Skip to main content
Erschienen in: BMC Cancer 1/2008

Open Access 01.12.2008 | Research article

Analysis of large deletions in BRCA1, BRCA2 and PALB2 genes in Finnish breast and ovarian cancer families

verfasst von: Katri Pylkäs, Hannele Erkko, Jenni Nikkilä, Szilvia Sólyom, Robert Winqvist

Erschienen in: BMC Cancer | Ausgabe 1/2008

Abstract

Background

BRCA1 and BRCA2 are the two most important genes associated with familial breast and ovarian cancer susceptibility. In addition, PALB2 has recently been identified as a breast cancer susceptibility gene in several populations. Here we have evaluated whether large genomic rearrangement in these genes could explain some of Finnish breast and/or ovarian cancer families.

Methods

Altogether 61 index patients of Northern Finnish breast and/or ovarian cancer families were analyzed by Multiplex ligation-dependent probe amplification (MLPA) method in order to identify exon deletions and duplications in BRCA1, BRCA2 and PALB2. The families have been comprehensively screened for germline mutation in these genes by conventional methods of mutation analysis and were found negative.

Results

We identified one large deletion in BRCA1, deleting the most part of the gene (exon 1A-13) in one family with family history of ovarian cancer. No large genomic rearrangements were identified in either BRCA2 or PALB2.

Conclusion

In Finland, women eligible for BRCA1 or BRCA2 mutation screening, when found negative, could benefit from screening for large genomic rearrangements at least in BRCA1. On the contrary, the genomic rearrangements in PALB2 seem not to contribute to the hereditary breast cancer susceptibility.
Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1471-2407-8-146) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

KP carried out the MLPA and data analysis, and drafted the manuscript. HE, JN and SS helped to draft the manuscript. RW participated in study design and in drafting the manuscript. All authors read and approved the final manuscript.

Background

Breast cancer is the most frequently occurring malignancy in women. BRCA1 and BRCA2 are the two major susceptibility genes, accounting for varying fraction of familial breast and ovarian cancer cases in different populations. In Finland, mutations in these genes explain approximately 20% of breast and ovarian cancer families [1, 2]. Most of the alterations identified in BRCA1 and BRCA2 are point mutations and small insertions/deletions, but increasing number of large genomic rearrangements in both genes have been identified in different populations [36]. Rearrangements have been described throughout the genes, and majority of them are unique and introduce a premature termination codon in the reading frame [3, 6]. The proportion of BRCA1 and BRCA2 mutations due to genomic rearrangements is not expected to vary markedly in different populations, although there might be accumulation of certain mutations due to a founder effect.
Previous studies performed in the Finnish population have not observed large genomic rearrangements in BRCA1 or BRCA2 [79]. However, in the previous studies either the method used (Southern blotting analysis on part of these genes) has not allowed sensitive testing [7], the study has concentrated only on male breast cancer cases [9] or the analyzed samples were derived from a geographically restricted area [8]. In Finland, the difference in geographical distribution has been reported for several cancer susceptibility alleles, including BRCA1, BRCA2, ATM and RAD50 mutations [2, 1012], which is the result of strong founder effect and population history. The settlement was restricted to the coastal areas during the 15th century, and it was not until the 17th century that the vast inland regions were gradually inhabited by a relatively small number of individuals, resulting in several regionally occurring founder mutations [2]. Consequently, large genomic rearrangements in BRCA1 and BRCA2 might still be at least partly responsible for the hereditary predisposition to breast and ovarian cancer in Finland.
PALB2 was recently identified as a breast cancer susceptibility gene [13, 14] and mutations in it have since been reported in other populations [1517]. PALB2 encodes a protein that binds to BRCA2 and this interaction is crucial for certain BRCA2 DNA damage response and tumor suppression functions [18]. The breast cancer associated mutations identified in PALB2 are expected to be deleterious, and all result in protein truncations. The risk estimates for PALB2 mutations have ranged from two- to fourfold, although some PALB2 mutations have been suggested to have higher penetrance [1315]. Here, we wanted to investigate whether large genomic rearrangements in PALB2 could also explain some of the Finnish breast and/or ovarian cancer families.
In the current study we have used Multiplex ligation-dependent probe amplification (MLPA) in order to identify exon deletions and duplications in the BRCA1, BRCA2 and PALB2 genes. MLPA has been proven to be very useful in detecting copy number changes in genomic sequences [19]. The families selected to this study have been comprehensively screened for germline mutation in these genes by conventional methods of mutation analysis [2, 13] and were found negative.

