Skip to main content
Top
Published in: BMC Cancer 1/2008

Open Access 01-12-2008 | Research article

Comprehensive analysis of NuMAvariation in breast cancer

Authors: Outi Kilpivaara, Matias Rantanen, Anitta Tamminen, Kristiina Aittomäki, Carl Blomqvist, Heli Nevanlinna

Published in: BMC Cancer | Issue 1/2008

Login to get access

Abstract

Background

A recent genome wide case-control association study identified NuMA region on 11q13 as a candidate locus for breast cancer susceptibility. Specifically, the variant Ala794Gly was suggested to be associated with increased risk of breast cancer.

Methods

In order to evaluate the NuMa gene for breast cancer susceptibility, we have here screened the entire coding region and exon-intron boundaries of NuMa in 92 familial breast cancer patients and constructed haplotypes of the identified variants. Five missense variants were further screened in 341 breast cancer cases with a positive family history and 368 controls. We examined the frequency of Ala794Gly in an extensive series of familial (n = 910) and unselected (n = 884) breast cancer cases and controls (n = 906), with a high power to detect the suggested breast cancer risk. We also tested if the variant is associated with histopathologic features of breast tumors.

Results

Screening of NuMA resulted in identification of 11 exonic variants and 12 variants in introns or untranslated regions. Five missense variants that were further screened in breast cancer cases with a positive family history and controls, were each carried on a unique haplotype. None of the variants, or the haplotypes represented by them, was associated with breast cancer risk although due to low power in this analysis, very low risk alleles may go unrecognized. The NuMA Ala794Gly showed no difference in frequency in the unselected breast cancer case series or familial case series compared to control cases. Furthermore, Ala794Gly did not show any significant association with histopathologic characteristics of the tumors, though Ala794Gly was slightly more frequent among unselected cases with lymph node involvement.

