Research News

Pediatric hematologist-oncologist Richa Sharma, MD, is starting her new Cleveland Clinic research laboratory with a bold beginning. She and collaborators from St. Jude Children's Research Hospital have discovered a new cancer predisposition gene for childhood osteosarcoma, a rare and aggressive bone cancer. The gene, SMARCAL1, emerged from a large-scale analysis of over 20,000 individuals with and without childhood cancer. 

The Journal of Clinical Oncology (JCO) expedited publication to ensure clinicians are aware of this newly identified risk gene. 

The journal’s expedited publication also shows that Dr. Sharma’s study is remarkable not just for the gene itself, but for the boldness and novelty of her approach. Most cancer genetics studies focus on a familiar list of known cancer predisposition genes. These are genes whose inherited mutations can increase the risk of developing cancer (an example would be the BRCA1/2 genes and breast cancer). Dr. Sharma’s team asked a different question: are there answers elsewhere? 

Thinking outside the gene list 

Although cancer genetics is well-established, it is a surprisingly narrow field. Despite decades of research, only 70-115 genes are currently recognized as cancer predisposition genes.  

Fewer than 20% of children with cancer have mutations in known cancer predisposition genes, but 40-80% of pediatric cases have family histories and other signs that suggest a genetic component. This means that there are genes that predispose to cancer that remain undiscovered.  

Identifying new cancer predisposition genes is a time and labor-intensive process. It requires expertise in data analysis and access to large databases. Dr. Sharma explains that these barriers widen the gap between what we currently know about cancer genetics and what we see in patients.  

To close this gap, Dr. Sharma and her team focused on DNA repair genes. These genes tell our cells to make proteins that protect and repair DNA. Many DNA repair genes are already implicated in many of the known cancer predisposition syndromes. 

“There are at least six main DNA repair pathways with over 200 genes,” Dr. Sharma explains. “DNA repair pathways can be looked at as tumor suppressor pathways, so it makes sense that cancers would mutate these protective measures set up by the cell to gain growth advantage. However, not many have comprehensively looked at whether children are born with mutations in these DNA repair pathways, which may increase the risk for a child having cancer."

Detecting rare but meaningful signals on the path to SMARCAL1 

Dr. Sharma’s team used what they call a “disease-agnostic, biology-first approach” to analyze the presence of mutations in DNA repair genes from over 20,000 individuals with and without cancer. Dr. Sharma began this work while she was working at St. Jude Children’s Research Hospital, alongside Kim Nichols, MD, Ninad Oak, PhD, and Wenan Chen, PhD. St. Jude has one of the most comprehensive pediatric cancer sequencing datasets in the world. 

“Casting a wide net to identify new DNA repair genes that predispose to pediatric cancers, rather than focusing on a single gene or cancer, lets the biology guide the investigation and keeps us from being constrained by a specific diagnosis or gene,” Dr. Sharma says. “In our study, we identified several known and new genes associated with cancers. The gene that had the highest signal in our cohort along with other cohorts was linked to osteosarcoma.” 

Unlike other studies, which sometimes rely on pre-analyzed datasets for individuals without cancer, Dr. Chen and others on the team analyzed all data using the same pipeline, which Dr. Sharma describes as a “herculean task.” This consistency gave the team an edge in detecting rare but meaningful signals. 

The team's strategy led them to SMARCAL1, a gene involved in helping with DNA replication and repair. Mutations in SMARCAL1 were significantly enriched in children with osteosarcoma across multiple datasets, including independent datasets the team analyzed after their initial findings.  

Tumors from these patients also showed signs of a specific type of manipulation, commonly seen among osteosarcomas, in regions at the end of their chromosomes called telomeres. The minor list of genes that predispose to osteosarcoma mostly belong to DNA repair pathways. Now, SMARCAL1, another DNA repair gene, offers a new avenue for early detection and family screening. 

 “This is another gene that a physician can look for when screening families that have osteosarcoma or cancer history,” Dr. Sharma says. “And because it’s also involved in aggressive adult brain and pancreatic cancers, understanding how it drives osteosarcoma could help even more patients.” 

Dr. Sharma is also working to establish a Telomere Center of Excellence at Cleveland Clinic, so that pediatric and adult physicians and scientists can pool knowledge and drive discovery about how the edges of our chromosomes can contribute to health and disease. She hopes her discovery and ongoing telomere research will eventually lead to targeted therapies for patients with SMARCAL1-related cancers.  

“Hopefully our study encourages other people to take an unbiased approach,” she says. “It is not the norm but may lead to finding novel genes that increase risk for cancers in children and adults.”