Methods

Breast and/or ovarian cancer families

Altogether 61 index patients of Northern Finnish breast and/or ovarian cancer families were selected for the study. These families have been screened for germline mutations in BRCA1, BRCA2 and PALB2 and were found negative [2, 13]. 41 of the families had three or more cases of breast and/or ovarian cancer in first- or second-degree relatives, and 11 families had two cases of breast and/or ovarian cancer in first- or second-degree relatives, of which at least one with early disease onset (≤ 35 years), bilateral disease or multiple primary tumors. Four families had one case of breast and ovarian cancer each, three families had two breast cancer cases, of which one diagnosed at young age ≤ 43 years, and two families showed one breast cancer case (≤ 40 years) with multiple primary tumors. The affected index cases of these families were analyzed, and the patient with youngest age at diagnosis or the one with multiple tumors was selected as an index. The study has been approved by the Ethical Board of the Northern Ostrobothnia Health Care District and the Finnish Ministry of Social Affairs and Health. All patients provided informed consent to participate in this study.

MLPA and data analysis

The SALSA MLPA kits for BRCA1 (primary screening kit P002B and confirmation kit P087), BRCA2 (P045B) and PALB2 (P057) kits (MRC-Holland, Netherlands) were used according to the manufacturer's instructions. After PCR amplification with IRD800 labeled primers the samples were analyzed with Li-Cor IR2 4200-S DNA Analysis system (Li-Cor Inc., Lincoln, NE) and Gene Profiler 4.05 analysis program (Scanalytics, Inc., Fairfax, VA). For BRCA1 analysis the used deletion control had deletions in exons 1A-2, for BRCA2 analysis the control sample showed constant 50% reduction in band intensity resulting from a SNP locating three base pairs from the ligation site, and for PALB2 analysis the used control had heterozygous deletions in exons 1–3 and 5–10 in addition to homozygous deletion of exon 4.
The information regarding the integrated density of each band received from GeneProfiler was analyzed by MLPA spreadsheets (National Genetics Reference Laboratory) in Excel Software according to the instructions. Dosage quotients 0.35–0.65 were considered deleted and dosage quotients 1.35–1.65 duplicated, and samples with quality value (standard deviation of the control ligation products) exceeding 0.1 were rejected. For the DNA sample positive for a genomic rearrangement, analysis was repeated using an independent sample in an independent assay.

Results

We have analyzed a total of 61 index patients for large genomic rearrangements in BRCA1, BRCA2 and PALB2 genes by MLPA. In BRCA2 and PALB2 no deletions or duplications were observed. We did, however, observe one large deletion in BRCA1 (exon 1A-13) (Figure 1), deleting the most part of the gene, including the promoter region. This deletion spans over 43 kb. The initial observation with P002B kit was subsequently confirmed by the BRCA1 confirmation kit P087. The patient carrying the deletion allele was diagnosed with ovarian cancer at the age of 49 years. The family had strong history of cancer, and there were altogether three cases of ovarian cancer (Figure 2). DNA was not available for testing from any other family members.

Discussion

Germline mutations in BRCA1 and BRCA2 cause an increased lifetime risk for breast and ovarian cancer [20]. In addition, PALB2 has recently been identified as a breast cancer susceptibility gene in several populations, but its association with increased risk for ovarian cancer has not been established [1317]. Although BRCA1 and BRCA2 rearrangements have previously been studied in the Finnish population, none have so far been reported [79]. The earlier studies have, however, been concentrating on families deriving from geographically restricted area or only on male breast cancer patients, or have used the less sensitive Southern blotting method. Therefore, a comprehensive analysis of genomic rearrangements in the BRCA1 and BRCA2 genes in the Northern Finnish patient cohort was needed. For PALB2 this is the first study designed to detect large genomic rearrangements in the Finnish population.
The index cases of 61 families included in this study were analyzed for rearrangements in the three genes by MLPA, and in one family we identified a large deletion in BRCA1. The observed deletion removes most of the gene including the promoter [21], thereby preventing the transcription of BRCA1. The mutation positive patient displayed a family history of ovarian cancer, which has been shown to increase the likelihood of finding a BRCA1 mutation in a family [22]. Deletions that remove the BRCA1 promoter have previously been described, but the earlier studies have not associated these changes with any particular phenotype [2326]. Our result provide the first evidence that, like in many other studied populations, large genomic changes in BRCA1 do also exist in Finland. However, these mutations seem to be rare, if not unique, as this deletion was seen in only one out of 61 families.
To date, only three different BRCA1 mutations have been identified in Northern Finnish breast and/or ovarian cancer families. Two of these mutations, 3745delT and 4216-2ntA>G, represent recurrent Finnish founder mutations [1, 2, 27], accounting for three mutation positive families each [2]. The third BRCA1 mutation is the currently identified large deletion of exons 1A-13, which represents 14.3% (1/7) of the identified Northern Finnish BRCA1 positive families. Even though the deletion allele was observed only in one out 61 currently analyzed families, our results suggests that women eligible for BRCA1 or BRCA2 mutation screening, when found negative, could benefit from screening for large genomic rearrangements, at least in BRCA1. Additional work is still needed in order to determine the prevalence of BRCA2 rearrangements in Finland, as the current study was based only on relatively small number of families.
Despite the identification of one large genomic deletion in BRCA1, our results support the previous conclusions that the genomic rearrangements in BRCA1 and BRCA2 are not a major cause for increased breast cancer susceptibility in Finland, and that the previously reported Finnish founder mutations represent the majority of BRCA1 and BRCA2 positive families [1, 2, 79, 27]. No exon deletions or duplications of the PALB2 gene were identified in the studied index cases of 61 families. This suggests that genomic rearrangements in PALB2 are very rare, which has also been indicated by a previous study [16]. At least in the Finnish population the major breast cancer associated aberration in PALB2 appears to be the previously reported founder truncation mutation [13].

