Insights into clonal haematopoiesis from 8,342 mosaic chromosomal alterations

Abstract

The selective pressures that shape clonal evolution in healthy individuals are largely unknown. Here we investigate 8,342 mosaic chromosomal alterations, from 50 kb to 249 Mb long, that we uncovered in blood-derived DNA from 151,202 UK Biobank participants using phase-based computational techniques (estimated false discovery rate, 6-9%). We found six loci at which inherited variants associated strongly with the acquisition of deletions or loss of heterozygosity in cis. At three such loci (MPL, TM2D3-TARSL2, and FRA10B), we identified a likely causal variant that acted with high penetrance (5-50%). Inherited alleles at one locus appeared to affect the probability of somatic mutation, and at three other loci to be objects of positive or negative clonal selection. Several specific mosaic chromosomal alterations were strongly associated with future haematological malignancies. Our results reveal a multitude of paths towards clonal expansions with a wide range of effects on human health.

Clonal hematopoiesis and preleukemia—Genetics, biology, and clinical implications

“…Recently, single-nucleotide polymorphism array analysis identified mosaic chromosomal aberrations in 7484 of 151 202 (4.9%) persons without a diagnosis of a hematologic neoplasm. 32 In the majority of these individuals, the estimated cell fraction harboring the CNA or LOH was below 5%. Small deletions frequently affected chromosomal regions 13q14, 2p (DNMT3A), and 4q (TET2).…”

“…Besides skewed X‐chromosome inactivation and gene mutations, CH can also become evident through gross chromosomal aberrations resulting in copy number alterations (CNA) or loss of heterozygosity (LOH). Recently, single‐nucleotide polymorphism array analysis identified mosaic chromosomal aberrations in 7484 of 151 202 (4.9%) persons without a diagnosis of a hematologic neoplasm . In the majority of these individuals, the estimated cell fraction harboring the CNA or LOH was below 5%.…”

“…31 Finally, several lines of evidence, including analyses of sibling pairs and genetic analyses, now provide evidence that there are hereditary traits leading to a predisposition to develop CH with specific genetic lesions, including TET2 mutations. 22,32,33…”

Inherited Causes of Clonal Hematopoiesis of Indeterminate Potential in TOPMed Whole Genomes

“…This variant was previously significantly associated with increased leukocyte telomere length. 15 This variant was also associated with myeloproliferative neoplasms (MPN, see Bao et al, co-submitted manuscript) and clonal chromosomal mosaicism 13 . In a phenome-wide association analysis (PheWAS) of rs34002450 in UK Biobank, we identified significant increased risk of MPN (p=2.6 x 10 -13 ), uterine leiomyoma (p=3.2 x 10 -9 ), brain cancer (p=3.6 x 10 -8 ) and a decreased risk of Seborrheic keratosis (p=1.4 x 10 -7 ).…”

“…Germline genetic variants have been previously associated with clonal hematopoiesis, defined either by somatic mosaicism of SNVs and indels 12 or by chromosomal rearrangements with appreciable clonal fraction 13 , in individuals of European ancestry, and identified variants at a single locus, TERT, that associates with clonal hematopoiesis. Given the distinct association of clonal hematopoiesis with known leukemogenic mutations (i.e., CHIP) with both cancer 14 and atherosclerotic cardiovascular disease 5 , we sought to specifically discover germline genetic variations conferring increased risk for CHIP acquisition.…”