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EVOLUTIONARY LANDSCAPE OF CLONAL HEMATOPOIESIS REVEALED BY LONGITUDINAL ERROR-CORRECTED SEQUENCING IN 3359 OLDER COMMUNITY-BASED INDIVIDUALS
Author(s): ,
Isabelle van Zeventer
Affiliations:
Hematology,UMCG,Groningen,Netherlands
,
Aniek de Graaf
Affiliations:
Laboratory medicine,Radboudumc,Nijmegen,Netherlands
,
Jonas Salzbrunn
Affiliations:
Hematology,UMCG,Groningen,Netherlands
,
Ilja Nolte
Affiliations:
Epidemiology,UMCG,Groningen,Netherlands
,
Priscilla Kamphuis
Affiliations:
Hematology,UMCG,Groningen,Netherlands
,
Avinash Dinmohamed
Affiliations:
Research and development,Netherlands Comprehensive Cancer Organization,Utrecht,Netherlands
,
Bert van der Reijden
Affiliations:
Laboratory medicine,Radboudumc,Nijmegen,Netherlands
,
Jan Jacob Schuringa
Affiliations:
Hematology,UMCG,Groningen,Netherlands
,
Joop Jansen
Affiliations:
Laboratory medicine,Radboudumc,Nijmegen,Netherlands
Gerwin Huls
Affiliations:
Hematology,UMCG,Groningen,Netherlands
(Abstract release date: 06/02/22) EHA Library. van Zeventer I. 06/12/22; 366211; LB2368
Isabelle van Zeventer
Isabelle van Zeventer
Contributions
Abstract
Presentation during EHA2022: Presentation during EHA2022: The Late-Breaking Oral Session will be held on Sunday, June 12, 2022 (09:45 - 11:15 CEST) and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: LB2368

Type: Late breaking oral

Session title: Late breaking abstract session

Background
Clonal hematopoiesis (CH) occurs frequently in older individuals and may predispose for development of malignancy. To investigate evolution of CH and fitness of specific mutations based on sequential measurements, we established a large-scale error-corrected smMIP-based sequencing initiative in the well-annotated population-based Lifelines cohort, using sequential samples from 3359 individuals (>60 years) taken median 3.6 years apart. The cohort was linked to the Netherlands Cancer Registry for incident diagnoses of myeloid and lymphoid cancer. 

Aims
This allowed the investigation of dynamics of early clonal lesions, the role of environmental pressures and risks of transformation to malignancy. 

Methods
In total, we identified 2518 clonal variants in 1573 individuals at one or both time points. As expected with increasing age, an increase of 3.8% in the prevalence of CH was observed during the median 3.6 years follow-up time (P<0.001). The serial samples revealed that the number of detected mutations indicative of CH is stable over time in the majority of individuals (n=2685, 80%) with changes observed for n=674 (20%). Patterns of both increase (n=451) and decrease (n=223) in the number of clonal gene mutations detected at ≥1% variant allele fraction (VAF) were observed. For newly developing variants, a relatively high proportion of spliceosome and TP53 variants was observed.

Results
To account for the large inter-individual variety in co-occurring mutations and the repeated measures over time, we evaluated clonal growth in a linear mixed model with a random intercept, corrected for age at baseline and sequencing depth. This resulted in an overall estimate of 0.0405, translating to a proportional increase of 4.1% (95% CI 2.9%-5.4%) in VAF per year for this cohort (P<0.001). The highest estimated proportional growth rates were observed for mutations in spliceosome genes SF3B1 (10.9% per year, 95%CI 1.1-21.7%), SRSF2 (17.9% per year, 95%CI 6.8-30.3%) and U2AF1 (14.3% per year, 95%CI -0.4-31.2%). JAK2 clones also showed considerable expansion (9.8% per year, 95%CI 1.2-19.0%). Genes most commonly implicated in age-related CH showed considerably lower growth rates, including DNMT3A (1.9% per year, 95%CI 0.3-3.5%), TET2 (7.1% per year, 95%CI 4.7-9.6%) and ASXL1 (3.9% per year, 95%CI -1.6-9.8%).

Interestingly, we also found no evidence of traditional cancer risk factors, including age (P=0.757), male sex (P=0.868), current smoking (P=0.931), excessive alcohol use (P=0.895) and overweight (P=0.917) to explain differences in clonal expansion. The risk to develop myeloid malignancy was highest for individuals with a peripheral cytosis or cytopenia and those with JAK2 (HR 74.4, 95% CI 36.0-153.7),  NRAS/KRAS (HR 12.4, 95%CI 2.9-52.4), SF3B1 (HR 10.7, 95%CI 3.2-35.5), SRSF2 (HR 10.1, 95%CI 2.4-42.3) or U2AF1 (HR 24.7, 95%CI 5.7-106.7) mutations. A highly variable pre-malignant evolutionary trajectory was observed. Importantly, most community-based individuals never developed malignant myeloid disease, even despite the presence of peripheral blood count abnormalities.

