The Impact of Genetic Ancestry on Cancer Prognosis in T-ALL Patients Revealed by Research
The recent study published in the journal Blood Cancer Discovery reveals a groundbreaking discovery from a collaborative research effort led by the Children’s Hospital of Philadelphia (CHOP) and St. Jude Children’s Research Hospital. This research has shown, for the first time, the significant influence of genetic ancestry on how mutations in certain genes impact the prognosis for patients suffering from T-cell acute lymphoblastic leukemia (T-ALL). By focusing on personalized medicine, the study aims to enhance treatment options for pediatric cancers such as T-ALL.
As previously noted, most children diagnosed with cancer in the United States receive treatment through clinical trials or established treatment regimens based on earlier trials. These trials increasingly employ prognostic biomarkers to delineate whether patients are at high risk or low risk of serious disease. Prior research has indicated that genetic ancestry plays a role in the manifestation of certain gene changes, but this novel study establishes that these changes can also affect treatment outcomes in a way that is contingent on the patient's ancestry.
David T. Teachey, MD, who is a lead author of the study and also serves as Chair of the Acute Lymphoblastic Leukemia Disease Committee for the Children’s Oncology Group (COG), emphasized the critical need for the equitable implementation of genomic biomarkers in treatment planning. "If we fail to take this essential step, we might unintentionally create disparities in treatment,” he cautioned. Misclassifying patients could lead to inadequate treatments and increased relapse risks or excessive treatments that result in debilitating side effects, particularly in non-European populations.
The investigation included participants from COG’s multicenter phase 3 clinical trial (AALL0434) spanning from 2007 to 2014, evaluating complete sequencing of 1,309 individuals. Remarkably, in this cohort, 80% exhibited mutations in genes with prognostic implications that varied based on genetic ancestry. For instance, the NOTCH1 gene appeared to correlate with improved survival rates for patients of European ancestry. However, it did not demonstrate the same advantage in African ancestry patients.
The collaborative effort united specialists in T-ALL diagnosis, leukemia genomics, genetic ancestry, and social health determinants, including Kira Bona, MD, MPH, from Dana Farber Cancer Institute, who contributed to the research.
Charles Mullighan, MBBS, MSc, MD, a senior co-author from St. Jude, reiterated the findings, illustrating how genetic variations—both inherited and those acquired through tumor evolution—interplay to influence leukemia behavior and characteristics.
Furthermore, the study evaluated existing tools that categorize patients by risk. One specific tool performed well across diverse ancestry groups, while another tool primarily based on European data misclassified patients from differing ancestries. The findings indicate that distinct genetic backgrounds can correlate with more aggressive disease variants and variable treatment responses.
"Our research interest in the intersection of genetic ancestry and pediatric cancer biology has produced several significant findings. This study stands as another testament to the fruitful collaboration with COG, which has further elucidated genetic bases for racial and ethnic disparities in leukemia,” remarked co-corresponding author Jun J. Yang, PhD, who holds an Endowed Chair in Pharmacogenomics at St. Jude.
The authors, including first author Haley M. Newman, MD, a junior faculty member at CHOP, proposed that the implications from this study should be expanded to investigate other cancer forms in both children and adults, promoting improved outcomes across all ancestral backgrounds.
Funding for this pivotal research was provided by various organizations including NIH grants and philanthropic foundations, emphasizing the critical support from cooperative bodies to enhance cancer treatment and understanding.
With a focus on improving the guidelines and tools in treatment protocols for T-ALL and potentially other pediatric cancers, this research not only showcases the importance of personalized medicine but also highlights an urgent need for equality in healthcare access based on genetic diversity.
As previously noted, most children diagnosed with cancer in the United States receive treatment through clinical trials or established treatment regimens based on earlier trials. These trials increasingly employ prognostic biomarkers to delineate whether patients are at high risk or low risk of serious disease. Prior research has indicated that genetic ancestry plays a role in the manifestation of certain gene changes, but this novel study establishes that these changes can also affect treatment outcomes in a way that is contingent on the patient's ancestry.
David T. Teachey, MD, who is a lead author of the study and also serves as Chair of the Acute Lymphoblastic Leukemia Disease Committee for the Children’s Oncology Group (COG), emphasized the critical need for the equitable implementation of genomic biomarkers in treatment planning. "If we fail to take this essential step, we might unintentionally create disparities in treatment,” he cautioned. Misclassifying patients could lead to inadequate treatments and increased relapse risks or excessive treatments that result in debilitating side effects, particularly in non-European populations.
The investigation included participants from COG’s multicenter phase 3 clinical trial (AALL0434) spanning from 2007 to 2014, evaluating complete sequencing of 1,309 individuals. Remarkably, in this cohort, 80% exhibited mutations in genes with prognostic implications that varied based on genetic ancestry. For instance, the NOTCH1 gene appeared to correlate with improved survival rates for patients of European ancestry. However, it did not demonstrate the same advantage in African ancestry patients.
The collaborative effort united specialists in T-ALL diagnosis, leukemia genomics, genetic ancestry, and social health determinants, including Kira Bona, MD, MPH, from Dana Farber Cancer Institute, who contributed to the research.
Charles Mullighan, MBBS, MSc, MD, a senior co-author from St. Jude, reiterated the findings, illustrating how genetic variations—both inherited and those acquired through tumor evolution—interplay to influence leukemia behavior and characteristics.
Furthermore, the study evaluated existing tools that categorize patients by risk. One specific tool performed well across diverse ancestry groups, while another tool primarily based on European data misclassified patients from differing ancestries. The findings indicate that distinct genetic backgrounds can correlate with more aggressive disease variants and variable treatment responses.
"Our research interest in the intersection of genetic ancestry and pediatric cancer biology has produced several significant findings. This study stands as another testament to the fruitful collaboration with COG, which has further elucidated genetic bases for racial and ethnic disparities in leukemia,” remarked co-corresponding author Jun J. Yang, PhD, who holds an Endowed Chair in Pharmacogenomics at St. Jude.
The authors, including first author Haley M. Newman, MD, a junior faculty member at CHOP, proposed that the implications from this study should be expanded to investigate other cancer forms in both children and adults, promoting improved outcomes across all ancestral backgrounds.
Funding for this pivotal research was provided by various organizations including NIH grants and philanthropic foundations, emphasizing the critical support from cooperative bodies to enhance cancer treatment and understanding.
With a focus on improving the guidelines and tools in treatment protocols for T-ALL and potentially other pediatric cancers, this research not only showcases the importance of personalized medicine but also highlights an urgent need for equality in healthcare access based on genetic diversity.
Topics Health）
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