Tesi Bianca, Robelius Anna, Baskin Berivan, Lazarevic Vladimir, Deneberg Stefan, Höglund Martin, Fogelstrand Linda, Ungerstedt Johanna, Pandzic Tatjana, Tobiasson Magnus, Garelius Hege Gravdahl, Kuchinskaya Ekaterina, Persson Fredrik, Ågerstam Helena, Hallböök Helene, Fioretos Thoas, Nordin Jessika, Norberg Anna, Thuresson Ann-Charlotte, Lehmann Sören, Ladenvall Claes, Barbany Gisela, Vennström Lovisa, Ejerblad Elisabeth, Cavelier Lucia, Cammenga Jörg, Jädersten Martin, Hellström-Lindberg Eva, Baliakas Panagiotis
Department of Clinical Genetics and Genomics, Karolinska University Hospital, Stockholm, Sweden.
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Clin Cancer Res. 2025 Jul 15;31(14):3062-3071. doi: 10.1158/1078-0432.CCR-24-4251.
In a multicenter prospective cohort study, we assessed the diagnostic yield of the Nordic guidelines for germline investigation in myeloid neoplasms and mapped the spectrum of inherited and somatic variants.
Eighty-five patients (acute myeloid leukemia, n = 38; myelodysplastic syndromes, n = 26; thrombocytopenia, n = 14; and other, n = 7) fulfilling the Nordic criteria for germline investigation, based on (i) medical history or family history suggestive of a germline condition and (ii) relevant findings from the somatic diagnostic work-up (CytoMol), were recruited. The genetic analysis included enhanced whole-exome sequencing (n = 69) or sequencing of specific variants of interest (n = 16).
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 family history 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 were also detected (TERT n = 2 and 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; and CHEK2; n = 1). Survival analysis showed a trend for longer survival among patients with acute myeloid leukemia and confirmed or suspected germline predisposition that underwent allogeneic stem cell transplantation.
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.
在一项多中心前瞻性队列研究中，我们评估了北欧骨髓肿瘤种系调查指南的诊断率，并绘制了遗传和体细胞变异谱。
招募了85例符合北欧种系调查标准的患者（急性髓系白血病，n = 38；骨髓增生异常综合征，n = 26；血小板减少症，n = 14；其他，n = 7），这些标准基于（i）提示种系疾病的病史或家族史，以及（ii）体细胞诊断检查（细胞分子学）的相关发现。基因分析包括增强型全外显子测序（n = 69）或对特定感兴趣变异的测序（n = 16）。
在35%的患者（30/85）中鉴定出致病性或可能致病性（P/LP）种系变异。诊断率从家族史组的6%（1/16）到细胞分子学组的52%（17/33）不等。种系DDX41 P/LP变异是最常见的发现（13/30，占所有阳性病例的43%），几乎仅在细胞分子学组中发现（12/13）。还检测到7个意义未明的变异（TERT，n = 2；DDX41、RTEL1、ETV6、PARN和SAMD9，n = 1）。5例患者在与另一种遗传性癌症综合征相关的基因中携带P/LP变异（BRCA1，n = 3；PALB2，n = 1；CHEK2，n = 1）。生存分析显示，接受异基因干细胞移植的急性髓系白血病且确诊或疑似有种系易感性的患者有生存期延长的趋势。
在瑞典前瞻性队列中实施北欧指南可获得较高的总体诊断率（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。
