TGen-led Study Discovers Genetic Cause of a Rare Type of Ovarian Cancer

TGen-led study discovers genetic cause of a rare type of ovarian cancer. Scientific breakthrough could lead to new cancer treatments; study inspired by the memory of Taryn Ritchey, a 22-year-old patient who lost her battle to the disease.

The cause of a rare type of ovarian cancer that most often strikes girls and young women has been uncovered by an international research team led by the Translational Genomics Research Institute (TGen), according to a study published online recently by the renowned scientific journal, Nature Genetics. [1] In a scientific rarity, two additional studies with similar results were also published online on the same day in Nature Genetics, producing immediate validation and reflecting a scientific consensus that usually takes months or even years to accomplish. [2-3]

By applying its groundbreaking work in genomics, TGen led a study that included: Scottsdale Healthcare, Mayo Clinic, Johns Hopkins University, St. Joseph’s Hospital and Medical Center; Evergreen Hematology and Oncology, Children’s Hospital of Alabama, the Autonomous University of Barcelona, British Columbia Cancer Agency, University of British Columbia, and the University Health Network-Toronto.

The findings revealed a “genetic superhighway” mutation in a gene found in the overwhelming majority of patients with small cell carcinoma of the ovary, hypercalcemic type, also known as “SCCOHT.” This rare type of ovarian cancer is usually not diagnosed until it is in its advanced stages. It does not respond to standard chemotherapy, and 65 percent of patients with the disease die within 2 years. SCCOHT can affect girls as young as 14 months, and women as old as 58 years – with a mean age of only 24 years old. In this study, the youngest patient was 9 years old.

The three separate groups of international researchers reported strikingly similar scientific findings related to SCCOHT, as provided below.

  • Identification of germline (i.e., inherited) and somatic (lifetime acquired) inactivating mutations in the SWI/SNF chromatin-remodeling gene SMARCA4 in 75% (9/12) of SCCOHT cases, in addition to SMARCA4 protein loss in 82% (14/17) of the SCCOHT tumors. Notably, only 0.4% (2/485) of the other primary ovarian tumors tested possessed similar genomic characteristics. [Ref. 1]
  • Identification of recurrent inactivating mutations in the SMARCA4 gene in 12 of 12 SCCOHT tumor samples. [Ref. 2]
  • Indentification of germline inactivating mutations in familial cases of SCCOHT. Through additional analysis of non-familial tumors, the researchers determined that nearly 100% of tumors carry SMARCA4 mutations, and 38 of 40 lack protein expression.[Ref. 3]

Collectively, these findings implicate inactivating mutations in the SMARCA4 gene as a major cause of SCCOHT, and may lead researchers to improvements in genetic counseling, as well as the development of new targeted therapy treatment approaches.

Dr. Jeffrey Trent, President and Research Director of TGen, is the study's senior author.

Dr. Jeffrey Trent, President and Research Director of TGen, is the study’s senior author.

“This is a thoroughly remarkable study. Many genetic anomalies can be like a one-lane road to cancer; difficult to negotiate. But these findings indicate a genetic superhighway that leads right to this highly aggressive disease,” said Dr. Jeffrey Trent, President and Research Director of TGen, and the study’s senior author. “The correlation between mutations in SMARCA4 and the development of SCCOHT is simply unmistakable.”

Dr. Trent added that while the breakthrough is for a relatively rare cancer, discovering the origins of this type of ovarian cancer could have implications for more common diseases.

Much of the work in this study was inspired by the memory of Taryn Ritchey, a 22-year-old TGen patient who in 2007 lost her battle with ovarian cancer, the 5th leading cause of cancer death among American women.

“Taryn would be incredibly excited about this amazing new study, and she would be glad and thankful that other young women like her might now be helped because of TGen’s ongoing research,” said Taryn’s mother Judy Jost of Cave Creek, Arizona. “My daughter never gave up, and neither has TGen.”

The SMARCA4 gene – previously associated with lung, brain and pancreatic cancer – was the only recurrently mutated gene in the study’s samples. The implications of this discovery, therefore, may be widespread.

