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

IF 2.8 3区生物学 Q2 GENETICS & HEREDITY

Frontiers in Genetics Pub Date : 2025-09-09 eCollection Date: 2025-01-01 DOI:10.3389/fgene.2025.1624306

Gizem Onder, Ozkan Ozdemir, Fulya Taylan, Cengiz Canpolat, Koray Yalcin, Fatih Erbey, Banu Oflaz Sozmen, Fikret Asarcikli, Turan Bayhan, Yunus Murat Akcabelen, Nese Yarali, Namik Yasar Ozbek, Ikbal Ok Bozkaya, Dilek Kacar, Berk Ergun, Alper Akkus, Davut Albayrak, Elif Ince, Ugur Demirsoy, Gul Nihal Ozdemir, Omer Dogru, Seda Aras, Eylul Aydin, Busra Unal, Ufuk Amanvermez, Ozlem Akgun Dogan, Sezer Akyoney, Muge Sayitoglu, Ann Nordgren, Nihat Bugra Agaoglu, Ugur Ozbek, Ozden Hatirnaz Ng

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引用次数: 0

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.

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儿童白血病/淋巴瘤的遗传异质性：具有强易感性的土耳其队列。

背景：白血病是儿童最常见的癌症，10%-15%的白血病/淋巴瘤患者携带致病性种系癌易感变异体。识别这些变异对于理解遗传易感性和优化临床管理至关重要。方法：我们对来自20个疑似白血病/淋巴瘤易感家族的36名个体进行了种系短读测序，其中包括20个指标病例、9个受影响亲属和7个未受影响成员。结果：我们在已知的癌症易感基因中鉴定出13种临床相关的种系变异，包括TP53、ETV6、MSH6、MLH1和BRCA1。值得注意的是，我们在ATR、TNFRSF9、ETAA1和KSR1中发现了新的候选变异，这得到了分离分析、血缘模式和继发性恶性表型的支持。几个指标病例表现出明显的家族性癌症综合征，包括血液和实体肿瘤，从ALL进展到AML或胶质瘤。深入的临床-基因组相关性使变体重新分类和改进诊断和治疗决策在多个病例。患者接受遗传咨询，对携带者进行监测，并对不同家庭成员进行风险评估。结论：这些发现强调了生殖系检测在儿童血液病中的临床应用，提供了对白血病/淋巴瘤易感性的新见解，有助于治疗方案、供体选择和诊断改进，特别是在高血缘人群中。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Frontiers in Genetics Biochemistry, Genetics and Molecular Biology-Molecular Medicine

CiteScore

5.50

自引率

8.10%

发文量

3491

审稿时长

14 weeks

期刊介绍： Frontiers in Genetics publishes rigorously peer-reviewed research on genes and genomes relating to all the domains of life, from humans to plants to livestock and other model organisms. Led by an outstanding Editorial Board of the world’s leading experts, this multidisciplinary, open-access journal is at the forefront of communicating cutting-edge research to researchers, academics, clinicians, policy makers and the public. The study of inheritance and the impact of the genome on various biological processes is well documented. However, the majority of discoveries are still to come. A new era is seeing major developments in the function and variability of the genome, the use of genetic and genomic tools and the analysis of the genetic basis of various biological phenomena.