Complex chromosomal abnormalities <i>in utero</i>, 5 years before leukaemia*

Broadfield, Zoë J.; Hain, Richard; Harrison, Christine J.; Jalali, G. Reza; McKinley, MJ; Michalová, K; Robinson, Hazel M.; Zemanová, Zuzana; Martineau, Mary

doi:10.1111/j.1365-2141.2004.05036.x

Cited by 19 publications

(19 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We assume that a ETV6-RUNX1 protein is the key functional product of this complex rearrangement but cannot rule out contributions from other components. This complexity of gene fusion is unusual in ALL but was suspected in this pair based on karyotype and FISH data (10) and is similar to chromosomal breakage/fusion cascades involved in generating the TMPRSS2-ERG fusion gene in prostate cancer (12).…”

Section: Resultsmentioning

confidence: 99%

Developmental timing of mutations revealed by whole-genome sequencing of twins with acute lymphoblastic leukemia

Dobbins

Sherborne

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Acute lymphoblastic leukemia (ALL) is the major pediatric cancer. At diagnosis, the developmental timing of mutations contributing critically to clonal diversification and selection can be buried in the leukemia's covert natural history. Concordance of ALL in monozygotic, monochorionic twins is a consequence of intraplacental spread of an initiated preleukemic clone. Studying monozygotic twins with ALL provides a unique means of uncovering the timeline of mutations contributing to clonal evolution, pre-and postnatally. We sequenced the whole genomes of leukemic cells from two twin pairs with ALL to comprehensively characterize acquired somatic mutations in ALL, elucidating the developmental timing of all genetic lesions. Shared, prenatal, coding-region single-nucleotide variants were limited to the putative initiating lesions. All other nonsynonymous single-nucleotide variants were distinct between tumors and, therefore, secondary and postnatal. These changes occurred in a background of noncoding mutational changes that were almost entirely discordant in twin pairs and likely passenger mutations acquired during leukemic cell proliferation.fusion gene | copy number variants T he sharing in monozygotic (MZ) twins of identical but nonconstitutive and clone-specific fusion gene sequences (e.g., ETV6-RUNX1) in acute lymphoblastic leukemia (ALL) provided the first unambiguous evidence that genetic lesions, generated by chromosomal translocation, arise in utero (1). These data were interpreted to suggest that ETV6-RUNX1 is likely to be a critical initiating lesion for ETV6-RUNX1-positive ALL, a view supported by single-cell genetic analysis (2) and modeling with murine (3) or human cells (4). However, such fusions are detectable in cord blood from newborn infants at rates ∼100-fold higher than the incidence of ALL, suggesting an obligatory requirement for additional mutations in leukemia development (5). Recurrent copy number variations (CNVs), mostly deletions, in ALL have been revealed by SNP arrays (6) and in twins with concordant ALL with ETV6-RUNX1. These CNVs are distinctive between twins of a pair, indicating a secondary, postnatal origin (7) that is also supported by single-cell clonal analysis (2). An additional layer of genetic complexity in acute leukemia is now apparent from genome sequencing (8, 9), and applying this technology to MZ twins with ALL provides a unique opportunity to decipher the timeline of all acquired genetic events in leukemogenesis.Predicated on the hypothesis that shared identical mutations are prenatal in origin and twin-specific mutations are likely to be secondary and postnatal, we performed whole-genome sequencing of two MZ twin pairs with ALL. ResultsWe studied two pairs of twins, twins 1.A and 1.B with ETV6-RUNX1 fusion-positive ALL (7, 10) and twins 2.A and 2.B with ETV6-RUNX1 fusion-negative ALL. Sequencing of matched tumor-normal (remission) samples from each patient was carried out using unchained combinatorial probe anchor ligation chemistry on arrays of self-assembling DNA n...

show abstract

Section: Resultsmentioning

confidence: 99%

Developmental timing of mutations revealed by whole-genome sequencing of twins with acute lymphoblastic leukemia

Dobbins

Sherborne

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…There is a mounting body of evidence that the leukaemic clone frequently originates during in utero development [39][40][41][42]. The most compelling evidence to support this comes from the high rate of leukaemia concordance among monozygotic twins who shared a monochorionic placenta [43][44][45][46].…”

Section: Neoplasiamentioning

confidence: 99%

The Fanconi anaemia pathway orchestrates incisions at sites of crosslinked DNA

Crossan

Patel

2011

The Journal of Pathology

View full text Add to dashboard Cite

Fanconi anaemia (FA) is a rare, autosomal recessive, genetically complex, DNA repair deficiency syndrome in man. Patients with FA exhibit a heterogeneous spectrum of clinical features. The most significant and consistent phenotypic characteristics are stem cell loss, causing progressive bone marrow failure and sterility, diverse developmental abnormalities and a profound predisposition to neoplasia. To date, 15 genes have been indentified, biallelic disruption of any one of which results in this clinically defined syndrome. It is now apparent that all 15 gene products act in a common process to maintain genome stability. At the molecular level, a fundamental defect in DNA repair underlies this complex phenotype. Cells derived from FA patients spontaneously accumulate broken chromosomes and exhibit a marked sensitivity to DNA-damaging chemotherapeutic agents. Despite complementation analysis defining many components of the FA DNA repair pathway, no direct link to DNA metabolism was established until recently. First, it is now evident that the FA pathway is required to make incisions at the site of damaged DNA. Second, a specific component of the FA pathway has been identified that regulates nucleases previously implicated in DNA interstrand crosslink repair. Taken together, these data provide genetic and biochemical evidence that the FA pathway is a bona fide DNA repair pathway that directly mediates DNA repair transactions, thereby elucidating the specific molecular defect in human Fanconi anaemia.

show abstract

“…The paper presents results of investigation of 70 ALL in children revealed, that karyotypes were obtained in 84% (Soszynska et al, 2008). M-FISH elucidated complex karyotypes (Broadfield et al, 2004;Harrison et al, 1999).…”

Section: Fig 2 Results Of Conventional Cytogenetic Investigation Inmentioning

confidence: 99%

Genetic Studies in Acute Lymphoblastic Leukemia, from Diagnosis to Optimal Patient’s Treatment

Krawczyk-Kuliś¹

2012

Recent Trends in Cytogenetic Studies - Methodologies and Applications

View full text Add to dashboard Cite

Complex chromosomal abnormalities in utero, 5 years before leukaemia*

Cited by 19 publications

References 17 publications

Developmental timing of mutations revealed by whole-genome sequencing of twins with acute lymphoblastic leukemia

Developmental timing of mutations revealed by whole-genome sequencing of twins with acute lymphoblastic leukemia

The Fanconi anaemia pathway orchestrates incisions at sites of crosslinked DNA

Genetic Studies in Acute Lymphoblastic Leukemia, from Diagnosis to Optimal Patient’s Treatment

Contact Info

Product

Resources

About