Conclusion

In Finland, women eligible for BRCA1 or BRCA2 mutation screening, when found negative, could benefit from screening for large genomic rearrangements at least in BRCA1. In contrast, the genomic rearrangements in PALB2 seem not to contribute to the hereditary breast cancer susceptibility in Finland.

Acknowledgements

We thank Dr Andrew Wallace for providing us the Excel MLPA spreadsheets and Dr Johan P. de Winter for PALB2 deletion control. We thank Drs Guillermo Blanco, Ulla Puistola, Aki Mustonen and Jaakko Ignatius, and Nurse Outi Kajula for their help in patient contacts. This study was financially supported by Orion-Farmos Research Foundation, Cancer Foundation of Northern Finland, Academy of Finland, Finnish Cancer Society, Sigrid Juselius Foundation, Finnish Cultural Foundation and Maud Kuistila Memorial Foundation.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

KP carried out the MLPA and data analysis, and drafted the manuscript. HE, JN and SS helped to draft the manuscript. RW participated in study design and in drafting the manuscript. All authors read and approved the final manuscript.
Anhänge

Authors’ original submitted files for images

Below are the links to the authors’ original submitted files for images.
Literatur
1.
Zurück zum Zitat Vehmanen P, Friedman LS, Eerola H, McClure M, Ward B, Sarantaus L, Kainu T, Syrjäkoski K, Pyrhönen S, Kallioniemi OP, Muhonen T, Luce M, Frank TS, Nevanlinna H: Low proportion of BRCA1 and BRCA2 mutations in Finnish breast cancer families: evidence for additional susceptibility genes. Hum Mol Genet. 1997, 6: 2309-2315. 10.1093/hmg/6.13.2309.CrossRefPubMed Vehmanen P, Friedman LS, Eerola H, McClure M, Ward B, Sarantaus L, Kainu T, Syrjäkoski K, Pyrhönen S, Kallioniemi OP, Muhonen T, Luce M, Frank TS, Nevanlinna H: Low proportion of BRCA1 and BRCA2 mutations in Finnish breast cancer families: evidence for additional susceptibility genes. Hum Mol Genet. 1997, 6: 2309-2315. 10.1093/hmg/6.13.2309.CrossRefPubMed
2.
Zurück zum Zitat Huusko P, Pääkkönen K, Launonen V, Pöyhönen M, Blanco G, Kauppila A, Puistola U, Kiviniemi H, Kujala M, Leisti J, Winqvist R: Evidence of founder mutations in Finnish BRCA1 and BRCA2 families. Am J Hum Genet. 1998, 62: 1544-1548. 10.1086/301880.CrossRefPubMedPubMedCentral Huusko P, Pääkkönen K, Launonen V, Pöyhönen M, Blanco G, Kauppila A, Puistola U, Kiviniemi H, Kujala M, Leisti J, Winqvist R: Evidence of founder mutations in Finnish BRCA1 and BRCA2 families. Am J Hum Genet. 1998, 62: 1544-1548. 10.1086/301880.CrossRefPubMedPubMedCentral
3.
Zurück zum Zitat Mazoyer S: Genomic rearrangements in the BRCA1 and BRCA2 genes. Hum Mutat. 2005, 25: 415-422. 10.1002/humu.20169.CrossRefPubMed Mazoyer S: Genomic rearrangements in the BRCA1 and BRCA2 genes. Hum Mutat. 2005, 25: 415-422. 10.1002/humu.20169.CrossRefPubMed
4.
Zurück zum Zitat Agata S, Dalla Palma M, Callegaro M, Scaini MC, Menin C, Ghiotto C, Nicoletto O, Zavagno G, Chieco-Bianchi L, D'Andrea E, Montagna M: Large genomic deletions inactivate the BRCA2 gene in breast cancer families. J Med Genet. 2005, 42: e64-10.1136/jmg.2005.032789.CrossRefPubMedPubMedCentral Agata S, Dalla Palma M, Callegaro M, Scaini MC, Menin C, Ghiotto C, Nicoletto O, Zavagno G, Chieco-Bianchi L, D'Andrea E, Montagna M: Large genomic deletions inactivate the BRCA2 gene in breast cancer families. J Med Genet. 2005, 42: e64-10.1136/jmg.2005.032789.CrossRefPubMedPubMedCentral
5.
Zurück zum Zitat Woodward AM, Davis TA, Silva AG, Kirk JA, Leary JA, kConFab Investigators: Large genomic rearrangements of both BRCA2 and BRCA1 are a feature of the inherited breast/ovarian cancer phenotype in selected families. J Med Genet. 2005, 42: e31-10.1136/jmg.2004.027961.CrossRefPubMedPubMedCentral Woodward AM, Davis TA, Silva AG, Kirk JA, Leary JA, kConFab Investigators: Large genomic rearrangements of both BRCA2 and BRCA1 are a feature of the inherited breast/ovarian cancer phenotype in selected families. J Med Genet. 2005, 42: e31-10.1136/jmg.2004.027961.CrossRefPubMedPubMedCentral