Conclusion
In conclusion, this study reports on the first large-scale longitudinal sequencing effort to characterize evolution of CH in community-based individuals. Driver gene mutations are important determinants for the future trajectories of hematopoietic clones, both in terms of clonal expansion and malignancy development. The results from this study provide important insight into potential high-risk evolution patterns for monitoring of CH.

Keyword(s): Clonal hematopoiesis of indeterminate potential, Clonal expansion, Development

Presentation during EHA2022: Presentation during EHA2022: The Late-Breaking Oral Session will be held on Sunday, June 12, 2022 (09:45 - 11:15 CEST) and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: LB2368

Type: Late breaking oral

Session title: Late breaking abstract session

Background
Clonal hematopoiesis (CH) occurs frequently in older individuals and may predispose for development of malignancy. To investigate evolution of CH and fitness of specific mutations based on sequential measurements, we established a large-scale error-corrected smMIP-based sequencing initiative in the well-annotated population-based Lifelines cohort, using sequential samples from 3359 individuals (>60 years) taken median 3.6 years apart. The cohort was linked to the Netherlands Cancer Registry for incident diagnoses of myeloid and lymphoid cancer. 

Aims
This allowed the investigation of dynamics of early clonal lesions, the role of environmental pressures and risks of transformation to malignancy. 

Methods
In total, we identified 2518 clonal variants in 1573 individuals at one or both time points. As expected with increasing age, an increase of 3.8% in the prevalence of CH was observed during the median 3.6 years follow-up time (P<0.001). The serial samples revealed that the number of detected mutations indicative of CH is stable over time in the majority of individuals (n=2685, 80%) with changes observed for n=674 (20%). Patterns of both increase (n=451) and decrease (n=223) in the number of clonal gene mutations detected at ≥1% variant allele fraction (VAF) were observed. For newly developing variants, a relatively high proportion of spliceosome and TP53 variants was observed.

Results
To account for the large inter-individual variety in co-occurring mutations and the repeated measures over time, we evaluated clonal growth in a linear mixed model with a random intercept, corrected for age at baseline and sequencing depth. This resulted in an overall estimate of 0.0405, translating to a proportional increase of 4.1% (95% CI 2.9%-5.4%) in VAF per year for this cohort (P<0.001). The highest estimated proportional growth rates were observed for mutations in spliceosome genes SF3B1 (10.9% per year, 95%CI 1.1-21.7%), SRSF2 (17.9% per year, 95%CI 6.8-30.3%) and U2AF1 (14.3% per year, 95%CI -0.4-31.2%). JAK2 clones also showed considerable expansion (9.8% per year, 95%CI 1.2-19.0%). Genes most commonly implicated in age-related CH showed considerably lower growth rates, including DNMT3A (1.9% per year, 95%CI 0.3-3.5%), TET2 (7.1% per year, 95%CI 4.7-9.6%) and ASXL1 (3.9% per year, 95%CI -1.6-9.8%).

Interestingly, we also found no evidence of traditional cancer risk factors, including age (P=0.757), male sex (P=0.868), current smoking (P=0.931), excessive alcohol use (P=0.895) and overweight (P=0.917) to explain differences in clonal expansion. The risk to develop myeloid malignancy was highest for individuals with a peripheral cytosis or cytopenia and those with JAK2 (HR 74.4, 95% CI 36.0-153.7),  NRAS/KRAS (HR 12.4, 95%CI 2.9-52.4), SF3B1 (HR 10.7, 95%CI 3.2-35.5), SRSF2 (HR 10.1, 95%CI 2.4-42.3) or U2AF1 (HR 24.7, 95%CI 5.7-106.7) mutations. A highly variable pre-malignant evolutionary trajectory was observed. Importantly, most community-based individuals never developed malignant myeloid disease, even despite the presence of peripheral blood count abnormalities.

Conclusion
In conclusion, this study reports on the first large-scale longitudinal sequencing effort to characterize evolution of CH in community-based individuals. Driver gene mutations are important determinants for the future trajectories of hematopoietic clones, both in terms of clonal expansion and malignancy development. The results from this study provide important insight into potential high-risk evolution patterns for monitoring of CH.

Keyword(s): Clonal hematopoiesis of indeterminate potential, Clonal expansion, Development

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