Driver mutation zygosity is a critical factor in predicting clonal hematopoiesis transformation risk
Abstract Clonal hematopoiesis (CH) can be caused by either single gene mutations (eg point mutations in JAK2 causing CHIP) or mosaic chromosomal alterations (e.g., loss of heterozygosity at chromosome 9p). CH is associated with a significantly increased risk of hematologic malignancies. However, the...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2024-01-01
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| Series: | Blood Cancer Journal |
| Online Access: | https://doi.org/10.1038/s41408-023-00974-9 |
| _version_ | 1797350143443337216 |
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| author | Ashwin Kishtagari M. A. Wasay Khan Yajing Li Caitlyn Vlasschaert Naimisha Marneni Alexander J. Silver Kelly von Beck Travis Spaulding Shannon Stockton Christina Snider Andrew Sochacki Dixon Dorand Taralynn M. Mack P. Brent Ferrell Yaomin Xu Cosmin A. Bejan Michael R. Savona Alexander G. Bick |
| author_facet | Ashwin Kishtagari M. A. Wasay Khan Yajing Li Caitlyn Vlasschaert Naimisha Marneni Alexander J. Silver Kelly von Beck Travis Spaulding Shannon Stockton Christina Snider Andrew Sochacki Dixon Dorand Taralynn M. Mack P. Brent Ferrell Yaomin Xu Cosmin A. Bejan Michael R. Savona Alexander G. Bick |
| author_sort | Ashwin Kishtagari |
| collection | DOAJ |
| description | Abstract Clonal hematopoiesis (CH) can be caused by either single gene mutations (eg point mutations in JAK2 causing CHIP) or mosaic chromosomal alterations (e.g., loss of heterozygosity at chromosome 9p). CH is associated with a significantly increased risk of hematologic malignancies. However, the absolute rate of transformation on an annualized basis is low. Improved prognostication of transformation risk is urgently needed for routine clinical practice. We hypothesized that the co-occurrence of CHIP and mCAs at the same locus (e.g., transforming a heterozygous JAK2 CHIP mutation into a homozygous mutation through concomitant loss of heterozygosity at chromosome 9) might have important prognostic implications for malignancy transformation risk. We tested this hypothesis using our discovery cohort, the UK Biobank (n = 451,180), and subsequently validated it in the BioVU cohort (n = 91,335). We find that individuals with a concurrent somatic mutation and mCA were at significantly increased risk of hematologic malignancy (for example, In BioVU cohort incidence of hematologic malignancies is higher in individuals with co-occurring JAK2 V617F and 9p CN-LOH; HR = 54.76, 95% CI = 33.92–88.41, P < 0.001 vs. JAK2 V617F alone; HR = 44.05, 95% CI = 35.06–55.35, P < 0.001). Currently, the ‘zygosity’ of the CHIP mutation is not routinely reported in clinical assays or considered in prognosticating CHIP transformation risk. Based on these observations, we propose that clinical reports should include ‘zygosity’ status of CHIP mutations and that future prognostication systems should take mutation ‘zygosity’ into account. |
| first_indexed | 2024-03-08T12:40:31Z |
| format | Article |
| id | doaj.art-8eae0d4d2063482883822364b8d4b942 |
| institution | Directory Open Access Journal |
| issn | 2044-5385 |
| language | English |
| last_indexed | 2024-03-08T12:40:31Z |
| publishDate | 2024-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Blood Cancer Journal |
| spelling | doaj.art-8eae0d4d2063482883822364b8d4b9422024-01-21T12:11:19ZengNature Publishing GroupBlood Cancer Journal2044-53852024-01-011411610.1038/s41408-023-00974-9Driver mutation zygosity is a critical factor in predicting clonal hematopoiesis transformation riskAshwin Kishtagari0M. A. Wasay Khan1Yajing Li2Caitlyn Vlasschaert3Naimisha Marneni4Alexander J. Silver5Kelly von Beck6Travis Spaulding7Shannon Stockton8Christina Snider9Andrew Sochacki10Dixon Dorand11Taralynn M. Mack12P. Brent Ferrell13Yaomin Xu14Cosmin A. Bejan15Michael R. Savona16Alexander G. Bick17Division of Hematology/Oncology, Vanderbilt University School of MedicineDivision of Genetic