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- Bang, Benedicte, et al.
(författare)
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A somatic UBA2 variant preceded ETV6-RUNX1 in the concordant BCP-ALL of monozygotic twins
- 2022
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 6:7, s. 2275-2289
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Tidskriftsartikel (refereegranskat)abstract
- Genetic analysis of leukemic clones in monozygotic twins with concordant acute lymphoblastic leukemia (ALL) has proved a unique opportunity to gain insight into the molecular phylogenetics of leukemogenesis. Using whole-genome sequencing, we characterized constitutional and somatic single nucleotide variants/insertion-deletions (indels) and structural variants in a monozygotic twin pair with concordant ETV6-RUNX1(+) B-cell precursor ALL (BCP-ALL). In addition, digital PCR (dPCR) was applied to evaluate the presence of and quantify selected somatic variants at birth, diagnosis, and remission. A shared somatic complex rearrangement involving chromosomes 11, 12, and 21 with identical fusion sequences in leukemias of both twins offered direct proof of a common clonal origin. The ETV6-RUNX1 fusion detected at diagnosis was found to originate from this complex rearrangement. A shared somatic frameshift deletion in UBA2 was also identified in diagnostic samples. In addition, each leukemia independently acquired analogous deletions of 3 genes recurrently targeted in BCP-ALLs (ETV6, ATF7IP, and RAG1/RAG2), providing evidence of a convergent clonal evolution only explained by a strong concurrent selective pressure. Quantification of the UBA2 deletion by dPCR surprisingly indicated it persisted in remission. This, for the first time to our knowledge, provided evidence of a UBA2 variant preceding the well-established initiating event ETV6-RUNX1. Further, we suggest the UBA2 deletion exerted a leukemia predisposing effect and that its essential role in Small Ubiquitin-like Modifier (SUMO) attachment (SUMOylation), regulating nearly all physiological and pathological cellular processes such as DNA-repair by nonhomologous end joining, may hold a mechanistic explanation for the predisposition.
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| 2. |
- Bang, Benedicte
(författare)
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Studies of congenital genetic aberrations behind childhood leukemia
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Acute lymphoblastic leukemia (ALL) is the most common cancer in childhood, and most frequently (85%) of B-cell precursor type (BCP-ALL). Acquired chromosomal rearrangements or aneuploidies are the recurrent, often prenatal, initiators of BCP-ALL. These aberrations define distinct molecular subtypes that are associated with differences in prognosis and used to guide treatment. Initiating variants are disease driving, but secondary variants are required to drive progression to overt disease. Although constitutional predisposing variants are found in an increasing share of cases (10-18%), BCP-ALL etiology remains largely unknown. Recent studies have suggested that exposure to common infections may modulate progression of BCP-ALL. The aim of this thesis was to identify, asses and quantify congenital genetic aberrations behind childhood BCP-ALL predisposition and initiation, as well as to characterize subsequent clonal evolution and identify drivers of progression to overt disease. To this end, we performed whole genome sequencing (WGS) to identify constitutional BCP-ALL-predisposing variants. In paper I, we reported familial predisposition mediated by a constitutional t(12;14), where haploinsufficiency of the powerful transcription factor ETV6 was suggested to cause predisposition. In paper III, monozygotic twins with concordant BCP-ALL shared a constitutional, maternally inherited, novel variant in NF1, predicted to be highly damaging. As none of the carriers has any clinical sign of the cancer syndrome neurofibromatosis type 1 (NF1), we classified the variant to be of unknown significance (VUS), but speculated its possible BCP-ALL-predisposing effect. We developed a sensitive and quantitative method for backtracking BCP-ALL to pre-leukemic clones (paper II), applying chip dPCR in combination with WGS to analyze DNA from neonatal dried blood spots. In paper II, only one case of BCP-ALL, diagnosed at age 1 month, had detectable copy numbers of genomic breakpoint sequence at birth. Failed detection in the remaining six cases was suggested to be caused by technical and sample related limitations, and less frequently postnatal initiation. In paper III, WGS identified a shared somatic complex rearrangement, generating ETV6- RUNX1, in the BCP-ALLs of monozygotic twins. Detection at birth by dPCR failed, but identical breakpoint sequences confirmed its prenatal origin. Surprisingly, a shared (prenatal) deletion in UBA2 was found to precede the complex rearrangement, persisting after several years in remission. Clonal evolution of concordant BCP-ALLs was characterized in paper III, detecting shared and unique overlapping secondary putative driver variants, supporting independent although convergent clonal evolution. In paper I, 7-10 secondary putative driver variants, in genes recurrently targeted in childhood ALL, were identified in BCP-ALLs with ETV6-mediated predisposition. This further supported that secondary drivers are required for progression, although phylogenetics of somatic events in ETV6-predisposed cases remains to be delineated. In paper IV, we assessed a Swedish population-based cohort of 1380 BCP-ALL cases and used GARIMAX to demonstrate informative seasonal variation in onset and interpreted peak onset to fall in August. Four explanatory models, related to exposure to common infections as a driver of final progression to overt disease, were suggested. The likelihood of each model depends on still unknown induction time of childhood BCP- ALL. Together, these studies add to our understanding of; congenital susceptibility to BCP-ALL through constitutional predisposing variants and prenatally initiated pre-leukemic clones, progression to overt disease through somatic clonal evolution and the genetic and environmental drivers of this process.
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