6.
Zurück zum Zitat Casilli F, Tournier I, Sinilnikova OM, Coulet F, Soubrier F, Houdayer C, Hardouin A, Berthet P, Sobol H, Bourdon V, Muller D, Fricker JP, Capoulade-Metay C, Chompret A, Nogues C, Mazoyer S, Chappuis P, Maillet P, Philippe C, Lortholary A, Gesta P, Bézieau S, Toulas C, Gladieff L, Maugard CM, Provencher DM, Dugast C, Delvincourt C, Nguyen TD, Faivre L, Bonadona V, Frébourg T, Lidereau R, Stoppa-Lyonnet D, Tosi M: The contribution of germline rearrangements to the spectrum of BRCA2 mutations. J Med Genet. 2006, 43: e49-10.1136/jmg.2005.040212.CrossRefPubMedPubMedCentral Casilli F, Tournier I, Sinilnikova OM, Coulet F, Soubrier F, Houdayer C, Hardouin A, Berthet P, Sobol H, Bourdon V, Muller D, Fricker JP, Capoulade-Metay C, Chompret A, Nogues C, Mazoyer S, Chappuis P, Maillet P, Philippe C, Lortholary A, Gesta P, Bézieau S, Toulas C, Gladieff L, Maugard CM, Provencher DM, Dugast C, Delvincourt C, Nguyen TD, Faivre L, Bonadona V, Frébourg T, Lidereau R, Stoppa-Lyonnet D, Tosi M: The contribution of germline rearrangements to the spectrum of BRCA2 mutations. J Med Genet. 2006, 43: e49-10.1136/jmg.2005.040212.CrossRefPubMedPubMedCentral
7.
Zurück zum Zitat Lahti-Domenici J, Rapakko K, Pääkkönen K, Allinen M, Nevanlinna H, Kujala M, Huusko P, Winqvist R: Exclusion of large deletions and other rearrangements in BRCA1 and BRCA2 in Finnish breast and ovarian cancer families. Cancer Genet Cytogenet. 2001, 129: 120-123. 10.1016/S0165-4608(01)00437-X.CrossRefPubMed Lahti-Domenici J, Rapakko K, Pääkkönen K, Allinen M, Nevanlinna H, Kujala M, Huusko P, Winqvist R: Exclusion of large deletions and other rearrangements in BRCA1 and BRCA2 in Finnish breast and ovarian cancer families. Cancer Genet Cytogenet. 2001, 129: 120-123. 10.1016/S0165-4608(01)00437-X.CrossRefPubMed
8.
Zurück zum Zitat Laurila E, Syrjäkoski K, Holli K, Kallioniemi A, Karhu R: Search for large genomic alterations of the BRCA1 gene in a Finnish population. Cancer Genet Cytogenet. 2005, 163: 57-61. 10.1016/j.cancergencyto.2005.05.014.CrossRefPubMed Laurila E, Syrjäkoski K, Holli K, Kallioniemi A, Karhu R: Search for large genomic alterations of the BRCA1 gene in a Finnish population. Cancer Genet Cytogenet. 2005, 163: 57-61. 10.1016/j.cancergencyto.2005.05.014.CrossRefPubMed
9.
Zurück zum Zitat Karhu R, Laurila E, Kallioniemi A, Syrjäkoski K: Large genomic BRCA2 rearrangements and male breast cancer. Cancer Detect Prev. 2006, 30: 530-534. 10.1016/j.cdp.2006.10.002.CrossRefPubMed Karhu R, Laurila E, Kallioniemi A, Syrjäkoski K: Large genomic BRCA2 rearrangements and male breast cancer. Cancer Detect Prev. 2006, 30: 530-534. 10.1016/j.cdp.2006.10.002.CrossRefPubMed
10.
Zurück zum Zitat Sarantaus L, Huusko P, Eerola H, Launonen V, Vehmanen P, Rapakko K, Gillanders E, Syrjäkoski K, Kainu T, Vahteristo P, Krahe R, Pääkkönen K, Hartikainen J, Blomqvist C, Löppönen T, Holli K, Ryynänen M, Bützow R, Borg Å, Wasteson Arver B, Holmberg E, Mannermaa A, Kere J, Kallioniemi OP, Winqvist R, Nevanlinna H: Multiple founder effects and geographical clustering of BRCA1 and BRCA2 families in Finland. Eur J Hum Genet. 2000, 8: 757-763. 10.1038/sj.ejhg.5200529.CrossRefPubMed Sarantaus L, Huusko P, Eerola H, Launonen V, Vehmanen P, Rapakko K, Gillanders E, Syrjäkoski K, Kainu T, Vahteristo P, Krahe R, Pääkkönen K, Hartikainen J, Blomqvist C, Löppönen T, Holli K, Ryynänen M, Bützow R, Borg Å, Wasteson Arver B, Holmberg E, Mannermaa A, Kere J, Kallioniemi OP, Winqvist R, Nevanlinna H: Multiple founder effects and geographical clustering of BRCA1 and BRCA2 families in Finland. Eur J Hum Genet. 2000, 8: 757-763. 10.1038/sj.ejhg.5200529.CrossRefPubMed
