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. 2025 Sep 9:16:1624306.
doi: 10.3389/fgene.2025.1624306. eCollection 2025.

Genetic heterogeneity in childhood leukemia/lymphoma: a Turkish cohort with strong predisposition

Gizem Onder  1   2   3 , Ozkan Ozdemir  2   4 , Fulya Taylan  3   5 , Cengiz Canpolat  6 , Koray Yalcin  7   8 , Fatih Erbey  9   10 , Banu Oflaz Sozmen  9   10 , Fikret Asarcikli  9   10 , Turan Bayhan  11   12 , Yunus Murat Akcabelen  11 , Nese Yarali  11   12 , Namik Yasar Ozbek  11 , Ikbal Ok Bozkaya  11 , Dilek Kacar  11 , Berk Ergun  13 , Alper Akkus  2   14 , Davut Albayrak  15 , Elif Ince  16 , Ugur Demirsoy  17 , Gul Nihal Ozdemir  18 , Omer Dogru  19 , Seda Aras  20 , Eylul Aydin  2   14 , Busra Unal  21 , Ufuk Amanvermez  2   22 , Ozlem Akgun Dogan  2   23 , Sezer Akyoney  24 , Muge Sayitoglu  25 , Ann Nordgren  3   5   26   27 , Nihat Bugra Agaoglu  21   28 , Ugur Ozbek  2   29 , Ozden Hatirnaz Ng  2   4
Affiliations

Genetic heterogeneity in childhood leukemia/lymphoma: a Turkish cohort with strong predisposition

Gizem Onder et al. Front Genet. .

Abstract

Background: Leukemia is the most common cancer in children, and 10%-15% of patients with leukemia/lymphoma carry pathogenic germline cancer-predisposing variants. Identifying these variants is critical for understanding the genetic predisposition and optimizing clinical management.

Methods: 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, which was 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.

Keywords: cancer predisposition; childhood leukemia; childhood lymphoma; germline variants; short-read sequencing.

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Conflict of interest statement

Author BE was employed by GENIVA Information Health Services Company. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Workflow of the study (WGS: whole-genome sequencing; WES: whole-exome sequencing; CES: clinical exome sequencing).
FIGURE 2
FIGURE 2
Cohort of the study.
FIGURE 3
FIGURE 3
Candidate genes in leukemia and lymphoma.
FIGURE 4
FIGURE 4
Signaling pathways of candidate genes (stars: genes identified as potential candidates in leukemia/lymphoma cases). (A) Leukemia signaling pathways: (cytoplasmic pathways; NF-κB pathway: activation through IL32 signaling leads to transcriptional regulation via the NF-κB complex. MAPK pathway: initiated through receptor tyrosine kinases, including EGFR, and mediated by KSR1 and MAP2K2, driving cell proliferation. PI3K/AKT/mTORC1 pathway: a critical survival and growth axis influenced by BCNP1 and TGFβ signaling. NOTCH and IL-2β signaling; NOTCH1: NICD (notch intracellular domain) signaling contributes to transcriptional regulation associated with leukemia progression. STAT3 activation: IL-2β receptor engagement results in STAT3 phosphorylation, which impacts the transcriptional activity. DNA repair mechanisms; mismatch repair (MMR): key components such as PMS, MLH, MSH, and EXO1 ensure genomic stability. DNA damage response (DDR): genes such as WRN, RECQL, and BRCA1/2 coordinate repair and apoptotic signaling via the ATM and ATR pathways. β-catenin pathway: dysregulation of WNT signaling (via GSK-3β inhibition) contributes to leukemic transformation. Tumor suppressor pathways; P53: central to apoptosis and cell cycle arrest and frequently inactivated in leukemias. ETV6: common in childhood leukemia and drives oncogenic processes.). (B) Lymphoma signaling pathways: NF-κB signaling via TNFRSF9: TNFRSF9 activation recruits adapter proteins (e.g., TRAF molecules), leading to the phosphorylation and degradation of IκB. This allows the NF-κB complex to translocate to the nucleus, where it regulates genes involved in inflammation, survival, and proliferation. Dysregulation of this pathway is a hallmark of many lymphomas. DNA repair pathways; RAD52: critical for homologous recombination repair and for addressing DNA double-strand breaks that arise during replication or due to genotoxic stress. MSH6 and MLH1: ensure replication fidelity by correcting mismatched base pairs. Loss of MMR function increases mutation rates and contributes to lymphomagenesis.
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