Mosaic chromosomal alterations and relation to haematological cancer in two large Danish cohorts

Mosaic chromosomal alterations (mCAs) are large somatic gains, losses and copy-neutral loss of heterozygosity identified in the peripheral blood, which represent a relatively unexplored spectrum of clonal haematopoiesis. We aimed to describe mCAs in two large Danish cohorts with extensive long-term registry-based follow-up and examine associations with haematological malignancy. We analysed genotype data from 97 752 participants from the Danish Blood Donor Study and 86 301 patients from the Copenhagen Hospital Biobank using the MoChA software. Association to haematological cancers was modelled with competing-risk methods and Cox regression, or logistic regression, via nationwide register linkage. Among 184 053 individuals, 15 459 (8%) carried autosomal mCAs and 14 322 females (17%) had loss of X, with prevalence increasing with age. In samples before or after diagnosis of haematological cancer, autosomal mCAs were detectable in 21%-62% of individuals depending on cancer subtype. Overall, the risk of haematological cancer was increased for individuals carrying autosomal mCA (hazard ratio [HR] 4.1 (95% confidence interval [CI] 3.1-5.5)), but not for individuals carrying loss of X chromosome (HR 1.1 [95% CI 0.7-1.6]). The level of malignancy risk was highly variable between different chromosomal aberrations, and cancer gene-related mCAs conveyed highest risk. Autosomal mCAs, especially those overlapping cancer gene loci, identify individuals at increased risk of haematological malignancy and may assist improvement of risk stratification and early detection.