11.
Zurück zum Zitat Heikkinen K, Rapakko K, Karppinen SM, Erkko H, Knuutila S, Lundán T, Mannermaa A, Børresen-Dale AL, Borg Å, Barkardottir RB, Petrini J, Winqvist R: RAD50 and NBS1 are Breast Cancer Susceptibility Genes Associated with Genomic Instability. Carcinogenesis. 2006, 27: 1593-1599. 10.1093/carcin/bgi360.CrossRefPubMedPubMedCentral Heikkinen K, Rapakko K, Karppinen SM, Erkko H, Knuutila S, Lundán T, Mannermaa A, Børresen-Dale AL, Borg Å, Barkardottir RB, Petrini J, Winqvist R: RAD50 and NBS1 are Breast Cancer Susceptibility Genes Associated with Genomic Instability. Carcinogenesis. 2006, 27: 1593-1599. 10.1093/carcin/bgi360.CrossRefPubMedPubMedCentral
12.
Zurück zum Zitat Pylkäs K, Tommiska J, Syrjäkoski K, Kere J, Gatei M, Waddell N, Allinen M, Karppinen SM, Rapakko K, Kääriäinen H, Aittomäki K, Blomqvist C, Mustonen A, Holli K, Khanna KK, Kallioniemi OP, Nevanlinna H, Winqvist R: Evaluation of the role of Finnish ataxia-telangiectasia mutations in hereditary predisposition to breast cancer. Carcinogenesis. 2007, 28: 1040-1045. 10.1093/carcin/bgl237.CrossRefPubMed Pylkäs K, Tommiska J, Syrjäkoski K, Kere J, Gatei M, Waddell N, Allinen M, Karppinen SM, Rapakko K, Kääriäinen H, Aittomäki K, Blomqvist C, Mustonen A, Holli K, Khanna KK, Kallioniemi OP, Nevanlinna H, Winqvist R: Evaluation of the role of Finnish ataxia-telangiectasia mutations in hereditary predisposition to breast cancer. Carcinogenesis. 2007, 28: 1040-1045. 10.1093/carcin/bgl237.CrossRefPubMed
13.
Zurück zum Zitat Erkko H, Xia B, Nikkilä J, Schleutker J, Syrjäkoski K, Mannermaa A, Kallioniemi A, Pylkäs K, Karppinen SM, Rapakko K, Miron A, Sheng Q, Li G, Mattila H, Bell DW, Haber DA, Grip M, Reiman M, Jukkola-Vuorinen A, Mustonen A, Kere J, Aaltonen LA, Kosma VM, Kataja V, Soini Y, Drapkin RI, Livingston DM, Winqvist R: A recurrent mutation in PALB2 in Finnish cancer families. Nature. 2007, 446: 316-319. 10.1038/nature05609.CrossRefPubMed Erkko H, Xia B, Nikkilä J, Schleutker J, Syrjäkoski K, Mannermaa A, Kallioniemi A, Pylkäs K, Karppinen SM, Rapakko K, Miron A, Sheng Q, Li G, Mattila H, Bell DW, Haber DA, Grip M, Reiman M, Jukkola-Vuorinen A, Mustonen A, Kere J, Aaltonen LA, Kosma VM, Kataja V, Soini Y, Drapkin RI, Livingston DM, Winqvist R: A recurrent mutation in PALB2 in Finnish cancer families. Nature. 2007, 446: 316-319. 10.1038/nature05609.CrossRefPubMed
14.
Zurück zum Zitat Rahman N, Seal S, Thompson D, Kelly P, Renwick A, Elliott A, Reid S, Spanova K, Barfoot R, Chagtai T, Jayatilake H, McGuffog L, Hanks S, Evans DG, Eccles D, Breast Cancer Susceptibility Collaboration (UK), Easton DF, Stratton MR: PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet. 2007, 39: 165-167. 10.1038/ng1959.CrossRefPubMed Rahman N, Seal S, Thompson D, Kelly P, Renwick A, Elliott A, Reid S, Spanova K, Barfoot R, Chagtai T, Jayatilake H, McGuffog L, Hanks S, Evans DG, Eccles D, Breast Cancer Susceptibility Collaboration (UK), Easton DF, Stratton MR: PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet. 2007, 39: 165-167. 10.1038/ng1959.CrossRefPubMed
15.
Zurück zum Zitat Tischkowitz M, Xia B, Sabbaghian N, Reis-Filho JS, Hamel N, Li G, van Beers EH, Li L, Khalil T, Quenneville LA, Omeroglu A, Poll A, Lepage P, Wong N, Nederlof PM, Ashworth A, Tonin PN, Narod SA, Livingston DM, Foulkes WD: Analysis of PALB2/FANCN-associated breast cancer families. Proc Natl Acad Sci USA. 2007, 104: 6788-6793. 10.1073/pnas.0701724104.CrossRefPubMedPubMedCentral Tischkowitz M, Xia B, Sabbaghian N, Reis-Filho JS, Hamel N, Li G, van Beers EH, Li L, Khalil T, Quenneville LA, Omeroglu A, Poll A, Lepage P, Wong N, Nederlof PM, Ashworth A, Tonin PN, Narod SA, Livingston DM, Foulkes WD: Analysis of PALB2/FANCN-associated breast cancer families. Proc Natl Acad Sci USA. 2007, 104: 6788-6793. 10.1073/pnas.0701724104.CrossRefPubMedPubMedCentral
