Genome-Wide Association Study of Susceptibility Loci for TCF3-PBX1 Acute Lymphoblastic Leukemia in Children

Author:

Lee Shawn H. R123,Qian Maoxiang4,Yang Wentao1,Diedrich Jonathan D1,Raetz Elizabeth5,Yang Wenjian1ORCID,Dong Qian1,Devidas Meenakshi67,Pei Deqing8,Yeoh Allen23,Cheng Cheng8,Pui Ching-Hon9,Evans William E1,Mullighan Charles G10,Hunger Stephen P11,Savic Daniel1,Relling Mary V1,Loh Mignon L12,Yang Jun J1ORCID

Affiliation:

1. Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA

2. Khoo Teck Puat–National University Children’s Medical Institute, National University Health System, Singapore

3. Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

4. Institute of Pediatrics and Department of Hematology and Oncology, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, China

5. Division of Pediatric Hematology and Oncology, New York University Langone Health, New York, NY, USA

6. Department of Global Pediatric Medicine, St Jude Children’s Research Hospital, Memphis, TN, USA

7. Department of Biostatistics, University of Florida, Gainesville, FL, USA

8. Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, USA

9. Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA

10. Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, USA

11. Department of Pediatrics and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia and the Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA, USA

12. Department of Pediatrics, Benioff Children’s Hospital and the Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA

Abstract

Abstract Acute lymphoblastic leukemia (ALL) is the most common cancer in children. TCF3-PBX1 fusion defines a common molecular subtype of ALL with unique clinical features, but the molecular basis of its inherited susceptibility is unknown. In a genome-wide association study of 1494 ALL cases and 2057 non-ALL controls, we identified a germline risk locus located in an intergenic region between BCL11A and PAPOLG: rs2665658, P = 1.88 × 10–8 for TCF3-PBX1 ALL vs non-ALL, and P = 1.70 × 10–8 for TCF3-PBX1 ALL vs other-ALL. The lead variant was validated in a replication cohort, and conditional analyses pointed to a single causal variant with subtype-specific effect. The risk variant is located in a regulatory DNA element uniquely activated in ALL cells with the TCF3-PBX1 fusion and may distally modulate the transcription of the adjacent gene REL. Our results expand the understanding of subtype-specific ALL susceptibility and highlight plausible interplay between germline variants and somatic genomic abnormalities in ALL pathogenesis.

Funder

US National Institutes of Health

American Lebanese Syrian Associated Charities

National Medical Research Council Singapore Research Training Fellowship

Program for Professor of Special Appointment

Shanghai Institutions of Higher Learning and the National Natural Science Foundation of China

NIH

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,Oncology

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