09:05pm Tuesday 19 September 2017

New collaboration targets rare, deadly malignancy

Now Valentin Dinu, a researcher at Arizona State University and specialist in bioinformatics and Joshua LaBaer, two members of the Virginia G. Piper Center for Personalized Diagnostics at the Biodesign Institute have teamed up with Pooja Hingorani, an oncology/hematology physician at Phoenix Children’s Hospital, to explore the underpinnings of DSRCT with unprecedented precision. Their insights will hopefully pave the way for the design of novel therapeutic agents to treat this deadly disease.

The new project is funded by a 3 year, $250K grant from Hyundai Hope on Wheels a non-profit organization, committed to the fight against pediatric cancer. Since its inception in 1998, Hyundai Hope on Wheels has donated $48 million to fund pediatric cancer research nationwide.

The lion’s share of the new award will be used to conduct next generation sequencing of the genomes derived from DSRCT pediatric tumor samples and to perform bioinformatic analyses of the resulting data.  

“We are very grateful to the Hyunday Hope on Wheels organization for financially supporting this research project,” Dinu says. “We look forward to working closely with our collaborators from Phoenix Children’s Hospital and the Biodesign Institute to study the biology of DSRCT by applying some of the most advanced genomics sequencing and informatics techniques.  Our ultimate goal is to develop improved diagnostic and treatment options for this devastating malignancy that affects young adolescents.”  

The Department of Biomedical Informatics (BMI) at ASU is engaged in a number of significant area partnerships, uniting academic researchers, clinical practitioners and regional health care providers. The department recently moved to its new home on the Scottsdale campus of Mayo Clinic as part of the university’s deepening ties with Mayo in health care, medical research and education. Here, Dinu will carry out the informatics and data analysis work. 

LaBaer will perform the genomic sequencing at the Center for Personalized Diagnostics at Biodesign, an institute devoted to developing new diagnostic tools to pinpoint the molecular manifestations of disease based on individual patient profiles. 

Using their combined expertise, the researchers hope to open a new window onto the particular genomic aberrations linked with DSRCT. “We are very excited about the opportunity to study the underlying genomics of this difficult disease that affects children,” LaBaer says. “The power of these new genome scale sequencing methods will fundamentally alter our understanding of how these cancers begin and how they change over time.”

Desmoplastic small-round-cell tumor is an aggressive, soft tissue sarcoma, typically causing the formation of masses in the abdomen, though affected areas may also include bone, soft tissue, lung, ovary, kidney and central nervous system. The cell origin for the disease is still unknown though it is believed to arise from the mesenchyme. 

The malignancy may metastasize from its original site to the liver, lungs, lymph nodes, brain, skull, and bones. DSRCT is 4 times as likely to occur in males and its occurrence in females may be mistaken for ovarian cancer. The incidence of DSRCT is also higher in African-Americans than Caucasians. 

The researchers explain that the rareness of the disease has thus far precluded comprehensive studies of DSRCT biology, hence a lack of clinically relevant targets on which to base an effective therapy. The goal of the proposed study is to identify novel genetic aberrations in DSRCTs through the use of next generation genomic sequencing (NGS) technology. 

Since the first successful draft of the human genome was released in 2000, the race has been on to find cheaper and more rapid techniques. The new armament of technologies involves strategies to parallelize the sequencing process, enabling researchers to concurrently sequence hundreds of millions of genomic fragments at a time, generating tens of billions of base reads per experiment.

NGS will allow Dinu and LaBaer to mine vital information from the genomes derived from DSRCT-positive samples, revealing copy number changes, allelic aberrations, somatic rearrangements and base pair mutations, producing an enormous quantity of genomic sequence data. Costs associated with whole genome sequencing have recently plummeted, permitting the design and execution of studies capable of rapidly pinpointing potential disease-associated genetic variants. The technique has been used successfully to identify genetic abberations in such diseases as pancreatic cancers, glioblastoma multiforme, lung cancer, ovarian cancer and breast cancer.

Dinu and LaBaer insist the time is ripe to apply such methods to less common (yet lethal) forms of cancer, including DSRCT in order to uncover therapeutic candidates and improve the chances for patients stricken with such diseases. The team will perform whole genome DNA and RNA sequencing on tumor samples and their corresponding matched normal samples, in order to identify novel mutations, single nucleotide polymorphisms or other genomic aberrations associated with these tumors. 

The researchers stress that while the sample size used for the current project is small, the enormous volume of genomic data acquired should allow a positive identification of variants implicated in the disease. A collection of these variants – identified in DSRCT samples but absent in normal tissue – will act as biomarkers for the disease and may be applied for earlier and more accurate diagnostic purposes, as well as to provide plausible targets for future treatment. The group’s results will be cross-checked and validated using additional testing methods, such as Sanger sequencing or quantitative PCR. 

Valentin Dinu is assistant professor in the Department of Biomedical Informatics at ASU and faculty member of the Virginia G. Piper Center for Personalized Diagnostics at ASU’s Biodesign Institute. 

Joshua LaBaer directs the Virginia G. Piper Center for Personalized Diagnostics at ASU’s Biodesign Institute and is a professor in the School of Liberal Arts and Sciences, Chemistry and Biochemistry

Richard Harth, Richard.Harth@asu.edu
The Biodesign Institute

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