16.
Zurück zum Zitat Foulkes WD, Ghadirian P, Akbari MR, Hamel N, Giroux S, Sabbaghian N, Darnel A, Royer R, Poll A, Fafard E, Robidoux A, Martin G, Bismar TA, Tischkowitz M, Rousseau F, Narod SA: Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women. Breast Cancer Res. 2007, 9 (6): R83-10.1186/bcr1828.CrossRefPubMedPubMedCentral Foulkes WD, Ghadirian P, Akbari MR, Hamel N, Giroux S, Sabbaghian N, Darnel A, Royer R, Poll A, Fafard E, Robidoux A, Martin G, Bismar TA, Tischkowitz M, Rousseau F, Narod SA: Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women. Breast Cancer Res. 2007, 9 (6): R83-10.1186/bcr1828.CrossRefPubMedPubMedCentral
17.
Zurück zum Zitat García MJ, Fernández V, Osorio A, Barroso A, Llort G, Lázaro C, Blanco I, Caldés T, de la Hoya M, Ramón Y, Cajal T, Alonso C, Tejada MI, San Román C, Robles-Díaz L, Urioste M, Benítez J: Analysis of FANCB and FANCN/PALB2 Fanconi Anemia genes in BRCA1/2-negative Spanish breast cancer families. Breast Cancer Res Treat. 2008 Feb 27, García MJ, Fernández V, Osorio A, Barroso A, Llort G, Lázaro C, Blanco I, Caldés T, de la Hoya M, Ramón Y, Cajal T, Alonso C, Tejada MI, San Román C, Robles-Díaz L, Urioste M, Benítez J: Analysis of FANCB and FANCN/PALB2 Fanconi Anemia genes in BRCA1/2-negative Spanish breast cancer families. Breast Cancer Res Treat. 2008 Feb 27,
18.
Zurück zum Zitat Xia B, Sheng Q, Nakanishi K, Ohashi A, Wu J, Christ N, Liu X, Jasin M, Couch FJ, Livingston DM: Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell. 2006, 22: 719-729. 10.1016/j.molcel.2006.05.022.CrossRefPubMed Xia B, Sheng Q, Nakanishi K, Ohashi A, Wu J, Christ N, Liu X, Jasin M, Couch FJ, Livingston DM: Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell. 2006, 22: 719-729. 10.1016/j.molcel.2006.05.022.CrossRefPubMed
19.
Zurück zum Zitat Sellner LN, Taylor GR: MLPA and MAPH: new techniques for detection of gene deletions. Hum Mutat. 2004, 23: 413-419. 10.1002/humu.20035.CrossRefPubMed Sellner LN, Taylor GR: MLPA and MAPH: new techniques for detection of gene deletions. Hum Mutat. 2004, 23: 413-419. 10.1002/humu.20035.CrossRefPubMed
20.
Zurück zum Zitat Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjörd JE, Hopper JL, Loman N, Olsson H, Johannson O, Borg Å, Pasini B, Radice P, Manoukian S, Eccles DM, Tang N, Olah E, Anton-culver H, Warner E, Lubinski J, Gronwald J, Górski B, Tulinius H, Thorlacius S, Eerola H, Nevanlinna H, Syrjäkoski K, Kallioniemi OP, Thompson D, Evans C, Peto J, Lalloo F, Evans DG, Easton DF: Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003, 72: 1117-1130. 10.1086/375033.CrossRefPubMedPubMedCentral Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjörd JE, Hopper JL, Loman N, Olsson H, Johannson O, Borg Å, Pasini B, Radice P, Manoukian S, Eccles DM, Tang N, Olah E, Anton-culver H, Warner E, Lubinski J, Gronwald J, Górski B, Tulinius H, Thorlacius S, Eerola H, Nevanlinna H, Syrjäkoski K, Kallioniemi OP, Thompson D, Evans C, Peto J, Lalloo F, Evans DG, Easton DF: Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003, 72: 1117-1130. 10.1086/375033.CrossRefPubMedPubMedCentral
21.
Zurück zum Zitat Xu CF, Chambers JA, Solomon E: Complex regulation of the BRCA1 gene. J Biol Chem. 1997, 272: 20994-20997. 10.1074/jbc.272.34.20994.CrossRefPubMed Xu CF, Chambers JA, Solomon E: Complex regulation of the BRCA1 gene. J Biol Chem. 1997, 272: 20994-20997. 10.1074/jbc.272.34.20994.CrossRefPubMed
22.
