Common fragile site <i>FRA11G</i> and rare fragile site <i>FRA11B</i> at 11q23.3 encompass distinct genomic regions

Fechter, Anne; Buettel, Isabel; Kuehnel, Elisabeth; Savelyeva, Larissa; Schwab, Manfred

doi:10.1002/gcc.20389

Cited by 25 publications

(12 citation statements)

References 45 publications

(62 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We were able to find high-resolution genomic coordinates of 18 autosomal cloned aCFS either using BAC accession numbers (Ciullo et al 2002;Fechter et al 2007;Reshmi et al 2007;Bosco et al 2010;Pelliccia et al 2010;Blumrich et al 2011) or data collected by Ruiz-Herrera and colleagues (Ruiz-Herrera et al 2006). Among these,14 (FRA2C,FRA2G,FRA2H,FRA3B,FRA4F,FRA6E,FRA6F,FRA7B,FRA7G,FRA7H,FRA9E,FRA11F,FRA11G, and FRA13A) overlapped with aCFSs cytogenetically defined by Mrasek and colleagues (Mrasek et al 2010), while high-resolution coordinates for the remaining four (FRA1E, FRA7E, FRA7I, and FRA16D) did not overlap with their cytogenetic coordinates (Supplemental Table S8).…”

Section: Validation In Cloned Acfssmentioning

confidence: 99%

See 1 more Smart Citation

A genome-wide analysis of common fragile sites: What features determine chromosomal instability in the human genome?

et al. 2012

View full text Add to dashboard Cite

Chromosomal common fragile sites (CFSs) are unstable genomic regions that break under replication stress and are involved in structural variation. They frequently are sites of chromosomal rearrangements in cancer and of viral integration. However, CFSs are undercharacterized at the molecular level and thus difficult to predict computationally. Newly available genome-wide profiling studies provide us with an unprecedented opportunity to associate CFSs with features of their local genomic contexts. Here, we contrasted the genomic landscape of cytogenetically defined aphidicolin-induced CFSs (aCFSs) to that of nonfragile sites, using multiple logistic regression. We also analyzed aCFS breakage frequencies as a function of their genomic landscape, using standard multiple regression. We show that local genomic features are effective predictors both of regions harboring aCFSs (explaining ∼81% of the deviance in logistic regression models) and of aCFS breakage frequencies (explaining ∼45% of the variance in standard regression models). In our optimal models (based on a combination of biological interpretability and high R-squared value), aCFSs are predominantly located in G-negative chromosomal bands and away from centromeres, are enriched in Alu repeats, and have high DNA flexibility. In alternative models, CpG island density, H3K4me1 coverage, and mononucleotide microsatellite coverage are significant predictors. Also, aCFSs have high fragility when colocated with evolutionarily conserved chromosomal breakpoints. Our models are predictive of the fragility of aCFSs mapped at a higher resolution. Importantly, the genomic features we identified here as significant predictors of fragility allow us to draw valuable inferences on the molecular mechanisms underlying aCFSs.

show abstract

Section: Validation In Cloned Acfssmentioning

confidence: 99%

“…Eighteen autosomal aCFSs mapped by fluorescence probes (i.e., "cloned") (Ciullo et al 2002;Ruiz-Herrera et al 2006;Fechter et al 2007;Reshmi et al 2007;Bosco et al 2010;Pelliccia et al 2010;Blumrich et al 2011) were studied. For analysis, we intersected their cloned and cytogenetically defined coordinates.…”

Section: Cloned Acfssmentioning

confidence: 99%

A genome-wide analysis of common fragile sites: What features determine chromosomal instability in the human genome?

et al. 2012

View full text Add to dashboard Cite

show abstract

“…FRA11G is a common fragile site located on 11q23.3, rendering this region susceptible to frequent genomic instability [19]. Deletion of the H2A histone family, member X (H2AFX) gene on chromosome 11q23.3 has been associated with genomic instability and tumorigenesis; recently, Srivastava et al found that deletion of H2AFX was associated with high-grade tumors and suggested that deletion of H2AFX may be an early event, leading to uncontrolled cellular proliferation and initiation of tumor development [20].…”

Section: Discussionmentioning

confidence: 99%

Molecular Changes in Primary Breast Tumors and the Nottingham Histologic Score

Ellsworth

Hooke

Love³

et al. 2009

Pathol. Oncol. Res.