Conclusion

Our results do not support the role of NuMA variants as breast cancer susceptibility alleles.
Literature
1.
go back to reference Kammerer S, Roth RB, Hoyal CR, Reneland R, Marnellos G, Kiechle M, Schwarz-Boeger U, Griffiths LR, Ebner F, Rehbock J, Cantor CR, Nelson MR, Braun A: Association of the NuMA region on chromosome 11q13 with breast cancer susceptibility. Proc Natl Acad Sci USA. 2005, 102: 2004-2009. 10.1073/pnas.0409806102.CrossRefPubMedPubMedCentral Kammerer S, Roth RB, Hoyal CR, Reneland R, Marnellos G, Kiechle M, Schwarz-Boeger U, Griffiths LR, Ebner F, Rehbock J, Cantor CR, Nelson MR, Braun A: Association of the NuMA region on chromosome 11q13 with breast cancer susceptibility. Proc Natl Acad Sci USA. 2005, 102: 2004-2009. 10.1073/pnas.0409806102.CrossRefPubMedPubMedCentral
2.
go back to reference Harborth J, Weber K, Osborn M: Epitope mapping and direct visualization of the parallel, in-register arrangement of the double-stranded coiled-coil in the NuMA protein. EMBO J. 1995, 14 (11): 2447-60.PubMedPubMedCentral Harborth J, Weber K, Osborn M: Epitope mapping and direct visualization of the parallel, in-register arrangement of the double-stranded coiled-coil in the NuMA protein. EMBO J. 1995, 14 (11): 2447-60.PubMedPubMedCentral
3.
go back to reference Merdes A, Ramyar K, Vechio JD, Cleveland DW: A complex of NuMA and cytoplasmic dynein is essential for mitotic spindle assembly. Cell. 1996, 87 (3): 447-58. 10.1016/S0092-8674(00)81365-3.CrossRefPubMed Merdes A, Ramyar K, Vechio JD, Cleveland DW: A complex of NuMA and cytoplasmic dynein is essential for mitotic spindle assembly. Cell. 1996, 87 (3): 447-58. 10.1016/S0092-8674(00)81365-3.CrossRefPubMed
4.
go back to reference Compton DA, Luo C: Mutation of the predicted p34cdc2 phosphorylation sites in NuMA impair the assembly of the mitotic spindle and block mitosis. J Cell Sci. 1995, 108 (Pt 2): 621-633.PubMed Compton DA, Luo C: Mutation of the predicted p34cdc2 phosphorylation sites in NuMA impair the assembly of the mitotic spindle and block mitosis. J Cell Sci. 1995, 108 (Pt 2): 621-633.PubMed
5.
go back to reference Gueth-Hallonet C, Weber K, Osborn M: NuMA: A bipartite nuclear location signal and other functional properties of the tail domain. Exp Cell Res. 1996, 225: 207-218. 10.1006/excr.1996.0171.CrossRefPubMed Gueth-Hallonet C, Weber K, Osborn M: NuMA: A bipartite nuclear location signal and other functional properties of the tail domain. Exp Cell Res. 1996, 225: 207-218. 10.1006/excr.1996.0171.CrossRefPubMed
6.
go back to reference Tang TK, Tang CJ, Chao YJ, Wu CW: Nuclear mitotic apparatus protein (NuMA): Spindle association, nuclear targeting and differential subcellular localization of various NuMA isoforms. J Cell Sci. 1994, 107 (Pt 6): 1389-1402.PubMed Tang TK, Tang CJ, Chao YJ, Wu CW: Nuclear mitotic apparatus protein (NuMA): Spindle association, nuclear targeting and differential subcellular localization of various NuMA isoforms. J Cell Sci. 1994, 107 (Pt 6): 1389-1402.PubMed
7.
go back to reference Compton DA, Cleveland DW: NuMA is required for the proper completion of mitosis. J Cell Biol. 1993, 120: 947-957. 10.1083/jcb.120.4.947.CrossRefPubMed Compton DA, Cleveland DW: NuMA is required for the proper completion of mitosis. J Cell Biol. 1993, 120: 947-957. 10.1083/jcb.120.4.947.CrossRefPubMed
8.
go back to reference Wells RA, Catzavelos C, Kamel-Reid S: Fusion of retinoic acid receptor alpha to NuMA, the nuclear mitotic apparatus protein, by a variant translocation in acute promyelocytic leukaemia. Nat Genet. 1997, 17: 109-113. 10.1038/ng0997-109.CrossRefPubMed Wells RA, Catzavelos C, Kamel-Reid S: Fusion of retinoic acid receptor alpha to NuMA, the nuclear mitotic apparatus protein, by a variant translocation in acute promyelocytic leukaemia. Nat Genet. 1997, 17: 109-113. 10.1038/ng0997-109.CrossRefPubMed
