncology and biology, to validate the researchers’ hypothesis, Santin said.

The study took over three years to execute and analyze, according to Santin, who added that he does not believe there are any significant shortcomings in the data.

But Powell said that the study, while robust, “doesn’t tell the whole story of these cancers.”

He added that epigenetic changes, mutations outside of the genome, could play a role in epithelial-mesenchymal transition in a process called DNA methylation. In DNA methylation, specific sequences are prevented from their normal function of encoding proteins. Powell also criticized the relatively small sample size of the study. According to the study, about half of the study participants were taken from Santin’s practice at Yale New Haven Hospital.

Since traditional therapies for ovarian and uterine cancer carcinosarcomas have not been effective, the study is useful for identifying potential targets for treatment, Powell said.

Sanaz Memarzadeh, a professor and gynecologic oncologist at the University of California, Los Angeles Medical Center, said that in clinical practice, it is sometimes assumed that given the presence of two different-appearing cell types in carcinosarcomas, chemotherapy regimens targeting each specific cell type should be administered.

“By showing that the two different cell types within the tumor share genetic alterations, this study suggests that the same therapy tailored to the patient’s cancer can potentially target both cell types simultaneously,” she said.

This is the second time a team led by Santin and Lifton has studied the genetic landscape of a rare gynecologic cancer. A 2012 study published in PNAS explored mutations in uterine serous carcinoma. The team’s research is now the basis for a current clinical trial at Yale that seeks to find a more effective treatment for this uterine cancer, Santin said.

Santin said he hopes that this new research on carcinosarcomas will progress on a similar timeline, adding that he plans to validate the discoveries in vitro and in vivo before beginning a clinical trial within the next few years.

Memarzadeh stressed the importance of further experimentation to understand the mechanism of the disease and to confirm whether specific genetic mutations found in the study are driving mutations for uterine and ovarian carcinosarcomas.

“To really show that a mutation is a driver mutation, one must show that when you take a normal cell and induce these mutations, that cell can then become that cancer subtype,” she said.

Patients with carcinosarcoma have a five-year survival rate of under 30 percent.