View full text Add to dashboard Cite

Pathological grade is routinely used to stratify breast cancer patients into favorable and less favorable outcome groups. Mechanisms by which genomic changes in breast tumors specifically contribute to the underlying components of tumor grade - tubule formation, nuclear pleomorphism, and mitoses - are unknown. This study examined 26 chromosomal regions known to be altered in breast cancer in 256 invasive breast carcinomas. Differences in overall levels and patterns of allelic imbalance (AI) at each chromosomal region were compared for tumors with favorable (=1) and unfavorable (=3) scores for tubule formation, nuclear pleomorphism and mitotic count. Levels of AI were significantly different between samples with high and low scores for tubule formation (P < 0.001), nuclear pleomorphism (P < 0.001) and mitotic count (P < 0.05). Significantly higher levels of AI were detected at regions 11q23 and 13q12 for tumors with reduced tubule formation, chromosomes 9p21, 11q23, 13q14, 17p13 and 17q12 for those with high levels of nuclear atypia, and chromosomes 1p36, 11q23, and 13q14 for those with high mitotic counts. Region 16q11-q22 showed significantly more AI events in samples with low nuclear atypia. Patterns of genetic changes associated with poorly-differentiated breast tumors were recapitulated by the individual components of the Nottingham Histologic Score. While frequent alteration of 11q23 is common for reduced tubule formation, high nuclear atypia and high mitotic counts, suggesting that this is an early genetic change in the development of poorly-differentiated breast tumors, alterations at the other seven loci associated with poorly-differentiated tumors may specifically influence cell structure, nuclear morphology and cellular proliferation.

show abstract

“…For 19 of these, namely FRA2G, FRA3B, FRA6F, FRA6E, FRA7E, FRA7G, FRA7H, FRA7I, FRA8C, FRA9E, FRA16D, FRAXB (Schwartz et al, 2006), FRA13A (Savelyeva et al, 2006a), FRA1E (Hormozian et al, 2006), FRA11E (Bester et al, 2006), FRA11F (Reshmi et al, 2007), FRA11G (Fechter et al, 2007a), FRA1H (Curatolo et al, 2007), and FRA18C (Debacker et al, 2007) DNA sequences have been determined and characterized at the molecular level. However, the exact number of common fragile sites appears to be even larger than those identified by classical cytogenetic analysis.…”

Section: Introductionmentioning

confidence: 97%

Novel aphidicolin‐inducible common fragile site FRA9G maps to 9p22.2, within the C9orf39 gene

Sawińska

Schmitt

Sagulenko

et al. 2007

Genes Chromosomes & Cancer

Self Cite

View full text Add to dashboard Cite

Common fragile sites represent a component of normal chromosome structure that form gaps and breaks on metaphase chromosomes after partial inhibition of DNA synthesis. In humans, cytogenetic locations of 89 common fragile sites are listed in the Genome Database; however, the exact number of fragile sites remains unknown. The application of high resolution mapping approaches continues to reveal new common fragile sites in the human genome. Here, we identified a novel aphidicolin-inducible common fragile site FRA9G, which maps to chromosomal band 9p22.2. We have characterized the structure of the fragile DNA sequence that extends over a genomic region of approximately 300 kb within the C9orf39 (chromosome 9 open reading frame 39) gene. Analysis of incidence in healthy individuals showed that FRA9G is commonly expressed in the population. Heterozygous BRCA2 mutation carriers exhibit an almost sevenfold increase of FRA9G expression compared to an unrelated control population group. Identification of a novel aphidicolin-inducible common fragile site at 9p22 may have implications for understanding the mechanism of genetic instability in tumorigenesis and other genetic disorders.

show abstract

Common fragile site FRA11G and rare fragile site FRA11B at 11q23.3 encompass distinct genomic regions

Cited by 25 publications

References 45 publications

A genome-wide analysis of common fragile sites: What features determine chromosomal instability in the human genome?

A genome-wide analysis of common fragile sites: What features determine chromosomal instability in the human genome?

Molecular Changes in Primary Breast Tumors and the Nottingham Histologic Score

Novel aphidicolin‐inducible common fragile site FRA9G maps to 9p22.2, within the C9orf39 gene

Contact Info

Product

Resources

About