FRA18C: a new aphidicolin-inducible fragile site on chromosome 18q22, possibly associated with in vivo chromosome breakage

Fragile sites are specific genomic regions that appear as gaps, constrictions or breaks on chromosomes in cells grown under conditions that perturb DNA replication. ¹ According to their frequency within the population, fragile sites are divided into two groups: rare and common. Rare fragile sites have a maximum frequency of 1/20 in the human population, whereas common fragile sites are considered as an intrinsic component of the chromosome structure, present in all individuals. To date, 30 rare and 88 common fragile sites have been described. ^{2- 4} The majority of rare fragile sites are expressed when cells are grown in folic acid deficient medium, whereas some are induced by bromodeoxyuridine or distamycin A. Most common fragile sites are induced by aphidicolin, which inhibits DNA polymerases α and δ.

Repeat expansions form the molecular basis of rare fragile sites. Six of the folate-sensitive type have been cloned to date, including FRAXA, FRAXE, FRAXF, FRA11B, FRA16A and FRA10A, and are all due to a CGG-repeat expansion. The distamycin-sensitive site FRA16B and the bromodeoxyuridine-inducible site FRA10B are caused by expansion of similar AT-rich minisatellites. ^{5, 6} All cloned common fragile sites to date (n=15) are characterised by enrichment of highly flexible AT-dinucleotide rich sequences ^{7, 8} and reviewed by Schwartz et al . ⁴

Rare fragile sites are often associated with human diseases. An expression of the fragile site FRAXA causes fragile X syndrome, the most frequent cause of inherited mental retardation. ⁹ Expansion of the FRAXE repeat is associated with a mild form of mental retardation. ¹⁰ In vivo chromosome breakage at or near the FRA11B locus has been implicated in Jacobsen syndrome, characterised by mental retardation and specific associated abnormalities. ¹¹

Common fragile sites have often been associated with chromosome breakpoints in tumour cells. First evidence for this was provided by statistical analyses, ^{12, 13} later confirmed by the cloning of common fragile sites, containing genes often deleted in tumour cells, reviewed in Arlt et al . ¹⁴ For example, the fragile site FRA3B maps within the large FHIT gene, and is often rearranged in tumour cells. ¹⁵ Next to deletions, amplification events and/or translocations are also associated with chromosomal breakage in common fragile sites. ¹⁶ Jamieson et al ¹⁷ described a family with a...