9.
go back to reference Harborth J, Weber K, Osborn M: GAS41, a highly conserved protein in eukaryotic nuclei, binds to NuMA. J Biol Chem. 2000, 275: 31979-31985. 10.1074/jbc.M000994200.CrossRefPubMed Harborth J, Weber K, Osborn M: GAS41, a highly conserved protein in eukaryotic nuclei, binds to NuMA. J Biol Chem. 2000, 275: 31979-31985. 10.1074/jbc.M000994200.CrossRefPubMed
10.
go back to reference Fischer U, Heckel D, Michel A, Janka M, Hulsebos T, Meese E: Cloning of a novel transcription factor-like gene amplified in human glioma including astrocytoma grade I. Hum Mol Genet. 1997, 6: 1817-1822. 10.1093/hmg/6.11.1817.CrossRefPubMed Fischer U, Heckel D, Michel A, Janka M, Hulsebos T, Meese E: Cloning of a novel transcription factor-like gene amplified in human glioma including astrocytoma grade I. Hum Mol Genet. 1997, 6: 1817-1822. 10.1093/hmg/6.11.1817.CrossRefPubMed
11.
go back to reference Syrjakoski K, Vahteristo P, Eerola H, Tamminen A, Kivinummi K, Sarantaus L, Holli K, Blomqvist C, Kallioniemi OP, Kainu T, Nevanlinna H: Population-based study of BRCA1 and BRCA2 mutations in 1035 unselected finnish breast cancer patients. J Natl Cancer Inst. 2000, 92: 1529-1531. 10.1093/jnci/92.18.1529.CrossRefPubMed Syrjakoski K, Vahteristo P, Eerola H, Tamminen A, Kivinummi K, Sarantaus L, Holli K, Blomqvist C, Kallioniemi OP, Kainu T, Nevanlinna H: Population-based study of BRCA1 and BRCA2 mutations in 1035 unselected finnish breast cancer patients. J Natl Cancer Inst. 2000, 92: 1529-1531. 10.1093/jnci/92.18.1529.CrossRefPubMed
12.
go back to reference Kilpivaara O, Bartkova J, Eerola H, Syrjakoski K, Vahteristo P, Lukas J, Blomqvist C, Holli K, Heikkila P, Sauter G, Kallioniemi OP, Bartek J, Nevanlinna H: Correlation of CHEK2 protein expression and c.1100delC mutation status with tumor characteristics among unselected breast cancer patients. Int J Cancer. 2005, 113: 575-580. 10.1002/ijc.20638.CrossRefPubMed Kilpivaara O, Bartkova J, Eerola H, Syrjakoski K, Vahteristo P, Lukas J, Blomqvist C, Holli K, Heikkila P, Sauter G, Kallioniemi OP, Bartek J, Nevanlinna H: Correlation of CHEK2 protein expression and c.1100delC mutation status with tumor characteristics among unselected breast cancer patients. Int J Cancer. 2005, 113: 575-580. 10.1002/ijc.20638.CrossRefPubMed
13.
go back to reference Eerola H, Blomqvist C, Pukkala E, Pyrhonen S, Nevanlinna H: Familial breast cancer in southern finland: How prevalent are breast cancer families and can we trust the family history reported by patients?. Eur J Cancer. 2000, 36: 1143-1148. 10.1016/S0959-8049(00)00093-9.CrossRefPubMed Eerola H, Blomqvist C, Pukkala E, Pyrhonen S, Nevanlinna H: Familial breast cancer in southern finland: How prevalent are breast cancer families and can we trust the family history reported by patients?. Eur J Cancer. 2000, 36: 1143-1148. 10.1016/S0959-8049(00)00093-9.CrossRefPubMed
14.
go back to reference Vehmanen P, Friedman LS, Eerola H, McClure M, Ward B, Sarantaus L, Kainu T, Syrjakoski K, Pyrhonen 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, Syrjakoski K, Pyrhonen 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
15.
go back to reference 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
16.
go back to reference Vahteristo P, Bartkova J, Eerola H, Syrjakoski K, Ojala S, Kilpivaara O, Tamminen A, Kononen J, Aittomaki K, Heikkila P, Holli K, Blomqvist C, Bartek J, Kallioniemi OP, Nevanlinna H: A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet. 2002, 71: 432-438. 10.1086/341943.CrossRefPubMedPubMedCentral Vahteristo P, Bartkova J, Eerola H, Syrjakoski K, Ojala S, Kilpivaara O, Tamminen A, Kononen J, Aittomaki K, Heikkila P, Holli K, Blomqvist C, Bartek J, Kallioniemi OP, Nevanlinna H: A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet. 2002, 71: 432-438. 10.1086/341943.CrossRefPubMedPubMedCentral
