S134 clonal hematopoiesis in elderly twins: concordance, discordance and survival

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is often caused by mutations in TET2 , DNMT3A and ASXL1 with a variant allele frequency of 2% and above. CHIP increases the risk of hematological cancer in healthy individuals, and it has been proposed that a genetic predisposition could lead to clonal hematopoiesis (Busque et al., Blood 2017 and Zink et al., Blood 2017). Aims: To assess, in a study of elderly twins, the familial predisposition to CHIP and to test whether CHIP is associated with survival when controlling for familial factors. Methods: A population based sample of 297 twin pairs aged 73–94 of which 128 were monozygotic (MZ) and 169 were dizygotic (DZ), provided a blood sample in 1997 and at end of follow up in 2018, 96% of the individuals were deceased. DNA from peripheral blood was sequenced with a customized 21 gene panel at a median coverage of 6100X. The probandwise concordance rates for mutations was calculated to assess the degree of genetic predisposition. The association between mutational status and survival was estimated both on an individual level and in pairs discordant for CHIP mutation. Results: We identified a total of 305 mutations in 226(38%) of the twins, with DNMT3A (n = 104), TET2 (n = 83) and ASXL1 (n = 23) being the most commonly mutated genes. The median VAF was 4.4 %, and 66(29%) of the 226 had a VAF of 10% or above, the range of mutated genes per individual was 1–3. Whereas several twin pairs had mutations within the same genes, the exact same mutation was only observed among two twin pairs. In one DZ pair both twins had a SRSF2 mutation at position c.284C>A causing P95H, with a VAF of 4.5% and 31%, respectively, without any other co‐occurring mutations. The second twin pair, which were MZ, both had a 5 base pair deletion c.912_916delCTGGT in DNMT3A giving rise to a frameshift at p.Trp305fs with a VAF of 11.7% and 26.8%, respectively. Both of these twins each had an additional DNMT3A mutation. For TET2 we found an overall prevalence of 14% and a probandwise concordance (pc) rate for MZ and DZ of 0.25 [95%CI] [0.08;0.46] and 0.19 [0.05;0.39], respectively pcMZ = pcDZ, p = 0.57. For DNMT3A we found similar results with an overall prevalence of 18% and concordance rates of 0.26 [0.10;0.45] and 0.21 [0.07;0.38], for MZ and DZ twins, respectively pcMZ = pcDZ, p = 0.73. The mutational status was associated with overall survival, Hazard Ratio (HR) 1.33[1.12;1.58], p < 0.001, but when adjusted for age, sex and tobacco consumption, the association was only borderline significant, HR 1.18[0.98;1.41], p = 0.076. In pairs discordant for CHIP mutations, we tested if the affected twin died before the unaffected twin, as a direct measurement of the impact of having clonal hematopoiesis when controlling for familial factors. A total of 133 twins were discordant for carrying a mutation, and in 64(48%) cases the affected twin died first, p = 0.73. Summary/Conclusion: A genetic predisposition to CHIP mutations could not be detected in our twin study which to our knowledge is the first hitherto performed. No difference in survival was observed in a direct comparison among twin pairs that were discordant for CHIP mutation.