Validation of Guidelines for Genetic Investigation of Myeloid Neoplasms with Germline Predisposition : Results from a Prospective Cohort Study
(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.
(Less)
- author
- organization
- publishing date
- 2025-07-15
- 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
-
- pmid:40388595
- scopus:105011672404
- 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
- 2025-08-08 13:44:01
@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}}, }