18.
22.
go back to reference Stephens M, Smith NJ, Donnelly P: A new statistical method for haplotype reconstruction from population data. Am J Hum Genet. 2001, 68: 978-989. 10.1086/319501.CrossRefPubMedPubMedCentral Stephens M, Smith NJ, Donnelly P: A new statistical method for haplotype reconstruction from population data. Am J Hum Genet. 2001, 68: 978-989. 10.1086/319501.CrossRefPubMedPubMedCentral
23.
go back to reference Stephens M, Donnelly P: A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet. 2003, 73: 1162-1169. 10.1086/379378.CrossRefPubMedPubMedCentral Stephens M, Donnelly P: A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet. 2003, 73: 1162-1169. 10.1086/379378.CrossRefPubMedPubMedCentral
24.
go back to reference Cox A, Dunning AM, Garcia-Closas M, Balasubramanian S, Reed MW, Pooley KA, Scollen S, Baynes C, Ponder BA, Chanock S, Lissowska J, Brinton L, Peplonska B, Southey MC, Hopper JL, McCredie MR, Giles GG, Fletcher O, Johnson N, dos Santos Silva I, Gibson L, Bojesen SE, Nordestgaard BG, Axelsson CK, Torres D, Hamann U, Justenhoven C, Brauch H, Chang-Claude J, Kropp S, Risch A, Wang-Gohrke S, Schurmann P, Bogdanova N, Dork T, Fagerholm R, Aaltonen K, Blomqvist C, Nevanlinna H, Seal S, Renwick A, Stratton MR, Rahman N, Sangrajrang S, Hughes D, Odefrey F, Brennan P, Spurdle AB, Chenevix-Trench G, Kathleen Cunningham Foundation Consortium for Research into Familial Breast Cancer, Beesley J, Mannermaa A, Hartikainen J, Kataja V, Kosma VM, Couch FJ, Olson JE, Goode EL, Broeks A, Schmidt MK, Hogervorst FB, Van't Veer LJ, Kang D, Yoo KY, Noh DY, Ahn SH, Wedren S, Hall P, Low YL, Liu J, Milne RL, Ribas G, Gonzalez-Neira A, Benitez J, Sigurdson AJ, Stredrick DL, Alexander BH, Struewing JP, Pharoah PD, Easton DF, Breast Cancer Association Consortium: A common coding variant in CASP8 is associated with breast cancer risk. Nat Genet. 2007, 39 (3): 352-358. 10.1038/ng1981.CrossRefPubMed Cox A, Dunning AM, Garcia-Closas M, Balasubramanian S, Reed MW, Pooley KA, Scollen S, Baynes C, Ponder BA, Chanock S, Lissowska J, Brinton L, Peplonska B, Southey MC, Hopper JL, McCredie MR, Giles GG, Fletcher O, Johnson N, dos Santos Silva I, Gibson L, Bojesen SE, Nordestgaard BG, Axelsson CK, Torres D, Hamann U, Justenhoven C, Brauch H, Chang-Claude J, Kropp S, Risch A, Wang-Gohrke S, Schurmann P, Bogdanova N, Dork T, Fagerholm R, Aaltonen K, Blomqvist C, Nevanlinna H, Seal S, Renwick A, Stratton MR, Rahman N, Sangrajrang S, Hughes D, Odefrey F, Brennan P, Spurdle AB, Chenevix-Trench G, Kathleen Cunningham Foundation Consortium for Research into Familial Breast Cancer, Beesley J, Mannermaa A, Hartikainen J, Kataja V, Kosma VM, Couch FJ, Olson JE, Goode EL, Broeks A, Schmidt MK, Hogervorst FB, Van't Veer LJ, Kang D, Yoo KY, Noh DY, Ahn SH, Wedren S, Hall P, Low YL, Liu J, Milne RL, Ribas G, Gonzalez-Neira A, Benitez J, Sigurdson AJ, Stredrick DL, Alexander BH, Struewing JP, Pharoah PD, Easton DF, Breast Cancer Association Consortium: A common coding variant in CASP8 is associated with breast cancer risk. Nat Genet. 2007, 39 (3): 352-358. 10.1038/ng1981.CrossRefPubMed
Metadata
Title
Comprehensive analysis of NuMAvariation in breast cancer
Authors
Outi Kilpivaara
Matias Rantanen
Anitta Tamminen
Kristiina Aittomäki
Carl Blomqvist
Heli Nevanlinna
Publication date
01-12-2008
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2008
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-8-71

Other articles of this Issue 1/2008

BMC Cancer 1/2008 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine