Top

Published in:

01-04-2013 | Epidemiology

Association of low-penetrance alleles with male breast cancer risk and clinicopathological characteristics: results from a multicenter study in Italy

Authors: L. Ottini, V. Silvestri, C. Saieva, P. Rizzolo, I. Zanna, M. Falchetti, G. Masala, A. S. Navazio, V. Graziano, S. Bianchi, S. Manoukian, M. Barile, P. Peterlongo, C. D’Amico, L. Varesco, S. Tommasi, A. Russo, G. Giannini, L. Cortesi, A. Viel, M. Montagna, P. Radice, D. Palli

Published in: Breast Cancer Research and Treatment | Issue 3/2013

Abstract

It is well-known that male breast cancer (MBC) susceptibility is mainly due to high-penetrance BRCA1/2 mutations. Here, we investigated whether common low-penetrance breast cancer (BC) susceptibility alleles may influence MBC risk in Italian population and whether variant alleles may be associated with specific clinicopathological features of MBCs. In the frame of the Italian Multicenter Study on MBC, we genotyped 413 MBCs and 745 age-matched male controls at 9 SNPs annotating known BC susceptibility loci. By multivariate logistic regression models, we found a significant increased MBC risk for 3 SNPs, in particular, with codominant models, for rs2046210/ESR1 (OR = 1.71; 95 % CI: 1.43–2.05; p = 0.0001), rs3803662/TOX3 (OR = 1.59; 95 % CI: 1.32–1.92; p = 0.0001), and rs2981582/FGFR2 (OR = 1.26; 95 % CI: 1.05–1.50; p = 0.013). Furthermore, we showed that the prevalence of the risk genotypes of ESR1 tended to be higher in ER− tumors (p = 0.062). In a case–case multivariate analysis, a statistically significant association between ESR1 and ER− tumors was found (OR = 1.88; 95 % CI: 1.03–3.49; p = 0.039). Overall, our data, based on a large and well-characterized MBC series, support the hypothesis that common low-penetrance BC susceptibility alleles play a role in MBC susceptibility and, interestingly, indicate that ESR1 is associated with a distinct tumor subtype defined by ER-negative status.

Available only for authorised users

Speirs V, Shaaban AM (2009) The rising incidence of male breast cancer. Breast Cancer Res Treat 115(2):429–430PubMedCrossRef

Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60(5):277–300PubMedCrossRef

Anderson WF, Jatoi I, Tse J, Rosenberg PS (2010) Male breast cancer: a population-based comparison with female breast cancer. J Clin Oncol 28:232–239PubMedCrossRef

Venturini M, Ferretti S, AIRTUM, Associazione Italiana Registri Tumori (2011) I numeri del cancro in Italia, 2011. Intermedia Editore, Brescia, p 88

Fentiman IS, Fourquet A, Hortobagyi GN (2006) Male breast cancer. Lancet 367(9510):595–604PubMedCrossRef

Ottini L, Palli D, Rizzo S, Federico M, Bazan V, Russo A (2010) Male breast cancer. Crit Rev Oncol Hematol 73(2):141–155PubMedCrossRef

Rizzolo P, Silvestri V, Falchetti M, Ottini L (2011) Inherited and acquired alterations in development of breast cancer. Appl Clin Genet 4:145–148

Falchetti M, Lupi R, Rizzolo P, Ceccarelli K, Zanna I, Calò V, Tommasi S, Masala G, Paradiso A, Gulino A, Giannini G, Russo A et al (2008) BRCA1/BRCA2 rearrangements and CHEK2 common mutations are infrequent in Italian male breast cancer cases. Breast Cancer Res Treat 110(1):161–167PubMedCrossRef

Silvestri V, Rizzolo P, Zanna I, Falchetti M, Masala G, Bianchi S, Papi L, Giannini G, Palli D, Ottini L (2010) PALB2 mutations in male breast cancer: a population-based study in Central Italy. Breast Cancer Res Treat 122(1):299–301PubMedCrossRef

10.

