RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability
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 desi...
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2006
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Online Access: | https://lup.lub.lu.se/record/397543 https://doi.org/10.1093/carcin/bgi360 |
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ftulundlup:oai:lup.lub.lu.se:39bd6ddb-86ed-4bd4-a6dc-2561675ed9b6 2023-05-15T16:51:24+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 Lundan, Tuija Mannermaa, Arto Borresen-Dale, Anne-Lise Borg, Åke Barkardottir, Rosa B. Petrini, John Winqvist, Robert 2006 https://lup.lub.lu.se/record/397543 https://doi.org/10.1093/carcin/bgi360 eng eng Oxford University Press https://lup.lub.lu.se/record/397543 http://dx.doi.org/10.1093/carcin/bgi360 wos:000239841100009 pmid:16474176 scopus:33747884830 Carcinogenesis; 27(8), pp 1593-1599 (2006) ISSN: 0143-3334 Cancer and Oncology contributiontojournal/article info:eu-repo/semantics/article text 2006 ftulundlup https://doi.org/10.1093/carcin/bgi360 2023-02-01T23:28:30Z 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 carboxyterminal (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 Lund University Publications (LUP) Norway Carcinogenesis 27 8 1593 1599 |
institution |
Open Polar |
collection |
Lund University Publications (LUP) |
op_collection_id |
ftulundlup |
language |
English |
topic |
Cancer and Oncology |
spellingShingle |
Cancer and Oncology Heikkinen, Katri Rapakko, Katrin Karppinen, Sanna-Maria Erkko, Hannele Knuutila, Sakari Lundan, Tuija Mannermaa, Arto Borresen-Dale, Anne-Lise Borg, Åke Barkardottir, Rosa B. Petrini, John Winqvist, Robert RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability |
topic_facet |
Cancer and Oncology |
description |
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 carboxyterminal (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 Lundan, Tuija Mannermaa, Arto Borresen-Dale, Anne-Lise Borg, Åke Barkardottir, Rosa B. Petrini, John Winqvist, Robert |
author_facet |
Heikkinen, Katri Rapakko, Katrin Karppinen, Sanna-Maria Erkko, Hannele Knuutila, Sakari Lundan, Tuija Mannermaa, Arto Borresen-Dale, Anne-Lise Borg, Åke 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 |
Oxford University Press |
publishDate |
2006 |
url |
https://lup.lub.lu.se/record/397543 https://doi.org/10.1093/carcin/bgi360 |
geographic |
Norway |
geographic_facet |
Norway |
genre |
Iceland |
genre_facet |
Iceland |
op_source |
Carcinogenesis; 27(8), pp 1593-1599 (2006) ISSN: 0143-3334 |
op_relation |
https://lup.lub.lu.se/record/397543 http://dx.doi.org/10.1093/carcin/bgi360 wos:000239841100009 pmid:16474176 scopus:33747884830 |
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_ |
1766041511570440192 |