Medicine, Vanderbilt University Medical CenterDepartment of Biostatistics, Vanderbilt University School of MedicineDepartment of Medicine, Queen’s UniversityDivision of Hematology/Oncology, Vanderbilt University School of MedicineProgram in Cancer Biology, Vanderbilt University School of MedicineVanderbilt University School of MedicineDivision of Hematology/Oncology, Vanderbilt University School of MedicineDivision of Hematology/Oncology, Vanderbilt University School of MedicineDepartment of Medicine, Vanderbilt University Medical CenterDivision of Hematology/Oncology, Vanderbilt University School of MedicineDivision of Hematology/Oncology, Vanderbilt University School of MedicineDivision of Genetic Medicine, Vanderbilt University Medical CenterDivision of Hematology/Oncology, Vanderbilt University School of MedicineDepartment of Biostatistics, Vanderbilt University School of MedicineDepartment of Biomedical Informatics, Vanderbilt University School of MedicineDivision of Hematology/Oncology, Vanderbilt University School of MedicineDivision of Genetic Medicine, Vanderbilt University Medical CenterAbstract Clonal hematopoiesis (CH) can be caused by either single gene mutations (eg point mutations in JAK2 causing CHIP) or mosaic chromosomal alterations (e.g., loss of heterozygosity at chromosome 9p). CH is associated with a significantly increased risk of hematologic malignancies. However, the absolute rate of transformation on an annualized basis is low. Improved prognostication of transformation risk is urgently needed for routine clinical practice. We hypothesized that the co-occurrence of CHIP and mCAs at the same locus (e.g., transforming a heterozygous JAK2 CHIP mutation into a homozygous mutation through concomitant loss of heterozygosity at chromosome 9) might have important prognostic implications for malignancy transformation risk. We tested this hypothesis using our discovery cohort, the UK Biobank (n = 451,180), and subsequently validated it in the BioVU cohort (n = 91,335). We find that individuals with a concurrent somatic mutation and mCA were at significantly increased risk of hematologic malignancy (for example, In BioVU cohort incidence of hematologic malignancies is higher in individuals with co-occurring JAK2 V617F and 9p CN-LOH; HR = 54.76, 95% CI = 33.92–88.41, P < 0.001 vs. JAK2 V617F alone; HR = 44.05, 95% CI = 35.06–55.35, P < 0.001). Currently, the ‘zygosity’ of the CHIP mutation is not routinely reported in clinical assays or considered in prognosticating CHIP transformation risk. Based on these observations, we propose that clinical reports should include ‘zygosity’ status of CHIP mutations and that future prognostication systems should take mutation ‘zygosity’ into account.https://doi.org/10.1038/s41408-023-00974-9 |
| spellingShingle | Ashwin Kishtagari M. A. Wasay Khan Yajing Li Caitlyn Vlasschaert Naimisha Marneni Alexander J. Silver Kelly von Beck Travis Spaulding Shannon Stockton Christina Snider Andrew Sochacki Dixon Dorand Taralynn M. Mack P. Brent Ferrell Yaomin Xu Cosmin A. Bejan Michael R. Savona Alexander G. Bick Driver mutation zygosity is a critical factor in predicting clonal hematopoiesis transformation risk Blood Cancer Journal |
| title | Driver mutation zygosity is a critical factor in predicting clonal hematopoiesis transformation risk |
| title_full | Driver mutation zygosity is a critical factor in predicting clonal hematopoiesis transformation risk |
| title_fullStr | Driver mutation zygosity is a critical factor in predicting clonal hematopoiesis transformation risk |
| title_full_unstemmed | Driver mutation zygosity is a critical factor in predicting clonal hematopoiesis transformation risk |
| title_short | Driver mutation zygosity is a critical factor in predicting clonal hematopoiesis transformation risk |
| title_sort | driver mutation zygosity is a critical factor in predicting clonal hematopoiesis transformation risk |
| url | https://doi.org/10.1038/s41408-023-00974-9 |
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