| 1. |
- 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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| 3. |
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| 4. |
- Jarviaho, Tekla, et al.
(författare)
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Predisposition to childhood acute lymphoblastic leukemia caused by a constitutional translocation disrupting ETV6
- 2019
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 3:18, s. 2722-2731
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Tidskriftsartikel (refereegranskat)abstract
- Pathogenic germline variants in ETV6 have been associated with familial predisposition to thrombocytopenia and hematological malignancies, predominantly childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In addition, overrepresentation of a high hyperdiploid subtype and older age at diagnosis have been reported among sporadic BCP-ALL cases with germline variants in ETV6. We studied a family with 2 second-degree relatives who developed childhood high hyperdiploid BCP-ALL at ages 8 and 12 years, respectively. A constitutional balanced reciprocal translocation t(12;14)(p13.2;q23.1) was discovered in both patients by routine karyotyping at diagnosis and, subsequently, in 7 healthy family members who had not experienced hematological malignancies. No carriers had thrombocytopenia. Whole-genome sequencing confirmed the translocation, resulting in 2 actively transcribed but nonfunctional fusion genes, causing heterozygous loss and consequently monoallelic expression of ETV6. Whole-genome sequencing analysis of the affected female subjects' leukemia excluded additional somatic aberrations in ETV6 and RTN1 as well as shared somatic variants in other genes. Expression studies, performed to confirm decreased expression of ETV6, were not conclusive. We suggest that germline aberrations resulting in monoallelic expression of ETV6 contribute to leukemia susceptibility, whereas more severe functional deficiency of ETV6 is required for developing THC5. To our knowledge, this report is the first of a constitutional translocation disrupting ETV6 causing predisposition to childhood ALL.
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| 6. |
- Sawcer, Stephen, et al.
(författare)
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Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
- 2011
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 476:7359, s. 214-219
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
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