Zurück zum Zitat Vahteristo P, Eerola H, Tamminen A, Blomqvist C, Nevanlinna H: A probability model for predicting BRCA1 and BRCA2 mutations in breast and breast-ovarian cancer families. Br J Cancer. 2001, 84: 704-708. 10.1054/bjoc.2000.1626.CrossRefPubMedPubMedCentral Vahteristo P, Eerola H, Tamminen A, Blomqvist C, Nevanlinna H: A probability model for predicting BRCA1 and BRCA2 mutations in breast and breast-ovarian cancer families. Br J Cancer. 2001, 84: 704-708. 10.1054/bjoc.2000.1626.CrossRefPubMedPubMedCentral
23.
Zurück zum Zitat Swensen J, Hoffman M, Skolnick MH, Neuhausen SL: Identification of a 14 kb deletion involving the promoter region of BRCA1 in a breast cancer family. Hum Mol Genet. 1997, 6: 1513-1517. 10.1093/hmg/6.9.1513.CrossRefPubMed Swensen J, Hoffman M, Skolnick MH, Neuhausen SL: Identification of a 14 kb deletion involving the promoter region of BRCA1 in a breast cancer family. Hum Mol Genet. 1997, 6: 1513-1517. 10.1093/hmg/6.9.1513.CrossRefPubMed
24.
Zurück zum Zitat Puget N, Gad S, Perrin-Vidoz L, Sinilnikova OM, Stoppa-Lyonnet D, Lenoir GM, Mazoyer S: Distinct BRCA1 rearrangements involving the BRCA1 pseudogene suggest the existence of a recombination hot spot. Am J Hum Genet. 2002, 70: 858-865. 10.1086/339434.CrossRefPubMedPubMedCentral Puget N, Gad S, Perrin-Vidoz L, Sinilnikova OM, Stoppa-Lyonnet D, Lenoir GM, Mazoyer S: Distinct BRCA1 rearrangements involving the BRCA1 pseudogene suggest the existence of a recombination hot spot. Am J Hum Genet. 2002, 70: 858-865. 10.1086/339434.CrossRefPubMedPubMedCentral
25.
Zurück zum Zitat Gad S, Bièche I, Barrois M, Casilli F, Pages-Berhouet S, Dehainault C, Gauthier-Villars M, Bensimon A, Aurias A, Lidereau R, Bressac-de Paillerets B, Tosi M, Mazoyer S, Stoppa-Lyonnet D: Characterisation of a 161 kb deletion extending from the NBR1 to the BRCA1 genes in a French breast-ovarian cancer family. Hum Mutat. 2003, 21: 654-10.1002/humu.9148.CrossRefPubMed Gad S, Bièche I, Barrois M, Casilli F, Pages-Berhouet S, Dehainault C, Gauthier-Villars M, Bensimon A, Aurias A, Lidereau R, Bressac-de Paillerets B, Tosi M, Mazoyer S, Stoppa-Lyonnet D: Characterisation of a 161 kb deletion extending from the NBR1 to the BRCA1 genes in a French breast-ovarian cancer family. Hum Mutat. 2003, 21: 654-10.1002/humu.9148.CrossRefPubMed
26.
Zurück zum Zitat Montagna M, Dalla Palma M, Menin C, Agata S, De Nicolo A, Chieco-Bianchi L, D'Andrea E: Genomic rearrangements account for more than one-third of the BRCA1 mutations in northern Italian breast/ovarian cancer families. Hum Mol Genet. 2003, 12: 1055-1061. 10.1093/hmg/ddg120.CrossRefPubMed Montagna M, Dalla Palma M, Menin C, Agata S, De Nicolo A, Chieco-Bianchi L, D'Andrea E: Genomic rearrangements account for more than one-third of the BRCA1 mutations in northern Italian breast/ovarian cancer families. Hum Mol Genet. 2003, 12: 1055-1061. 10.1093/hmg/ddg120.CrossRefPubMed
27.
Zurück zum Zitat Hartikainen JM, Kataja V, Pirskanen M, Arffman A, Ristonmaa U, Vahteristo P, Ryynänen M, Heinonen S, Kosma VM, Mannermaa A: Screening for BRCA1 and BRCA2 mutations in Eastern Finnish breast/ovarian cancer families. Clin Genet. 2007, 72: 311-320.CrossRefPubMed Hartikainen JM, Kataja V, Pirskanen M, Arffman A, Ristonmaa U, Vahteristo P, Ryynänen M, Heinonen S, Kosma VM, Mannermaa A: Screening for BRCA1 and BRCA2 mutations in Eastern Finnish breast/ovarian cancer families. Clin Genet. 2007, 72: 311-320.CrossRefPubMed
Metadaten
Titel
Analysis of large deletions in BRCA1, BRCA2 and PALB2 genes in Finnish breast and ovarian cancer families
verfasst von
Katri Pylkäs
Hannele Erkko
Jenni Nikkilä
Szilvia Sólyom
Robert Winqvist
Publikationsdatum
01.12.2008
Verlag
BioMed Central
Erschienen in
BMC Cancer / Ausgabe 1/2008
Elektronische ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-8-146

