PF196 IDENTICAL TWINS DO NOT DISPLAY INCREASED CONCORDANCE FOR CLONAL HEMATOPOIESIS

• Published in: HemaSphere 2019-06, Vol.3 (S1), p.50-n/a
• Main Authors: Fabre, M., McKerrell, T., Zwiebel, M., Vijayabaskar, M., Rad, R., Deloukas, P., Small, K., Steves, C.J., Vassiliou, G.
• Format: Article
• Language: English
• ISSN: 2572-9241; 2572-9241
• DOI: 10.1097/01.HS9.0000559000.31086.4d

Background: Acquisition of leukemia‐associated somatic mutations by one or more haematopoietic stem cells (HSCs) is inevitable in healthy individuals by the age of 50–60 years1. However, the consequences of mutation acquisition are highly variable, even amongst those with identical mutations, and range from long‐term clinically silent clonal haematopoiesis (CH) to leukemic progression. Aims: To investigate the role of the inherited genome in determining CH emergence and behaviour, by studying CH concordance patterns in monozygotic (MZ) and dizygotic (DZ) twin pairs. Methods: 154 individuals from the TwinsUK cohort were studied, comprising 52 MZ and 27 DZ twin pairs, aged 70–99 years2. Deep sequencing was performed on blood DNA, targeting 41 genes implicated in CH and myeloid malignancies (Agilent SureSelect, ELID 0735431). Somatic single nucleotide variants and small indels were called using the Shearwater algorithm (v.1.21.5) and verified using CaVEMan (v.1.11.2) and Pindel (v.2.2), and curation of variant oncogenicity was performed, as described previously3. Statistical analyses were performed in R (version 3.4.0). Fisher's Exact Test was used to assess twin concordance for CH. Null distributions of CH within the MZ and DZ groups were generated using random permutation (1000 iterations). Results: Using deep sequencing (mean 1650X) and sensitive variant‐calling, we identified CH (VAF≥0.5%) in 62% of individuals (95/154) (Figure 1A), with mutations in the epigenetic regulators DNMT3A and TET2 predominant (Figure 1B). The overall prevalence of CH was very similar among individuals belonging to the MZ and DZ groups (59% and 54% respectively; p = 0.70). We did not observe higher concordance for CH within MZ twin pairs as compared to DZ pairs (p = 0.59, Figure 1C). Furthermore, using random sample permutation to model the null distribution, we found no difference in the observed distribution of CH among either MZ or DZ twins as compared to that expected by chance (p = 1 for MZ; p = 0.86 for DZ; Figure 1C). Increased twin concordance was also not observed when separately considering CH with: (i) mutations in DNMT3A, (ii) mutations in TET2, and (iii) larger clones (VAF > 2%). Despite the overall lack of concordance for CH, we identified two MZ twin pairs in which both twins harbored identical rare somatic nonsense mutations, KDM6A Q692X (NM_021140:c.C2074T) in one pair and DNMT3A R598X (NM_175629:c.C1792T) in the other. Finally, in 4 MZ twin pairs, serial blood