Multicolor FISH Mapping of YAC Clones in 3p14 and Identification of a YAC Spanning both FRA3B and the t(3;8) Associated with Hereditary Renal Cell Carcinoma

Wilke, Cailin Moira; Guo, Sun Wei; Hall, Brad; Boldog, Ferenc; Gemmill, Robert M.; Chandrasekharappa, Settara C.; Barcroft, Christine L.; Drabkin, Harry A.; Glover, Thomas W.

doi:10.1006/geno.1994.1390

Cited by 65 publications

(33 citation statements)

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“…The recently identi®ed FHIT gene encompasses the FRA3B region and the hRCC breakpoint. The hRCC breakpoint and FRA3B are cytologically indistinguishable from each other (Wilke et al, 1994), but detailed molecular analysis with a YAC clone identi®ed by Boldog et al (1993) revealed that the hRCC breakpoint was proximal to both aphidicolin-induced breakpoints generated in a chromosome 3-only somatic cell hybrid (Wang et al, 1993) and a region of consistent breakage observed when lymphocytes were cultured in the presence of aphidicolin (Paradee et al, 1995(Paradee et al, , 1996.…”

Section: Discussionmentioning

confidence: 98%

Frequent breakpoints in the region surrounding FRA3B in sporadic renal cell carcinomas

et al. 1997

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The constitutive fragile site at chromosomal band 3p14.2, FRA3B, is the most active common fragile site in the human genome. We have localized aphidicolininduced breakpoints to two distinct clusters, separated by 200 Kb, in FRA3B (Paradee et al., 1996). Sequence analysis of these regions identi®ed two polymorphic microsatellite markers immediately adjacent to each of these breakpoint clusters. In this report we have used these two new microsatellites and 14 additional 3p microsatellites to analyse chromosome 3p breakage and loss in 94 sporadic RCC samples, including nonpapillary, papillary and oncocytomas. We have found heterozygous loss of 3p14 sequences in 460% of the RCC samples, including both clear cell and papillary renal cell carcinomas. We have found frequent breakage in the region immediately surrounding FRA3B, demonstrating that FRA3B does play a role in chromosome breakage and loss in RCC. In contrast to other reports, 450% of the papillary tumors also showed LOH of 3p markers. We also observed microsatellite instability (MIN) with most of the tested markers in seven of eight oncocytomas and one of 69 clear cell carcinomas. The MIN in some oncocytomas was of the RER+ (replication error) type I phenotype. None of the ®ve 3p14.2 markers detected any homozygous deletions in tumor samples, but 69/94 (73%) of the tumors had LOH for the region, which includes the recently identi®ed FHIT gene.

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Section: Discussionmentioning

confidence: 98%

Frequent breakpoints in the region surrounding FRA3B in sporadic renal cell carcinomas

et al. 1997

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“…Even though multiple markers which span this breakpoint region have been isolated, a gene has yet to be identi®ed in RCC, with altered expression as a result of the 3;8 rearrangement. One cDNA clone, HCRA1, was identi®ed which mapped adjacent to the 3;8 translocation, but is not rearranged or expressed in RCC patients (Boldog et al, 1993;Wilke et al, 1994). A second gene, FHIT, has been mapped by hybridization to markers from within the t(3;8) RCC breakpoint to the 3p14.2 region.…”

Section: Introductionmentioning

confidence: 99%

The FHIT gene is alternatively spliced in normal kidney and renal cell carcinoma

et al. 1997

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“…The expanded FRA16B and FRA10B repeats are highly similar and contain inverted repeats able to form hairpin structures (reviewed in reference 19). Six common fragile sites have been cloned and characterized: FRA3B (3,40,43,58,59,62), FRA7G (24,27), FRA7H (37), FRA16D (34, 45), FRAXB (1), and FRA6F (38). The cytogenetic expression (gaps and constrictions) of these sites is visible along large genomic regions spanning hundreds to thousands of kilobases.…”

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confidence: 99%

Molecular Basis for Expression of Common and Rare Fragile Sites

Zlotorynski

Rahat

Skaug

et al. 2003

Molecular and Cellular Biology

219

252

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Fragile sites are specific loci that form gaps, constrictions, and breaks on chromosomes exposed to partial replication stress and are rearranged in tumors. Fragile sites are classified as rare or common, depending on their induction and frequency within the population. The molecular basis of rare fragile sites is associated with expanded repeats capable of adopting unusual non-B DNA structures that can perturb DNA replication. The molecular basis of common fragile sites was unknown. Fragile sites from R-bands are enriched in flexible sequences relative to nonfragile regions from the same chromosomal bands. Here we cloned FRA7E, a common fragile site mapped to a G-band, and revealed a significant difference between its flexibility and that of nonfragile regions mapped to G-bands, similar to the pattern found in R-bands. Thus, in the entire genome, flexible sequences might play a role in the mechanism of fragility. The flexible sequences are composed of interrupted runs of AT-dinucleotides, which have the potential to form secondary structures and hence can affect replication. These sequences show similarity to the AT-rich minisatellite repeats that underlie the fragility of the rare fragile sites FRA16B and FRA10B. We further demonstrate that the normal alleles of FRA16B and FRA10B span the same genomic regions as the common fragile sites FRA16C and FRA10E. Our results suggest that a shared molecular basis, conferred by sequences with a potential to form secondary structures that can perturb replication, may underlie the fragility of rare fragile sites harboring AT-rich minisatellite repeats and aphidicolin-induced common fragile sites.Fragile sites are specific loci that appear as constrictions, gaps, or breaks on chromosomes from cells exposed to partial inhibition of DNA replication (16). They are classified as rare or common, depending on their frequency within the population and their specific mode of induction. Rare fragile sites (n ϭ 28, as listed in the Genome Database [GDB]) appear in Ͻ5% of the human population and segregate in specific families. Most rare fragile sites are induced by folate deficiency, and others are induced by DNA minor groove binders (52). Common fragile sites (n ϭ 89, as listed in the GDB), on the other hand, are considered to be an intrinsic part of the chromosomal structure and are thought to be present in all individuals. Most common fragile sites (n ϭ 76) are induced by aphidicolin (16), an inhibitor of DNA polymerases ␣ and ␦. After induction with replication inhibitors these sites are involved in sister chromatid exchange, deletions and translocations, gene amplification, and plasmid integration (reviewed in reference 15). Common fragile sites also correlate with chromosomal breakpoints in tumors (22, 61) and were shown to play a role in the in vivo occurrence of deletions and translocations (reviewed in reference 44), gene amplification (24), and integration of foreign DNA (37,54,59). Despite their inherent instability, several common fragile sites are conserved between mice...

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Multicolor FISH Mapping of YAC Clones in 3p14 and Identification of a YAC Spanning both FRA3B and the t(3;8) Associated with Hereditary Renal Cell Carcinoma

Cited by 65 publications

References 0 publications

Frequent breakpoints in the region surrounding FRA3B in sporadic renal cell carcinomas

Frequent breakpoints in the region surrounding FRA3B in sporadic renal cell carcinomas

The FHIT gene is alternatively spliced in normal kidney and renal cell carcinoma

Molecular Basis for Expression of Common and Rare Fragile Sites

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