Ottini L, Silvestri V, Rizzolo P, Falchetti M, Zanna I, Saieva C, Masala G, Bianchi S, Manoukian S, Barile M, Peterlongo P, Varesco L et al (2012) Clinical and pathologic characteristics of BRCA-positive and BRCA-negative male breast cancer patients: results from a collaborative multicentre study in Italy. Breast Cancer Res Treat 134(1):411–418PubMedCrossRef

11.

Pharoah PD, Antoniou A, Bobrow M, Zimmern RL, Easton DF, Ponder BA (2002) Polygenic susceptibility to breast cancer and implications for prevention. Nat Genet 31(1):33–36PubMedCrossRef

12.

Antoniou AC, Easton DF (2006) Models of genetic susceptibility to breast cancer. Oncogene 25(43):5898–5905PubMedCrossRef

13.

Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D, Ballinger DG, Struewing JP, Morrison J, Field H, Luben R, Wareham N, Ahmed S et al (2007) Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447:1087–1093PubMedCrossRef

14.

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 et al (2007) A common coding variant in CASP8 is associated with breast cancer risk. Nat Genet 39:352–358PubMedCrossRef

15.

Stacey SN, Manolescu A, Sulem P, Thorlacius S, Gudjonsson SA, Jonsson GF, Jakobsdottir M, Bergthorsson JT, Gudmundsson J, Aben KK, Strobbe LJ, Swinkels DW et al (2008) Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 40:703–706PubMedCrossRef

16.

Thomas G, Jacobs KB, Kraft P, Yeager M, Wacholder S, Cox DG, Hankinson SE, Hutchinson A, Wang Z, Yu K, Chatterjee N, Garcia-Closas M et al (2009) A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1). Nat Genet 41:579–584PubMedCrossRef

17.

Zheng W, Long J, Gao YT, Li C, Zheng Y, Xiang YB, Wen W, Levy S, Deming SL, Haines JL, Gu K, Fair AM et al (2009) Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1. Nat Genet 41(3):324–328PubMedCrossRef

18.

Ahmed S, Thomas G, Ghoussaini M, Healey CS, Humphreys MK, Platte R, Morrison J, Maranian M, Pooley KA, Luben R, Eccles D, Evans DG et al (2009) Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2. Nat Genet 41:585–590PubMedCrossRef

19.

Turnbull C, Ahmed S, Morrison J, Pernet D, Renwick A, Maranian M, Seal S, Ghoussaini M, Hines S, Healey CS, Hughes D, Warren-Perry M et al (2010) Genome-wide association study identifies five new breast cancer susceptibility loci. Nat Genet 42:504–507PubMedCrossRef

20.

Antoniou AC, Wang X, Fredericksen ZS, McGuffog L, Tarrell R, Sinilnikova OM, Healey S, Morrison J, Kartsonaki C, Lesnick T, Ghoussaini M, Barrowdale D et al (2010) A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population. Nat Genet 42(10):885–892PubMedCrossRef

21.

Ghoussaini M, Fletcher O, Michailidou K, Turnbull C, Schmidt MK, Dicks E, Dennis J, Wang Q, Humphreys MK, Luccarini C, Baynes C, Conroy D et al (2012) Genome-wide association analysis identifies three new breast cancer susceptibility loci. Nat Genet 44(3):312–318PubMedCrossRef

22.

Orr N, Cooke R, Jones M, Fletcher O, Dudbridge F, Chilcott-Burns S, Tomczyk K, Broderick P, Houlston R, Ashworth A, Swerdlow A (2011) Genetic variants at chromosomes 2q35, 5p12, 6q25.1, 10q26.13, and 16q12.1 influence the risk of breast cancer in men. PLoS Genet 7(9):e1002290PubMedCrossRef

23.

Orr N, Lemnrau A, Cooke R, Fletcher O, Tomczyk K, Jones M, Johnson N, Lord CJ, Mitsopoulos C, Zvelebil M, McDade SS, Buck G et al (2012) Genome-wide association study identifies a common variant in RAD51B associated with male breast cancer risk. Nat Genet 44(11):1182–1184PubMedCrossRef

24.

