Genetic Heterogeneity in Childhood Leukemia/Lymphoma: A Turkish Cohort with Strong Predisposition

Gizem Onder^1,2,3Ozkan Ozdemir^2,4Fulya Taylan^3,5Cengiz Canpolat⁶Koray Yalçın^7,8Fatih Erbey^10,9Banu Oflaz Sozmen^10,9Fikret Asarcikli^10,9Turan Bayhan^11,12Yunus Murat Akcabelen¹²Nese Yarali^11,12Namik Yasar Ozbek¹²Ikbal Ok Bozkaya¹²Dilek Kacar¹²Berk Ergun¹³Alper Akkus^14,2Davut Albayrak¹⁵Elif Ince¹⁶Ugur Demirsoy¹⁷Gul Nihal Ozdemir¹⁸Omer Dogru¹⁹Seda Aras²⁰Eylül Aydın^14,2Busra Unal²¹Ufuk Amanvermez^2,22Ozlem Akgun-Dogan^2,23Sezer Akyoney²⁴Muge Sayitoglu²⁵Ann Nordgren^26,27,3,5Nihat Bugra Agaoglu^21,28Ugur Ozbek^2,29Ozden Hatirnaz Ng^2,30*

• ¹Department of Biochemistry and Molecular Biology, Health Sciences Institute, Acıbadem Mehmet Ali Aydınlar University, Acibadem University, Istanbul, Türkiye
• ²Acıbadem University, Rare Diseases and Orphan Drugs Application and Research Center (ACURARE), Istanbul, Türkiye
• ³Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
• ⁴Department of Medical Biology, School of Medicine, Acıbadem Mehmet Ali Aydınlar University, İstanbul, Türkiye
• ⁵Department of Clinical Genetics and Genomics, Karolinska University Hospital, Stockholm, Sweden
• ⁶Department of Pediatric Oncology, School of Medicine, Acıbadem Mehmet Ali Aydınlar University, Istanbul, Türkiye
• ⁷Department of Medical Biotechnology, Health Sciences Institute, Acıbadem Mehmet Ali Aydınlar University, İstanbul, Türkiye
• ⁸Department of Pediatric Hematology, Bahçeşehir University, Goztepe Medical Park Hospital, Istanbul, Türkiye
• ⁹Department of Pediatric Hematology and Oncology, Hospital of Koç University, Istanbul, Türkiye
• ¹⁰Department of Pediatric, Koç University, School of Medicine, Istanbul, Türkiye
• ¹¹Department of Pediatric Hematology and Oncology, Ankara Yıldırım Beyazıt University, Ankara, Türkiye
• ¹²Department of Pediatric Hematology and Oncology, Ankara Bilkent City Hospital, Ankara, Türkiye
• ¹³GENIVA Information Health Services Company, Istanbul, Türkiye
• ¹⁴Department of Translational Medicine, Institute of Health Sciences, Acıbadem Mehmet Ali Aydınlar University, Istanbul, Türkiye
• ¹⁵Department of Pediatric Hematology, Samsun Medical Park Hospital, Samsun, Türkiye
• ¹⁶Department of Pediatric Hematology and Oncology, Ankara University, Faculty of Medicine, Ankara, Türkiye
• ¹⁷Department of Pediatric Oncology, Faculty of Medicine, Kocaeli University, Izmit, Kocaeli, Türkiye
• ¹⁸Department of Pediatric Hematology, Istinye University, Faculty of Medicine, Istanbul, Türkiye
• ¹⁹Department of Pediatric Hematology, Biruni University, Istanbul, Türkiye
• ²⁰Department of Pediatric Hematology Oncology, Hatay Training and Research Hospital, Hatay, Türkiye
• ²¹Department of Cancer Genetics, Umraniye Traning and Research Hospital, Istanbul, Türkiye
• ²²Department of Genome Studies, Acıbadem Mehmet Ali Aydınlar University, Institute of Health Sciences, Istanbul, Türkiye
• ²³Department of Medical Genetics, School of Medicine, Acıbadem Mehmet Ali Aydınlar University, Istanbul, Türkiye
• ²⁴Department of Bioinformatics and Biostatistic, Acıbadem Mehmet Ali Aydınlar University, Institute of Health Sciences, Istanbul, Türkiye
• ²⁵Department of Genetics, Istanbul University, Institute of Aziz Sancar Experimental Medicine, İstanbul, Türkiye
• ²⁶Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden
• ²⁷Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, Gothenburg, Sweden
• ²⁸Krankenhaus Nordwest, Frankfurt, Germany, Frankfurt, Germany
• ²⁹International Biomedicine and Genome Institute (iBG), Izmir Dokuz Eylül University, Izmir, Türkiye
• ³⁰Department of Medical Biology, School of Medicine, Acıbadem Mehmet Ali Aydınlar University, Istanbul, Türkiye

Background: Leukemia is the most common type of cancer in children, and 10%-15% of patients with leukemia/lymphoma carry pathogenic germline cancer predisposing variants. Identifying these variants is critical for understanding genetic predisposition and optimizing clinical management.: We performed germline short-read sequencing in 36 individuals from 20 families with suspected leukemia/lymphoma predisposition, including 20 index cases, 9 affected relatives, and 7 unaffected members. Results: We identified 13 clinically relevant germline variants in known cancer predisposition genes including TP53, ETV6, MSH6, MLH1, and BRCA1. Notably, we uncovered novel candidate variants in ATR, TNFRSF9, ETAA1, and KSR1, supported by segregation analysis, consanguinity patterns, and secondary malignancy phenotypes. Several index cases exhibited striking familial cancer syndromes involving both hematologic and solid tumors, with progression from ALL to AML or glioma. Deep clinical-genomic correlation enabled reclassification of variants and refined diagnostic and therapeutic decision-making in multiple cases. The patients were referred to genetic counseling for surveillance of carriers and risk assessment for various family members. Conclusion: These findings emphasize, the clinical utility of germline testing in pediatric hematologic cancers by providing novel insights into the predisposition to leukemia/lymphoma and contributing to treatment regimens, donor selection, and diagnostic refinement, particularly in populations with high consanguinity.