Validation of guidelines for genetic investigation of myeloid neoplasms with germline predisposition: results from a prospective cohort study

IF 10 1区医学 Q1 ONCOLOGY

Clinical Cancer Research Pub Date : 2025-05-19 DOI:10.1158/1078-0432.ccr-24-4251

Bianca Tesi, Anna Robelius, Berivan Baskin, Vladimir Lazarevic, Stefan Deneberg, Martin Höglund, Linda Fogelstrand, Johanna Ungerstedt, Tatjana Pandzic, Magnus Tobiasson, Hege Gravdahl. Garelius, Ekaterina Kuchinskaya, Fredrik Persson, Helena Ågerstam, Helene Hallböök, Thoas Fioretos, Jessika Nordin, Anna Norberg, Ann-Charlotte Thuresson, Sören Lehmann, Claes Ladenvall, Gisela Barbany, Lovisa Vennström, Elisabeth Ejerblad, Lucia Cavelier, Jörg Cammnega, Martin Jädersten, Eva Hellström-Lindberg, Panagiotis Baliakas

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Abstract

Purpose: In a multicenter prospective cohort-study we assessed the diagnostic yield of the Nordic guidelines for germline investigation in myeloid neoplasms (MN) and mapped the spectrum of inherited and somatic variants. Experimental Design: Eighty-five patients (acute myeloid leukemia (AML): n=38; myelodysplastic syndromes (MDS): n=26; thrombocytopenia: n=14; other: n=7) fulfilling the Nordic criteria for germline investigation: (1) medical history (MH) or family history (FH) suggestive of a germline condition; (2), relevant findings from the somatic diagnostic work-up (CytoMol), were recruited. The genetic analysis included enhanced whole-exome sequencing (WES, n=69) or sequencing of specific variants of interest (n=16). Results: Pathogenic or likely pathogenic (P/LP) germline variants were identified in 35% of patients (30/85). The diagnostic yield varied from 6% (1/16) in the FH group to 52% (17/33) in the CytoMol group. Germline DDX41 P/LP variants were the most frequent finding (13/30, 43% of all positive cases), almost exclusively found within the CytoMol group (12/13). Seven variants of unknown significance (VUS) were also detected (TERT n=2; DDX41, RTEL1, ETV6, PARN and SAMD9: n=1). Five patients carried a P/LP variant in genes associated with another hereditary cancer syndrome (BRCA1 n=3; PALB2 n=1; CHEK2; n=1). Survival analysis showed a trend for longer survival among patients with AML and confirmed or suspected germline predisposition that underwent allogeneic stem cells transplantation (allo-HSCT). Conclusions: The implementation of the Nordic guidelines in a prospective Swedish cohort, results in a high overall diagnostic yield (35%), proving the feasibility and utility of these or similar guidelines in a clinical setting.

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髓系肿瘤生殖系易感性遗传调查指南的验证：来自一项前瞻性队列研究的结果

目的：在一项多中心前瞻性队列研究中，我们评估了北欧髓系肿瘤（MN）生殖系调查指南的诊出率，并绘制了遗传和体细胞变异的谱。实验设计：85例患者(急性髓性白血病（AML）： n=38；骨髓增生异常综合征（MDS）： 26例；血小板减少症:n = 14;其他：n=7)符合北欧生殖系调查标准：(1)病史（MH）或家族史（FH）提示生殖系疾病；(2)收集了体细胞诊断检查（CytoMol）的相关结果。遗传分析包括增强的全外显子组测序（WES, n=69）或感兴趣的特定变异测序（n=16）。结果：35%的患者（30/85）发现致病性或可能致病性（P/LP）种系变异。FH组的诊断率为6%(1/16)，而CytoMol组为52%（17/33）。生殖系DDX41 P/LP变异是最常见的发现（13/30，占所有阳性病例的43%），几乎只在流式细胞瘤组发现（12/13）。7个未知显著性变异（VUS）也被检测到(TERT n=2；DDX41, RTEL1, ETV6， PARN和SAMD9: n=1)。5例患者携带与另一种遗传性癌症综合征相关基因的P/LP变异(BRCA1 n=3；PALB2 n = 1;CHEK2;n = 1)。生存分析显示，接受同种异体干细胞移植（alloo - hsct）的AML患者和确诊或疑似种系易感患者的生存期有延长的趋势。结论：北欧指南在前瞻性瑞典队列中的实施，导致高总体诊断率（35%），证明了这些或类似指南在临床环境中的可行性和实用性。

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来源期刊

Clinical Cancer Research 医学-肿瘤学

CiteScore

20.10

自引率

1.70%

发文量

1207

审稿时长

2.1 months

期刊介绍： Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.