Inherited Genetic Variants Increase the Likelihood of Developing Clonal Hematopoiesis: Something Akin to Pre-CHIP

Clonal hematopoiesis is commonly observed in persons without cancer or significant cytopenias, and its incidence increases with age.^1,2  This includes so-called clonal hematopoiesis of indeterminate potential (CHIP).^3-5  CHIP is associated with an increased risk of developing a hematologic cancer (estimated at approximately 1% per year6) and all-cause mortality related to an elevated risk of cardiovascular events.^5,7  However, most people with clonal hematopoiesis do not go on to develop cancer or significant cytopenias. The causes, genetics (e.g., which genes and the size of the clone), and clinical import of nonmalignant clonal hematopoiesis are not fully understood and most certainly context-related. Cell-extrinsic selection pressures such as chemotherapy or hematopoietic stem cell transplantation may favor its development.^8,9  An individual’s inherited genetic background is also emerging as influencing its incidence.^1,10  A recent study by Dr. Po-Ru Loh and colleagues offers additional insight on how inherited variation acting via different mechanisms contributes to clonal expansion.

Using genotyping array data derived from 151,202 United Kingdom Biobank participants aged 40 to 70 years and a newly developed sensitive statistical method for detecting clonal genetic changes affecting large pieces of chromosomes, the investigators identified clonal chromosomal abnormalities in approximately 5 percent of individuals studied. Many such chromosomal alterations were present at an inferred cell fraction less than 5 percent and ranged in size from 50 kilobases to nearly 250 megabases. The authors termed these changes “mosaic chromosomal alterations” (mCAs). To identify any inherited predisposition to mCA development, investigators performed chromosome-wide scans for associations between specific acquired mCAs and germline variants on the same chromosome, followed by whole-genome sequencing of identified loci to understand the potential mechanisms underlying the associations.

Their work identified several interesting inherited biological traits favoring clonal hematopoiesis characterized by mCAs. Somatic terminal 10q deletions strongly associated with a common single-nucleotide polymorphism (SNP) (rs118137427) near FRA10B, a known genomic fragile site located at the estimated common breakpoint of the 10q deletion. All individuals carrying this common SNP possessed variable number tandem repeat motifs at FRA10B on the rs118137427 haplotype. Additional studies in families demonstrated an acquired 10q terminal deletion in two parent-child duos in which both parent and child possessed germline expanded AT-rich repeats in FRA10B, rendering the genomic site subject to breakage. Thus, a child who inherited a variant from their parent went on to develop the same clonal cytogenetic change as was also acquired in the parent.

Copy-number–neutral loss of heterozygosity (CNN-LOH), also referred to as “uniparental disomy,” leads to loss of heterozygosity by duplication of either the maternal or paternal chromosome, or chromosomal region, and concurrent loss of the other allele. The authors showed that CNN-LOH on chromosome 1p strongly associated with three rare risk haplotypes at the MPL gene. The lead SNP on one haplotype (rs369156948) truncates the MPL protein leading to loss of function. Notably, the somatic CNN-LOH was always a loss of the allele encoding the nonfunctional MPL protein, suggesting that among individuals with rare inherited variants that reduce MPL function, recovery of the normal MPL gene activity by CNN-LOH provides a proliferative advantage favoring clonal expansion. CNN-LOH events on chromosome 11q associated with a rare risk haplotype surrounding ATM, a gene that encodes a DNA-damage response kinase that promotes DNA repair and limits cell division and that is often mutated in cancer. In this case, the somatic CNN-LOH was always a loss of the wildtype allele, suggesting that the risk allele confers a proliferative advantage in the homozygous state. Most notably, the CNN-LOH risk variants were highly penetrant, with a large fraction of carriers of the inherited alleles subsequently acquiring and then clonally amplifying the mCA. The authors inferred that mitotic recombination must be sufficiently common to predictably unleash latent, inherited opportunities for clonal selection of homozygous cells within a person’s lifetime.

Using data on health outcomes for UK Biobank participants four to nine years after DNA sampling, investigators additionally identified several mCAs associated with increased risk of developing hematologic malignancies. Chromosome 12 trisomy was associated with increased risk of developing chronic lymphocytic leukemia, and other mCAs seemed to increase risk of developing other hematologic cancers.