Weitere Artikel der Ausgabe 1/2008

BMC Cancer 1/2008 Zur Ausgabe

Erhöhte Mortalität bei postpartalem Brustkrebs

07.05.2024 Mammakarzinom Nachrichten

Auch für Trägerinnen von BRCA-Varianten gilt: Erkranken sie fünf bis zehn Jahre nach der letzten Schwangerschaft an Brustkrebs, ist das Sterberisiko besonders hoch.

Hypertherme Chemotherapie bietet Chance auf Blasenerhalt

07.05.2024 Harnblasenkarzinom Nachrichten

Eine hypertherme intravesikale Chemotherapie mit Mitomycin kann für Patienten mit hochriskantem nicht muskelinvasivem Blasenkrebs eine Alternative zur radikalen Zystektomie darstellen. Kölner Urologen berichten über ihre Erfahrungen.

Ein Drittel der jungen Ärztinnen und Ärzte erwägt abzuwandern

07.05.2024 Medizinstudium Nachrichten

Extreme Arbeitsverdichtung und kaum Supervision: Dr. Andrea Martini, Sprecherin des Bündnisses Junge Ärztinnen und Ärzte (BJÄ) über den Frust des ärztlichen Nachwuchses und die Vorteile des Rucksack-Modells.

Bessere Prognose mit links- statt rechtsseitigem Kolon-Ca.

06.05.2024 Kolonkarzinom Nachrichten

Menschen mit linksseitigem Kolonkarzinom leben im Mittel zweieinhalb Jahre länger als solche mit rechtsseitigem Tumor. Auch aktuell ist das Sterberisiko bei linksseitigen Tumoren US-Daten zufolge etwa um 11% geringer als bei rechtsseitigen.

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.