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Validation of Guidelines for Genetic Investigation of Myeloid Neoplasms with Germline Predisposition : Results from a Prospective Cohort Study

Tesi, Bianca ; Robelius, Anna ; Baskin, Berivan ; Lazarevic, Vladimir LU orcid ; Deneberg, Stefan ; Höglund, Martin ; Fogelstrand, Linda ; Ungerstedt, Johanna ; Pandzic, Tatjana and Tobiasson, Magnus , et al. (2025) In Clinical Cancer Research 31(14). p.3062-3071
Abstract

Purpose: 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. Experimental Design: 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). Results:... (More)

Purpose: 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. Experimental Design: 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). 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 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. 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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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Clinical Cancer Research
volume
31
issue
14
pages
10 pages
publisher
American Association for Cancer Research Inc.
external identifiers
  • scopus:105011672404
  • pmid:40388595
ISSN
1078-0432
DOI
10.1158/1078-0432.CCR-24-4251
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2025 The Authors.
id
00e58be7-9039-44c6-a340-1ee951fb7512
date added to LUP
2025-08-06 19:46:08
date last changed
2025-08-20 21:00:27
@article{00e58be7-9039-44c6-a340-1ee951fb7512,
  abstract     = {{<p>Purpose: 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. Experimental Design: 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). 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 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. 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.</p>}},
  author       = {{Tesi, Bianca and Robelius, Anna and Baskin, Berivan and Lazarevic, Vladimir and Deneberg, Stefan and Höglund, Martin and Fogelstrand, Linda and Ungerstedt, Johanna and Pandzic, Tatjana and Tobiasson, Magnus and Garelius, Hege Gravdahl and Kuchinskaya, Ekaterina and Persson, Fredrik and Ågerstam, Helena and Hallböök, Helene and Fioretos, Thoas and Nordin, Jessika and Norberg, Anna and Thuresson, Ann Charlotte and Lehmann, Sören and Ladenvall, Claes and Barbany, Gisela and Vennström, Lovisa and Ejerblad, Elisabeth and Cavelier, Lucia and Cammenga, Jörg and Jädersten, Martin and Hellström-Lindberg, Eva and Baliakas, Panagiotis}},
  issn         = {{1078-0432}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{14}},
  pages        = {{3062--3071}},
  publisher    = {{American Association for Cancer Research Inc.}},
  series       = {{Clinical Cancer Research}},
  title        = {{Validation of Guidelines for Genetic Investigation of Myeloid Neoplasms with Germline Predisposition : Results from a Prospective Cohort Study}},
  url          = {{http://dx.doi.org/10.1158/1078-0432.CCR-24-4251}},
  doi          = {{10.1158/1078-0432.CCR-24-4251}},
  volume       = {{31}},
  year         = {{2025}},
}