Peripheral blood somatic mosaicism and clonal hematopoiesis across ancestry backgrounds

Area of Science:

• Genetics
• Genomics
• Oncology

Background:

• Somatic mosaicism (SM) and clonal hematopoiesis (CH) are age-related genetic alterations in blood cells.
• CH is linked to increased risks of hematologic malignancies and cardiovascular disease.
• Existing research on CH is heavily biased towards individuals of European ancestry.

Purpose of the Study:

• To catalog somatic mosaicism and clonal hematopoiesis variants across diverse genetic ancestries.
• To investigate the prevalence of CH and myeloid/lymphoid CH (M-CHIP/L-CHIP) variants across different ancestral groups.
• To explore the association of CH variants with cancer, including solid tumors and hematologic malignancies.

Main Methods:

• Whole exome sequencing of peripheral blood from 125,748 individuals of diverse ancestries.
• Identification of SM mutations using low variant allele frequency distributions.
• Detection of CH variants based on age-skewing and analysis of pathogenic variants in M-CHIP and L-CHIP.
• Linking CH variants to a cancer database to assess prevalence in tumors.

Main Results:

• Cataloged over 500,000 SM mutations and 89,000 CH variants.
• CH and M-CHIP variants were most prevalent in individuals of European non-Finnish ancestry; males showed a trend toward more M-CHIP variants.
• Significant ancestry-specific differences were observed in CH variant prevalence (e.g., NF1 in African/African American, TP53 in European, CUX1 in Asian/Latino).
• CH variants were found in 14% of patient tumors, with 25-40% prevalence in some solid tumors.
• M-CHIP variants in solid tumors were associated with younger age at diagnosis compared to hematologic malignancies.

Conclusions:

• This study provides a comprehensive catalog of SM, CH, and CHIP variants across diverse populations.
• Identified significant ancestry and sex-based differences in CH prevalence and specific gene mutations.
• Findings underscore the importance of considering genetic diversity in clinical care, drug discovery, and research design for generalizability.