Uncompromised ten-year survival of oldest old carrying somatic mutations in DNMT3A and TET2

Abstract: Recent large-scale sequencing studies report recurrent somatic mutations in the blood of normal elderly individuals in genes linked to clonal expansion of hematopoietic stem cells. Particularly for DNMT3A and TET2, two key genes in DNA methylation processes, a steep age-associated increase in the incidence of somatic mutations is observed from middle age onward. Hence, these data suggest a rapidly increasing vulnerability amongst the elderly for adverse health effects associated with clonal expansion of hematopoietic stem cells. We analysed blood-derived whole-exome and whole-genome sequencing data of elderly subsamples from the Rotterdam Study (RS; N=646; mean age 85 years [range 80-106]) and the Leiden Longevity Study (LLS, N=218, mean age 94 years [range 89-103]). We set out to identify small somatic mutations in 15 genes preciously linked with clonal expansion and analysed their presence for an association with prospective mortality during an 8-10 year follow-up. A mutational analysis identified 39 (6.0%) and 40 (18.3%) unique carriers of respectively 42 and 46 mutations for the RS and LLS elderly subsamples respectively, predominantly in DNMT3A and TET2. Sanger sequencing confirmed the presence of 17 out of 18 selected mutations in DNMT3A and TET2. Moreover, the spatial correlation between the identified variants within DNMT3A and TET2 with respect to the primary protein sequence and previous reports in Catalogue of Somatic Mutations in Cancer further corroborated our findings. Carriership, however, was not associated with an increased risk on mortality in neither the RS (HR=0.83 (0.58-1.17), p=0.29) nor the LLS (HR=0.94 (0.65-1.35), p=0.61), nor in a fixed effect meta-analysis combining the results in the elderly subsamples (HR=0.88 (0.68-1.13), p=0.32). We conclude that, that somatic mutations in genes previously associated with clonal outgrowth are very common among the oldest old, especially in DNMT3A and TET2. Unlike previous reports in predominantly middle-aged individuals, somatic mutations in genes linked to clonal expansion of hematopoietic stem cells do not compromise the 8-10 year survival in the oldest old.

 Selected talk @ Keystone 2016 & Travel Award Scholarship
Erik van den Akker, Steven J. Pitts, Joris Deelen, Mathijs H. Moed, Shobha Potluri, et al. Uncompromised ten-year survival of oldest old carrying somatic mutations in DNMT3A and TET2. Blood, 127(11): pp. 1512–1515, 2016.
@article { bib:2016_blood_dnmt3a,
author = { Erik van den Akker and Steven J. Pitts and Joris Deelen and Mathijs H. Moed and Shobha Potluri and Jeroen van Rooij and H. Eka D. Suchiman and Nico Lakenberg and Wesley J. de Dijcker and Andre G. Uitterlinden and Robert Kraaij and Albert Hofman and Anton J.M. de Craen and Jeanine J. Houwing-Duistermaat and Gert-Jan B. van Ommen and david R. Cox and Joyce B.J. van meurs and Marian Beekman and Marcel Reinders and P.E. Slagboom },
title = { Uncompromised ten-year survival of oldest old carrying somatic mutations in DNMT3A and TET2 },
journal = { Blood },
volume = { 127 },
number = { 11 },
pages = { 1512 -- 1515 },
year = { 2016 },
doi = { 10.1182/blood-2015-12-685925 },
}