Convergent somatic evolution commences in utero in a germline ribosomopathy

Abstract

Clonal tracking of cells using somatic mutations permits exploration of clonal dynamics in human disease. Here, we perform whole genome sequencing of 323 haematopoietic colonies from 10 individuals with the inherited ribosomopathy Shwachman-Diamond syndrome to reconstruct haematopoietic phylogenies. In ~30% of colonies, we identify mutually exclusive mutations in TP53, EIF6, RPL5, RPL22, PRPF8, plus chromosome 7 and 15 aberrations that increase SBDS and EFL1 gene dosage, respectively. Target gene mutations commence in utero, resulting in a profusion of clonal expansions, with only a few haematopoietic stem cell lineages (mean 8, range 1-24) contributing ~50% of haematopoietic colonies across 8 individuals (range 4-100% clonality) by young adulthood. Rapid clonal expansion during disease transformation is associated with biallelic TP53 mutations and increased mutation burden. Our study highlights how convergent somatic mutation of the p53-dependent nucleolar surveillance pathway offsets the deleterious effects of germline ribosomopathy but increases opportunity for TP53-mutated cancer evolution.

Azacitidine combined with venetoclax alleviates AML-MR with TP53 mutation in SDS: a case report and literature review

“…The complex karyotypes and TP53 mutation carried in this case conferred an increased risk of malignant transformation [19]. Moreover, TP53 mutation was detected early when MDS was diagnosed, which has been identified as early and initiating events in malignant transformation [4,21]. SBDS cooperates with the GTPase elongation factor-like-1 (EFL1) to catalyze eukaryotic initiation factor 6 (eIF6) removal from the 60S ribosome subunit, allowing the joining of 40S and 60S ribosome subunit to facilitate the formation of the actively translating 80S subunit [22].…”