RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability Journal Article
| Authors: | Heikkinen, K.; Rapakko, K.; Karppinen, S. M.; Erkko, H.; Knuutila, S.; Lundán, T.; Mannermaa, A.; Børresen-Dale, A. L.; Borg, A.; Barkardottir, R. B.; Petrini, J.; Winqvist, R. |
| Article Title: | RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability |
| Abstract: | The Mre11 complex, composed of RAD50, NBS1 and MRE11, has an essential role in the maintenance of genomic integrity and preventing cells from malignancy. Here we report the association of three Mre11 complex mutations with hereditary breast cancer susceptibility, studied by using a case-control design with 317 consecutive, newly diagnosed Northern Finnish breast cancer patients and 1000 geographically matched healthy controls (P = 0.0004). RAD50 687delT displayed significantly elevated frequency in the studied patients (8 out of 317, OR 4.3, 95% CI 1.5-12.5, P = 0.008), which indicates that it is a relatively common low-penetrance risk allele in this cohort. Haplotype analysis and the screening of altogether 512 additional breast cancer cases from Sweden, Norway and Iceland suggest that RAD50 687delT is a Finnish founder mutation, not present in the other Nordic cohorts. The RAD50 IVS3-1G>A splicing mutation leading to translational frameshift was observed in one patient, and the NBS1 Leu150Phe missense mutation affecting a conserved residue in the functionally important BRCA1 carboxy-terminal (BRCT) domain in two patients, both being absent from 1 000 controls. Microsatellite marker analysis showed that loss of the wild-type allele was not involved in the tumorigenesis in any of the studied mutation carriers, but they all showed increased genomic instability assessed by cytogenetic analysis of peripheral blood T-lymphocytes (P = 0.006). In particular, the total number of chromosomal rearrangements was significantly increased (P = 0.002). These findings suggest an effect for RAD50 and NBS1 haploinsufficiency on genomic integrity and susceptibility to cancer. © 2006 Oxford University Press. |
| Keywords: | adult; controlled study; human tissue; aged; aged, 80 and over; middle aged; human cell; major clinical study; case control study; frameshift mutation; missense mutation; mutation; case-control studies; dna-binding proteins; t lymphocyte; t-lymphocytes; cell cycle proteins; mre11 protein; rad50 protein; cancer susceptibility; genetic predisposition to disease; cohort studies; breast cancer; carboxy terminal sequence; cohort analysis; genetic association; genotype; gene frequency; haplotypes; mass screening; mutational analysis; breast neoplasms; brca1 protein; wild type; nibrin; haplotype; nuclear proteins; pedigree; sweden; genome analysis; tumor suppressor gene; gene rearrangement; genomic instability; genetic susceptibility; gene identification; dna repair enzymes; gene loss; chromosome rearrangement; microsatellite marker; leucine; genetic screening; chromosome analysis; breast carcinogenesis; genetic code; genetic conservation; cytogenetic analysis; rna splicing; phenylalanine; penetrance; microsatellite repeats; norway; peripheral lymphocyte; iceland; chromosome number |
| Journal Title: | Carcinogenesis |
| Volume: | 27 |
| Issue: | 8 |
| ISSN: | 0143-3334 |
| Publisher: | Oxford University Press |
| Date Published: | 2006-08-01 |
| Start Page: | 1593 |
| End Page: | 1599 |
| Language: | English |
| DOI: | 10.1093/carcin/bgi360 |
| PUBMED: | 16474176 |
| PROVIDER: | scopus |
| PMCID: | PMC3006189 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 55" - "Export Date: 4 June 2012" - "CODEN: CRNGD" - "Source: Scopus" |