“The findings in this study represent a landmark in the field. The work identifies SMARCA4 mutations as the culprit, and most future research on this disease will be based on this remarkable discovery,” said Dr. Bert Vogelstein, Director of the Ludwig Center at Johns Hopkins University, Investigator at the Howard Hughes Medical Institute, and pioneer in the field of cancer genomics. He did not participate in the study but is familiar with its findings.

“The past decade of research has taught us that cancer is a vastly complex disease. Profound patient-to-patient variability has made treatment and diagnosis for many tumor types at times very difficult. In this case, however, we have found a single genetic event driving SCCOHT in nearly every patient,” said Dr. William Hendricks, a TGen Staff Scientist and another author of the study.

“We have shown that loss of SMARCA4 protein expression is extremely specific to SCCOHT and can facilitate the diagnosis of SCCOHT,” said Dr. Anthony N. Karnezis, a fellow at the British Columbia Cancer Agency located in Vancouver, Canada, and one of the study’s authors.

Pilar Ramos, a TGen Research Associate, is the study's lead author.

Pilar Ramos, a TGen Research Associate, is the study’s lead author. “By definitively identifying the relationship between SMARCA4 and SCCOHT, we have high confidence that we have set the stage for clinical trials that could provide patients with immediate benefit.”

“By definitively identifying the relationship between SMARCA4 and SCCOHT, we have high confidence that we have set the stage for clinical trials that could provide patients with immediate benefit.”

“We set out to uncover any small sliver of hope for women afflicted with this rare cancer. What we found instead are the nearly universal underpinnings of SCCOHT,” said Pilar Ramos, a TGen Research Associate, and the study’s lead author. “By definitively identifying the relationship between SMARCA4 and SCCOHT, we have high confidence that we have set the stage for clinical trials that could provide patients with immediate benefit.”

The TGen-led study was supported by grants from: the Marsha Rivkin Center for Ovarian Cancer Research, the Anne Rita Monahan Foundation, the Ovarian Cancer Alliance of Arizona, the Small Cell Ovarian Cancer Foundation, and philanthropic support to the TGen Foundation. Further support was provided by the Terry Fox Research Initiative’s New Frontiers Program in Cancer, and the Canadian Institutes of Health Research.

For more information about TGen’s research into small cell carcinoma of the ovary (SCCO), or to participate in a future study, visit: www.tgen.org/scco.

About TGen

Translational Genomics Research Institute (TGen) is a Phoenix, Arizona-based non-profit organization dedicated to conducting cutting-edge genomic research to accelerate breakthroughs in healthcare. TGen is focused on helping patients with cancer, neurological disorders and diabetes, through cutting edge translational research (the process of rapidly moving research towards patient benefit). TGen physicians and scientists work to unravel the genetic components of both common and rare complex diseases in adults and children. Working with collaborators in the scientific and medical communities literally worldwide, TGen makes a substantial contribution to help our patients through efficiency and effectiveness of the translational process. For more information, visit: www.tgen.org.

References:

1./ Ramos P, et al.  Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4. Nature Genetics (published online 23 March 2014) doi:10.1038/ng.2928.

2./ Jelinic P, et al. Recurrent SMARCA4 mutations in small cell carcinoma of the ovaryNature Genetics (published online 23 March 2014) doi:10.1038/ng.2922.

3./ Witkowski L, et al.  Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type.  Nature Genetics (published online 23 March 2014) doi:10.1038/ng.2931

Additional Information:

 

York University Researchers Identify Genetic Process That May Underlie Ovarian Cancer Chemoresistance

York University researchers have identified a genetic process that may allow ovarian cancer to resist chemotherapy.

York University researchers have zeroed in on a genetic process that may allow ovarian cancer to resist chemotherapy.

Researchers in the York University Faculty of Science & Engineering studied a tiny strand of our genetic makeup known as a microRNA (miRNA), involved in the regulation of gene expression. Cancer occurs when gene regulation goes haywire.

