Co-corresponding author Paul Northcott, PhD, St. Jude Department of Developmental Neurobiology.
A study published in Nature Genetics reveals new insights into how medulloblastoma, the most common malignant brain tumor of childhood, can arise as the cerebellum develops. Researchers discovered that the same gene, ZIC1, can drive highly similar cancers by distinct, context-dependent mechanisms. Led by researchers at Baylor College of Medicine, Texas Children’s Cancer Center, University of Toronto, St. Jude Children’s Research Hospital and Mayo Clinic College of Medicine and Science, these findings have direct implications for tumor prevention and treatment.
“Medulloblastoma arises from malignant transformation of developing neurons in the cerebellum,” said co-corresponding author Michael Taylor, MD, PhD, Baylor College of Medicine and Texas Children’s Cancer Center. He also is the Cyvia and Melvyn Wolff Chair of Pediatric Neuro-Oncology at Texas Children’s Cancer and Hematology Center. “Although many driver genes of medulloblastoma are well-known, many others are less well understood. In the current study, we investigate the ZIC1 gene, which plays crucial roles in the development of the central nervous system.”
The researchers worked with two types of human medulloblastoma, G4 and SHH, which are suspected to arise from a common cell of origin in the developing cerebellum. The team discovered that G4 and SHH medulloblastoma have mutations in ZIC1 gene that drive their growth, but they do it by different mechanisms.
Context is everything
“G4 medulloblastoma tumors have ZIC1 mutations that produce proteins that have lost their function. In contrast, SHH medulloblastoma tumors have ZIC1 mutations that produce proteins with a new function that is different from that of the original gene,” said co-corresponding author Paul Northcott, PhD, St. Jude Department of Developmental Neurobiology and Center of Excellence in Neuro-Oncology Sciences director. “Tumor-driving ZIC1 mutations in medulloblastoma are context dependent.”
“Distinct ZIC1 mutations affect cells of the rhombic lip area of the cerebellum where the tumors arise in diametrically opposed ways, suggesting that ZIC1 is a critical developmental regulator in both the normal and transformed rhombic lip,” Taylor said.
Supporting the role of ZIC1 mutations as true driver events of medulloblastoma, the researchers found that over-expression of ZIC1promotes malignancy in SHH medulloblastoma precursor cells.
“Identifying how mutations in the same gene drive different medulloblastoma groups has genuine consequences for developing treatments,” Northcott said. “Our findings highlight the importance of identifying the correct context before designing an approach to treating each medulloblastoma. In one subgroup, ZIC1 mutations produce active proteins that are potentially good targets to inhibit. In the other group it's a loss-of-function mutation, therefore restoring its function would be a potential therapeutic avenue.”
Authors and funding
The studies co-first authors are John Lee, University of Toronto; Ran Tao, St. Jude and Zhen You, Mayo Clinic College of Medicine and Science. The other corresponding author is L. Frank Huang, Mayo Clinic College of Medicine and Science.
The study’s other authors are Anders Erickson and Hamza Farooq, University of Toronto; Liam Hendriske, Namal Abeysundara and Cory Richman, The Hospital for Sick Children; Christopher Mount and Mario Suva, Massachusetts General Hospital and Harvard Medical School; Zhen You, Frank Huang and Miao Liu, Mayo Clinic College of Medicine and Science; Parthiv Haldipur, Kathleen Millen and Sarah Leary, Seattle Children’s Research Institute; Pim French and Johan Kros, Erasmus University Medical Center; Andrey Korshunov and Marcel Kool, German Cancer Research Center (DKFZ); Boleslaw Lach and Sheila Singh, McMaster University; Byung-Kyu Cho, Seung-Ki Kim and Ji-Yeoun Lee, Seoul National University Children’s Hospital; William Weiss, Joanna Phillips and Shizhong Dai, University of California San Francisco; Ian Pollack and Ronald Hamilton, University of Pittsburgh School of Medicine; Reid Thompson and Michael Cooper, Vanderbilt Medical Center; Livia Garzia and Nada Jabado, McGill University; Kulandaimanuvel Antony Michealraj and Marco Gallo, Baylor College of Medicine; Hiromichi Suzuki, National Cancer Center; Fernando Chico Ponce de León, Hospital Infantil de Mexico Federico Gomez; Mario Perezpeña-Diazconti, Instituto Nacional de Pediatria; Wieslawa Grajkowska and Marta Perek-Polnik, The Children’s Memorial Health Institute; Teiji Tominaga, Tohoku University, László Bognár and Almos Klekner; University of Debrecen and Neha Das Gupta and Jennifer Hadley, St. Jude.
The study was supported by grants from the Cancer Prevention and Research Institute of Texas (CPRIT—RR220051), National Institutes of Health (R01NS106155, R01CA159859 and R01CA255369), Pediatric Brain Tumor Foundation, Terry Fox Research Institute, Canadian Institutes of Health Research, Cure Search Foundation, Matthew Larson Foundation (IronMatt), b.r.a.i.n.child, Meagan’s Walk, SWIFTY Foundation, Brain Tumour Charity, Genome Canada, Genome BC, Genome Quebec, Ontario Research Fund, Worldwide Cancer Research, V-Foundation for Cancer Research and Ontario Institute for Cancer Research, Canadian Cancer Society Research Institute, Cancer Research UK Brain Tumor Award, Stand Up To Cancer (SU2C-AACR-DT1113 and SU2C-AACR-DT-19-15), Canadian Institutes of Health Research and Ontario Institute for Cancer Research, Government of Ontario, Brain Tumor Charity (Quest for Cures), National Cancer Institute (P01CA096832-16A1 and 1R01CA270785-01A1), Department of Defense PRCRP Award (CA191188), Mayo Clinic Foundation (Start-up funds), University of Toronto Fellowship, Ontario Graduate Scholarship, University of Debrecen (2017-1.2.1-NKP-2017-00002 National Brain Research Program NAP 2.0) and ALSAC, the fundraising and awareness organization of St. Jude.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is leading the way the world understands, treats and cures childhood cancer, sickle cell disease, and other life-threatening disorders. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 60 years ago. St. Jude shares the breakthroughs it makes to help doctors and researchers at local hospitals and cancer centers around the world improve the quality of treatment and care for even more children. To learn more, visit stjude.org, read St. Jude Progress, a digital magazine, and follow St. Jude on social media at @stjuderesearch.
Baylor College of Medicine
Baylor College of Medicine (www.bcm.edu) in Houston is recognized as a health sciences university and is known for excellence in education, research and patient care. Baylor is a top-ranked medical school and listed 20th among all U.S. medical schools for National Institutes of Health funding and No. 1 in Texas. Located in the Texas Medical Center, Baylor has affiliations with seven teaching hospitals and jointly owns and operates Baylor St. Luke’s Medical Center, part of St. Luke’s Health. Currently, Baylor has more than 3,000 trainees in medical, graduate, nurse anesthesia, physician assistant, orthotics and genetic counseling as well as residents and postdoctoral fellows.