Disabled‐1 is a large common fragile site gene, inactivated in multiple cancers

Abstract

Common fragile sites (CFS) are large, genomically unstable regions, which are hot-spots for deletions and other alterations, especially in cancer cells. Several have been shown to contain genes that span large genomic regions, such as FHIT (1.5 Mb), WWOX (1.0 Mb), GRID2 (1.36 Mb), PARK2 (1.3 Mb), and RORA (730 kb). These genes are frequently inactivated in multiple different cancers, and FHIT and WWOX are shown to function as tumor suppressors. The disabled-1 gene (DAB1) is one of the human homologs of the Drosophila disabled locus, which in mammals is involved in neuronal migration and lamination in the developing cerebral cortex. Mice DAB1 inactivation results in the neurological mutant Scrambler, having similarities to mice with the inactivation of PARK2 (Quaker), GRID2 (Lurcher), and RORA (Staggerer). We were interested in whether DAB1 was another large CFS gene that could have cancer development importance. We demonstrated here that the human DAB1 gene (spanning 1.25 Mb) mapped within FRA1B CFS region on chromosomal band 1p32.2. Real-time RT-PCR analysis revealed that the expression level of DAB1 was decreased in many human cancer samples, including primary tumor tissues and cancer-derived cell lines, from several different cancers, especially in brain and endometrial cancer. Additionally, the introduction of an over-expression DAB1 plasmid into two different cell lines, having insignificant endogenous DAB1 expression, resulted in decreased cell growth. In summary, DAB1 is another gene that resides within an unstable CFS region and might play a role in human tumorigenesis. These data may provide further linkage between neurological development and cancer.

Replication dynamics at common fragile site FRA6E

“…The region of genomic instability extends over at least 500 kb for all of them, even though breakages may occur in hot spots along this very large genomic sequence (Krummel et al 2000;Ried et al 2000;Becker et al 2002;Arlt et al 2002;Callahan et al 2003;Denison et al 2003c;Rozier et al 2004;McAvoy et al 2008). Sequence analysis did not help to elucidate the reason for chromosome instability at these loci (Schwartz et al 2006;Lukusa and Fryns 2008).…”

Correlation between array-comparative genomic hybridization-defined genomic gains and losses and survival: identification of 1p31-32 deletion as a prognostic factor in myeloma

“…Of the potentially important genes with correlated reduced expression on 1p31-32, DAB1 has been recently implicated as a potential tumor suppressor gene on a large genomic region that is a fragile site commonly deleted in cancers 32 . MSH4 is a member of the MutH homolog family that has been implicated in DNA instability in cancer, as it is involved in DNA repair 33.…”

Parkin and PINK1 mutations in early-onset Parkinson's disease: comprehensive screening in publicly available cases and control

“…It is located on chromosome 6q25.2-q27 in a highly unstable genomic region. 4 Point mutations and exon rearrangements in parkin are the most common genetic causes of early-onset PD; approximately 18% of sporadic and 50% of all familial early-onset cases have been attributed to parkin mutations. 5 PINK1, located on chromosome 1p36, has been implicated in PD based on linkage studies in families with autosomal recessive early-onset parkinsonism.…”