RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability.
To access publisher full text version of this article. Please click on the hyperlink in Additional Links field 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 t...
Published in: | Carcinogenesis |
---|---|
Main Authors: | , , , , , , , , , , , |
Format: | Article in Journal/Newspaper |
Language: | English |
Published: |
Irl Press At Oxford University Press
2008
|
Subjects: | |
Online Access: | http://hdl.handle.net/2336/21772 https://doi.org/10.1093/carcin/bgi360 |
id |
ftlandspitaliuni:oai:www.hirsla.lsh.is:2336/21772 |
---|---|
record_format |
openpolar |
spelling |
ftlandspitaliuni:oai:www.hirsla.lsh.is:2336/21772 2023-05-15T16:52:20+02:00 RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability. Heikkinen, Katri Rapakko, Katrin Karppinen, Sanna-Maria Erkko, Hannele Knuutila, Sakari Lundán, Tuija Mannermaa, Arto Børresen-Dale, Anne-Lise Borg, Ake Barkardottir, Rosa B Petrini, John Winqvist, Robert 2008-03-28 http://hdl.handle.net/2336/21772 https://doi.org/10.1093/carcin/bgi360 en eng Irl Press At Oxford University Press http://carcin.oxfordjournals.org/cgi/content/abstract/27/8/1593 Carcinogenesis 2006, 27(8):1593-9 0143-3334 16474176 doi:10.1093/carcin/bgi360 http://hdl.handle.net/2336/21772 Carcinogenesis Adult Aged Breast Neoplasms Case-Control Studies Cell Cycle Proteins Cohort Studies Cytogenetic Analysis DNA Repair Enzymes DNA-Binding Proteins Gene Rearrangement Genetic Predisposition to Disease Genomic Instability Genotype Haplotypes Mass Screening Microsatellite Repeats Middle Aged Mutation Nuclear Proteins Pedigree T-Lymphocytes Article 2008 ftlandspitaliuni https://doi.org/10.1093/carcin/bgi360 2022-05-29T08:21:07Z To access publisher full text version of this article. Please click on the hyperlink in Additional Links field 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 1000 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. Article in Journal/Newspaper Iceland Hirsla - Landspítali University Hospital research archive Norway Carcinogenesis 27 8 1593 1599 |
institution |
Open Polar |
collection |
Hirsla - Landspítali University Hospital research archive |
op_collection_id |
ftlandspitaliuni |
language |
English |
topic |
Adult Aged Breast Neoplasms Case-Control Studies Cell Cycle Proteins Cohort Studies Cytogenetic Analysis DNA Repair Enzymes DNA-Binding Proteins Gene Rearrangement Genetic Predisposition to Disease Genomic Instability Genotype Haplotypes Mass Screening Microsatellite Repeats Middle Aged Mutation Nuclear Proteins Pedigree T-Lymphocytes |
spellingShingle |
Adult Aged Breast Neoplasms Case-Control Studies Cell Cycle Proteins Cohort Studies Cytogenetic Analysis DNA Repair Enzymes DNA-Binding Proteins Gene Rearrangement Genetic Predisposition to Disease Genomic Instability Genotype Haplotypes Mass Screening Microsatellite Repeats Middle Aged Mutation Nuclear Proteins Pedigree T-Lymphocytes Heikkinen, Katri Rapakko, Katrin Karppinen, Sanna-Maria Erkko, Hannele Knuutila, Sakari Lundán, Tuija Mannermaa, Arto Børresen-Dale, Anne-Lise Borg, Ake Barkardottir, Rosa B Petrini, John Winqvist, Robert RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability. |
topic_facet |
Adult Aged Breast Neoplasms Case-Control Studies Cell Cycle Proteins Cohort Studies Cytogenetic Analysis DNA Repair Enzymes DNA-Binding Proteins Gene Rearrangement Genetic Predisposition to Disease Genomic Instability Genotype Haplotypes Mass Screening Microsatellite Repeats Middle Aged Mutation Nuclear Proteins Pedigree T-Lymphocytes |
description |
To access publisher full text version of this article. Please click on the hyperlink in Additional Links field 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 1000 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. |
format |
Article in Journal/Newspaper |
author |
Heikkinen, Katri Rapakko, Katrin Karppinen, Sanna-Maria Erkko, Hannele Knuutila, Sakari Lundán, Tuija Mannermaa, Arto Børresen-Dale, Anne-Lise Borg, Ake Barkardottir, Rosa B Petrini, John Winqvist, Robert |
author_facet |
Heikkinen, Katri Rapakko, Katrin Karppinen, Sanna-Maria Erkko, Hannele Knuutila, Sakari Lundán, Tuija Mannermaa, Arto Børresen-Dale, Anne-Lise Borg, Ake Barkardottir, Rosa B Petrini, John Winqvist, Robert |
author_sort |
Heikkinen, Katri |
title |
RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability. |
title_short |
RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability. |
title_full |
RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability. |
title_fullStr |
RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability. |
title_full_unstemmed |
RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability. |
title_sort |
rad50 and nbs1 are breast cancer susceptibility genes associated with genomic instability. |
publisher |
Irl Press At Oxford University Press |
publishDate |
2008 |
url |
http://hdl.handle.net/2336/21772 https://doi.org/10.1093/carcin/bgi360 |
geographic |
Norway |
geographic_facet |
Norway |
genre |
Iceland |
genre_facet |
Iceland |
op_relation |
http://carcin.oxfordjournals.org/cgi/content/abstract/27/8/1593 Carcinogenesis 2006, 27(8):1593-9 0143-3334 16474176 doi:10.1093/carcin/bgi360 http://hdl.handle.net/2336/21772 Carcinogenesis |
op_doi |
https://doi.org/10.1093/carcin/bgi360 |
container_title |
Carcinogenesis |
container_volume |
27 |
container_issue |
8 |
container_start_page |
1593 |
op_container_end_page |
1599 |
_version_ |
1766042473758457856 |