Studies link SMARCAL1 to increased risk for pediatric bone cancer

If scientists could run a test to better predict whether children would develop cancer, care for pediatric patients would be very different from what it is today. While that may not be our current reality, investigators are making significant strides in our understanding of the genetic variants that can predispose children to cancer — valuable information that can shape future treatment strategies and alter outcomes.

Osteosarcoma is the most common malignant bone tumor in children and young adults. Patients with localized disease have a survival rate of 70-75%, while those with metastatic disease do not fare as well, with only 30% five-year survival. There have been tantalizing hints of hereditary predispositions to the disease, the most common of which are germline mutations in the TP53 gene. However, other than TP53 mutations, the genetic variant landscape has been, to date, cloudy. This is due to the relative rarity of osteosarcoma, which makes it difficult to put together a large enough patient group with both clinical and germline (inherited DNA) genetic information to make statistically meaningful inferences.

Investigators at St. Jude recently announced progress in the effort to understand osteosarcoma predisposition better. Two efforts — one co-led by Lillian Guenther, MD, Assistant Member in the Division of Molecular Oncology,  Department of Oncology, and one co-led by Kim Nichols, MD, Director of the St. Jude Cancer Predisposition Division and Member in the Department of Oncology — recently announced SMARCAL1 as a new predisposition gene for the disease. The findings, which were published in the Journal of the National Cancer Institute and the Journal of Clinical Oncology, respectively, bolster each other as the projects examined the same gene independently.

Finding a way to study a rare disease’s genetic predisposition

To tackle the issue of the rarity of osteosarcoma stymying research, Guenther and colleagues leveraged germline sequencing information housed in the Clinical Genetics Branch at the National Cancer Institute. The repository contains over 2,000 osteosarcoma cases, which represent the largest collection of osteosarcoma cases with germline data reported to date. These data gave the researchers the statistical power to find a meaningful association.

They discovered that loss-of-function variants of the gene SMARCAL1, which encodes an important protein involved in DNA repair, confer a statistical increase in osteosarcoma risk compared to matched healthy controls, establishing it as a significant predisposition gene. Furthermore, they also found that SMARCAL1 germline variants are associated with a favorable overall survival in patients with osteosarcoma, emphasizing the clinical importance.

“Our findings on SMARCAL1 are a step forward in our understanding of the underpinnings of osteosarcoma development,” Guenther said. “Furthermore, the discovery that SMARCAL1 variants are associated with improved survival will hopefully lead to better prognostication for patients with this challenging disease.”

Converging on SMARCAL1 as a predisposition gene for osteosarcoma

In a separate study, Nichols and colleagues performed the first comprehensive analysis of over 180 DNA damage repair genes for their role in childhood cancer predisposition. While genes involved in the recognition and repair of DNA damage are known to be often mutated in tumor cells, it has been unclear how variants in these same genes, when present in germline cells, predispose children to certain cancers. 

The researchers looked at germline DNA sequence information from almost 6,000 children with a variety of cancers and also found that variants in SMARCAL1 are associated with increased osteosarcoma risk. Further, several of the osteosarcoma tumors from patients with germline SMARCAL1 variants exhibited mutations in the remaining SMARCAL1 gene copy, suggesting that complete loss of SMARCAL1 protein function is associated with osteosarcoma formation.

“We are very excited about these findings because they provide new insights into the development of osteosarcoma, an aggressive cancer for which there has been little improvement in therapy for several decades,” Nichols said. “In addition, genetic testing for germline SMARCAL1 gene changes will help to identify individuals who might benefit from screening to detect new osteosarcoma tumors at their earliest and most curable stages.””

“By harnessing one of the largest pediatric cancer datasets and applying an unbiased analytic framework, we underscored the importance of DNA damage response pathways in pediatric cancer risk,” said first author of the study, Ninad Oak, PhD, Department of Oncology. “This data-driven approach not only sheds light on SMARCAL1’s role in osteosarcoma but also provides a scalable framework to explore additional gene sets of interest.”

Changing the future for patients with osteosarcoma

Together, the findings from both projects address an urgent need to better understand this rare pediatric bone cancer. By uncovering a previously unknown genetic contribution to osteosarcoma development, the researchers have gained new insight into what fuels this disease. This greater understanding may provide an opportunity for novel therapeutic interventions in the future. However, right now, this new knowledge will empower clinicians to improve outcomes through screening and surveillance. The researchers’ work stands as a testament to how collaborative predisposition research has the capacity to make real differences in the lives of children and families with increased genetic risk for cancer.

Authors

Journal of the National Cancer Institute 

The study’s other first author is Maryam Rafati, National Cancer Institute, National Institutes of Health. The study’s other co-corresponding author is Lisa Mirabello, National Cancer Institute, National Institutes of Health. The study’s other authors are Laura Egolf, Matthew Gianferante, Jung Kim, Kevin Wang, Bin Zhu, Lindsay Morton, Meredith Yeager, Michael Dean, Douglas Stewart, Aurelie Vogt, Jia Liu, Belynda Hicks, Wen-Yi Huang, Maria Teresa Landi, Sharon Savage and Stephen Chanock,  National Institutes of Health; Gregory Armstrong and Yadav Sapkota, St. Jude Children’s Research Hospital; Logan Spector and Nathan Anderson, University of Minnesota; Katherine Janeway, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Harvard Medical School; Donald Barkauskas, University of Southern California; Douglas Hawkins, University of Washington; Ana Patiño-Garcia, Cima-Universidad de Navarra, Pamplona, Spain; Philip Lupo and Michael Scheurer, Emory University; M. Monica Gramatges, Baylor College of Medicine; Massimo Serra, Claudia Hattinger and Katia Scotlandi, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy; Irene Andrulis and Jay Wunder, Sinai Health System, University of Toronto; Mandy Ballinger and David Thomas, University of New South Wales; Adriana Lori and Ryan Diver, American Cancer Society.

Journal of Clinical Oncology

The study’s other co-corresponding authors are Richa Sharma, Cleveland Clinic (formerly of St. Jude), and Robert Autry, Hopp Children’s Cancer Center Heidelberg (KiTZ). The study’s other authors are Alise Blake, Lynn Harrison, Jiaming Li, Yadav Sapkota, Kirsten Ness, Lillian Guenther, Zhaoming Wang, Greg Armstrong, Melissa Hudson, and Gang Wu, St. Jude; Wenan Chen, Mayo Clinic (formerly of St. Jude), Martha O’Brien, Christopher Previti, Gnanaprakash Balasubramanian, Kendra Maass, Steffen Hirsch, Barbara Jones, Kathrin Schramm, Kristian Pajtler, David Jones, Olaf Witt and Stefan Pfister, Hopp Children’s Cancer Center Heidelberg (KiTZ); Judith Penkert, Michaela Nathrath and Christian Kratz, Hannover Medical School and Uta Dirksen, West German Cancer Center, University Hospital Essen.