St. Jude authors Charles Mullighan, MBBS, and Jun J. Yang, PhD, co-led the research with investigators from Children’s Hospital of Philadelphia.
Investigators at Children’s Hospital of Philadelphia (CHOP), St. Jude Children’s Research Hospital (St. Jude), Dana-Farber Cancer Institute (DFCI) and the Children’s Oncology Group (COG) unveiled for the first time that changes in certain genes affect an aggressive cancer, T-cell acute lymphoblastic leukemia (T-ALL), differently depending on genetic ancestry. The collaborative study, published recently in the journal Blood Cancer Discovery further reinforces the critical role of personalized medicine in advancing the treatment of pediatric cancers such as T-ALL.
Most children in the U.S. newly diagnosed with cancer are treated through clinical trials or with regimens established by earlier trial findings. Increasingly, these frontline trials use prognostic biomarkers to guide treatments related to whether patients have high risk or low risk disease. While previous studies found that genetic ancestry affects how certain gene changes appear in cancer, researchers can now show that these gene changes may also predict outcomes differently depending upon an individual’s ancestry.
“Our research demonstrates it is essential to ensure the equitable implementation of genomic biomarkers in treatment decisions or we may introduce disparities,” said David Teachey, MD, a lead study author at CHOP and Chair of the Acute Lymphoblastic Leukemia Disease Committee in the COG. “Without this critical step, we risk misclassifying patients into the incorrect high- or low-risk groups, potentially causing undertreatment and increased risk of relapse, or overtreatment and unnecessary side effects, especially in populations of non-European descent.”
Study participants were enrolled in the COG’s multicenter phase 3 randomized clinical trial AALL0434 (NCT04408005) conducted from 2007 to 2014. Of the eligible participants evaluable with T-ALL, researchers analyzed complete sequencing for 1,309 individuals included in this study. They found that 80% had mutations in genes where prognostic impact varied depending on their genetic ancestry. For example, a gene called NOTCH1 was linked to better survival in patients of European ancestry but was not associated with better survival in patients of African ancestry. Importantly, this collaborative study brought together experts in the diagnosis and treatment of T-ALL, leukemia genomics, genetic ancestry and social determinants of health research, including study co-author Kira Bona, MD, MPH from DFCI.
“The study provides another important example of the way in which heritable and tumor-acquired genetic variations interact to determine the features and behavior of leukemia,” said study author Charles Mullighan, MBBS (Hons), MSc, MD, Senior Deputy Director of the St. Jude Comprehensive Cancer Center.
The study evaluated tools that group patients into risk categories. One method worked well for everyone, no matter their ancestry. But another tool used, developed mainly from European data, sometimes gave misleading results for people from backgrounds other than European ancestry. The researchers also emphasized that certain genetic ancestries may be associated with more aggressive disease forms or different responses to treatment
“Our groups have a long-standing interest in how genetic ancestry affects cancer biology in children. This study is another example of the fruitful collaboration with COG that led to the discovery of new genetic basis of racial/ethnic differences in leukemia,” said co-corresponding author Jun J. Yang, PhD, St. Jude Department of Pharmacy and Pharmaceutical Sciences.
“The lessons learned from this work should be investigated in other types of cancer in children and adults to improve outcomes for patients of all ancestral backgrounds,” said first author Haley Newman, MD, a junior faculty member at CHOP.
Authors and funding
The study’s other co-second authors are Shawn Lee and Petri Polonen of St. Jude and Rawan Shraim, Yimei Li and Hongyan Liu of Children’s Hospital of Philadelphia. Additional authors are Richard Alpenc, Shovik Bandyopadhyay, Changya Chen, Caroline Diorio, Omar Elghawy, Amira Elhachimi, Tori Fuller, Junior Hall, Andre Hughes, Stephen Hunger, Zachary Martinez, Michael McCoy, Cassidy Mullen, Gongping Shi, Jonathan Sussman, Kai Tan, Lahari Uppuluri, Tiffaney Vincent, Jason Xu of CHOP; Meenakshi Devidas, Stanley Pounds, Anna Eames Seffernick, Ruth Wang’ondu, Gang Wu, and Wenjian Yang of St. Jude; Kimberly Dunsmore, University of Virginia Children’s Hospital; Sumit Gupta, The Hospital for Sick Children; Mignon Loh, Seattle Children’s Hospital, University of Washington; Elizabeth Raetz, New York University Langone Health; Lena Winestone, UCSF Benioff Children’s Hospitals, San Francisco; Stuart Winter, Children’s Minnesota Research Institute and Cancer and Blood Disorders Program; and Brent Wood, Children’s Hospital Los Angeles.
The research was supported by K12CA076931-24, Gabriella Miller Kids First (X01HD100702), R03CA256550, Alex’s Lemonade Stand Foundation, the Leukemia and Lymphoma Society, Singapore NMRC, Singapore NUHS NCSP, Hyundai Hope on Wheels, (R01CA193776), (U10CA180886), (R01CA264837), (U24CA114766), (U24CA196173), (U10CA180899, St. Baldricks Research Foundation, Pennsylvania Department of Health, the Harrison Willing Memorial Research Fund, The Invisible Prince Foundation, the Aiden Everett Davies Innovation Fund, ALSAC the fundraising and awareness organization of St. Jude, The St. Jude Chromatin Collaborative, (P30CA021765), (R35CA197695), (U54CA243124) and the Canadian Institute for Health Research.
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.
Children’s Hospital of Philadelphia
A non-profit, charitable organization, Children’s Hospital of Philadelphia was founded in 1855 as the nation’s first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, the hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. The institution has a well-established history of providing advanced pediatric care close to home through its CHOP Care Network, which includes more than 50 primary care practices, specialty care and surgical centers, urgent care centers, and community hospital alliances throughout Pennsylvania and New Jersey. CHOP also operates the Middleman Family Pavilion and its dedicated pediatric emergency department in King of Prussia, the Behavioral Health and Crisis Center (including a 24/7 Crisis Response Center) and the Center for Advanced Behavioral Healthcare, a mental health outpatient facility. Its unique family-centered care and public service programs have brought Children’s Hospital of Philadelphia recognition as a leading advocate for children and adolescents. For more information, visit https://www.chop.edu.