Milne RL, Antoniou AC (2011) Genetic modifiers of cancer risk for BRCA1 and BRCA2 mutation carriers. Ann Oncol 22(Suppl 1):111–117CrossRef

25.

Garcia-Closas M, Chanock S (2008) Genetic susceptibility loci for breast cancer by estrogen receptor status. Clin Cancer Res 14(24):8000–8009PubMedCrossRef

26.

Garcia-Closas M, Hall P, Nevanlinna H, Pooley K, Morrison J, Richesson DA, Bojesen SE, Nordestgaard BG, Axelsson CK, Arias JI, Milne RL, Ribas G et al (2008) Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics. PLoS Genet 4(4):e1000054PubMedCrossRef

27.

Fletcher O, Houlston RS (2010) Architecture of inherited susceptibility to common cancer. Nat Rev Cancer 10(5):353–361PubMedCrossRef

28.

Fanale D, Amodeo V, Corsini LR, Rizzo S, Bazan V, Russo A (2012) Breast cancer genome-wide association studies: there is strength in numbers. Oncogene 31(17):2121–2128PubMedCrossRef

29.

Stevens KN, Vachon CM, Lee AM, Slager S, Lesnick T, Olswold C, Fasching PA, Miron P, Eccles D, Carpenter JE, Godwin AK, Ambrosone C et al (2011) Common breast cancer susceptibility loci are associated with triple-negative breast cancer. Cancer Res 71(19):6240–6249PubMedCrossRef

30.

Cai Q, Wen W, Qu S, Li G, Egan KM, Chen K, Deming SL, Shen H, Shen CY, Gammon MD, Blot WJ, Matsuo K et al (2011) Replication and functional genomic analyses of the breast cancer susceptibility locus at 6q25.1 generalize its importance in women of Chinese, Japanese, and European ancestry. Cancer Res 71(4):1344–1355PubMedCrossRef

31.

Hein R, Maranian M, Hopper JL, Kapuscinski MK, Southey MC, Park DJ, Schmidt MK, Broeks A, Hogervorst FB, Bueno-de-Mesquit HB, Muir KR, Lophatananon A et al (2012) Comparison of 6q25 breast cancer hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC). PLoS One 7(8):e42380PubMedCrossRef

32.

Styrkarsdottir U, Halldorsson BV, Gretarsdottir S, Gudbjartsson DF, Walters GB, Ingvarsson T, Jonsdottir T, Saemundsdottir J, Center JR, Nguyen TV, Bagger Y, Gulcher JR et al (2008) Multiple genetic loci for bone mineral density and fractures. N Engl J Med 358:2355–2365PubMedCrossRef

33.

Brinton LA, Richesson DA, Gierach GL, Lacey JV Jr, Park Y, Hollenbeck AR, Schatzkin A (2008) Prospective evaluation of risk factors for male breast cancer. J Natl Cancer Inst 100(20):1477–1481PubMedCrossRef

Title: Association of low-penetrance alleles with male breast cancer risk and clinicopathological characteristics: results from a multicenter study in Italy
Authors: L. Ottini
V. Silvestri
C. Saieva
P. Rizzolo
I. Zanna
M. Falchetti
G. Masala
A. S. Navazio
V. Graziano
S. Bianchi
S. Manoukian
M. Barile
P. Peterlongo
C. D’Amico
L. Varesco
S. Tommasi
A. Russo
G. Giannini
L. Cortesi
A. Viel
M. Montagna
P. Radice
D. Palli
Publication date: 01-04-2013
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 3/2013
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-013-2459-4

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

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

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2013

Time to ROLL with it?

MicroSPECT/CT imaging of co-expressed HER2 and EGFR on subcutaneous human tumor xenografts in athymic mice using 111In-labeled bispecific radioimmunoconjugates

Incremental impact of breast cancer SNP panel on risk classification in a screening population of white and African American women

Intake of specific fruits and vegetables in relation to risk of estrogen receptor-negative breast cancer among postmenopausal women

Genetic associations with toxicity-related discontinuation of aromatase inhibitor therapy for breast cancer

The role of intratumoral and systemic IL-6 in breast cancer

Keynote webinar | Spotlight on antibody–drug conjugates in cancer