For many years, DNA and proteins have been viewed as the real movers and shakers in genomic studies, with RNA seen as little more than a messenger that shuttles information between the two. In fact, miRNA was considered relatively unimportant less than a decade ago; that is no longer the case. MiRNA seems to stifle the production of proteins exclusively — a function opposite that of its better-known relative, messenger RNA, or mRNA, which translates instructions from genes to create proteins.  MiRNA attaches to a piece of mRNA – which is the master template for building a protein, thereby acting as a signal to prevent translation of the mRNA into a protein. The “silencing” of proteins by miRNAs can be a good or a bad thing, depending on the circumstances.

Chun Peng, Ph.D., Professor of Biology, York University, and her team identified a genetic process involving a "microRNA" that may underlie a form of ovarian cancer chemoresistance.

“Ovarian cancer is a very deadly disease because it’s hard to detect,” says biology professor Chun Peng, who co-authored the study. “By the time it’s diagnosed, usually it is in its late stages. And by that point there’s really no way to treat the disease.” “Even when the disease is discovered in its early stages, chemotherapy doesn’t always work,” she says.

Peng was among a team of researchers that discovered a receptor, ALK7 (activin receptor-like kinase 7), that induces cell-death in epithelial ovarian cancer cells.[1] They have now discerned that miRNA 376c targets this crucial receptor, inhibiting its expression and allowing ovarian cancer cells to thrive.[2]

“Our evidence suggests that miRNA 376c is crucial to determining how a patient will respond to a chemotherapeutic agent,” says Peng. “It allows cancer cells to survive by targeting the very process that kills them off,” she says.

In examining tumors taken from patients who were non-responsive to chemotherapy, researchers found a higher expression of miRNA 376c and a much lower expression of ALK7.  Peng believes that this research is a step towards being able to make chemotherapy drugs more effective in the treatment of the disease.

“Further study is needed, but ultimately if we can introduce anti-microRNAs that would lower the level of those microRNAs that make cancer cells resistant to chemotherapeutic drugs, we will be able to make chemotherapy more effective against ovarian cancer,” Peng says.

She urges women to educate themselves about the risk factors and symptoms of the disease. For more information, visit http://www.ovariancanada.org.

Peng is a world expert in the area of ovarian cancer and the molecular basis of complications in pregnancy. Her research on chemoresistance has also contributed to knowledge and prediction of pre-eclampsia, a pregnancy disorder that is a leading cause of maternal and perinatal complications and death.

The article, MicroRNA 376c enhances ovarian cancer cell survival by targeting activin receptor-like kinase 7: implications for chemoresistance, was published in the Journal of Cell Science.[2]

The study’s lead author, Gang Ye, is a Research Associate in Peng’s lab. Several trainees in Peng’s lab, as well as scientists in Toronto’s Sunnybrook Research Institute and in China, also participated in the project.

The research was supported by an operating grant from the Canadian Institutes of Health Research (CIHR) and a mid-career award to Peng from the Ontario Women’s Health Council/CIHR. Ye was supported in part by a Fellowship from the Toronto Ovarian Cancer Research Network.

About York University

York University is the leading interdisciplinary research and teaching university in Canada. York offers a modern, academic experience at the undergraduate and graduate level in Toronto, Canada’s most international city. The third largest university in the country, York is host to a dynamic academic community of 50,000 students and 7,000 faculty and staff, as well as 200,000 alumni worldwide. York’s 10 Faculties and 28 research centres conduct ambitious, groundbreaking research that is interdisciplinary, cutting across traditional academic boundaries. This distinctive and collaborative approach is preparing students for the future and bringing fresh insights and solutions to real-world challenges. York University is an autonomous, not-for-profit corporation.

References:

1/Xu G, Zhou H, Wang Q, et. al. Activin receptor-like kinase 7 induces apoptosis through up-regulation of Bax and down-regulation of Xiap in normal and malignant ovarian epithelial cell lines. Mol Cancer Res. 2006 Apr;4(4):235-46. PubMed PMID: 16603637.

2/Ye G, Fu G, Cui S, et. al. MicroRNA 376c enhances ovarian cancer cell survival by targeting activin receptor-like kinase 7: implications for chemoresistance. J Cell Sci. 2011 Feb 1;124(Pt 3):359-68. Epub 2011 Jan 11. PubMed PMID: 21224400.

Source: York U researchers uncovering how ovarian cancer resists chemotherapy, Press Release, York University, March 2, 2011.