title: Novel and known genetic variants for male breast cancer risk at 8q24.21, 9p21.3, 11q13.3 and 14q24.1: results from a multicenter study in Italy.
abstract: Increasing evidence indicates that common genetic variants may contribute to the heritable risk of breast cancer (BC). In this study, we investigated whether single nucleotide polymorphisms (SNPs), within the 8q24.21 multi-cancer susceptibility region and within BC-associated loci widespread in the genome, may influence the risk of BC in men, and whether they may be associated with specific clinical-pathologic characteristics of male BC (MBC). In the frame of the ongoing Italian Multicenter Study on MBC, we performed a case-control study on 386 MBC cases, including 50 BRCA1/2 mutation carriers, and 1105 healthy male controls, including 197 unaffected BRCA1/2 mutation carriers. All 1491 subjects were genotyped by Sequenom iPLEX technology for a total of 29 susceptibility SNPs. By logistic regression models, we found a significant association with MBC risk for five SNPs: rs1562430 (p=0.002) and rs445114 (p=0.026) both within the 8q24.21 region; rs1011970/9p21.3 (p=0.011), rs614367/11q13.3 (p=0.016) and rs1314913/14q24.1 (p<0.0001). Differences in the distribution of rs614367/11q13.3 genotypes according to oestrogen receptor (ER) status (p=0.006), and of rs1011970/9p21.3 genotypes according to human epidermal growth factor receptor 2 (HER2) status (p=0.002) emerged. Association of rs1011970/9p21.3 risk genotype with HER2+MBC was confirmed by a multivariate analysis. rs1314913/14q24.1 was associated with increased MBC risk in analyses restricted to male BRCA1/2 mutation carriers (p=0.041). In conclusion, we provided the first evidence that the 8q24.21 region is associated with MBC risk. Furthermore, we showed that the SNPs rs1562430/8q24.21 and rs1314913/14q24.1 strongly influence BC risk in men and suggested that the SNP rs1314913/14q24.1 may act as a risk modifier locus in male BRCA1/2 mutation carriers.
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Silvestri
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Italy.
authors.forename: Piera
authors.initials: P
authors.lastname: Rizzolo
authors.affiliation: CINECA (Inter University Consortium for Super Computing), Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Scarnò
authors.affiliation: CINECA (Inter University Consortium for Super Computing), Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Chillemi
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Italy.
authors.forename: Anna Sara
authors.initials: AS
authors.lastname: Navazio
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Italy.
authors.forename: Virginia
authors.initials: V
authors.lastname: Valentini
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Zelli
authors.affiliation: Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute (ISPO), Florence, Italy.
authors.forename: Ines
authors.initials: I
authors.lastname: Zanna
authors.affiliation: Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute (ISPO), Florence, Italy.
authors.forename: Calogero
authors.initials: C
authors.lastname: Saieva
authors.affiliation: Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute (ISPO), Florence, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Masala
authors.affiliation: Division of Pathological Anatomy, Department of Medical and Surgical Critical Care, University of Florence, Florence, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Bianchi
authors.affiliation: Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Siranoush
authors.initials: S
authors.lastname: Manoukian
authors.affiliation: Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Barile
authors.affiliation: Fondazione Istituto FIRC di Oncologia Molecolare (IFOM) and Cogentech Cancer Genetic Test Laboratory, Milan, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Pensotti
authors.affiliation: Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Peterlongo
authors.affiliation: Unit of Hereditary Cancers, IRCCS AOU San Martino - IST, Genoa, Italy.
authors.forename: Liliana
authors.initials: L
authors.lastname: Varesco
authors.affiliation: Molecular Genetics Laboratory, Istituto Tumori "Giovanni Paolo II", Bari, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Tommasi
authors.affiliation: Section of Medical Oncology, Department of Surgical and Oncological Sciences, University of Palermo, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Russo
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giannini
authors.affiliation: Department of Oncology and Haematology, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Cortesi
authors.affiliation: Unit of Experimental Oncology 1, CRO Aviano, National Cancer Institute, Aviano (PN), Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Viel
authors.affiliation: Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Montagna
authors.affiliation: Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Radice
authors.affiliation: Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute (ISPO), Florence, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Palli
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Italy. Electronic address: laura.ottini@uniroma1.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Ottini
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics*; D018567:Breast Neoplasms, Male / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D002880:Chromosomes, Human, Pair 11; D002883:Chromosomes, Human, Pair 14; D002898:Chromosomes, Human, Pair 8; D002899:Chromosomes, Human, Pair 9; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007558:Italy; D016014:Linear Models; D016015:Logistic Models; D008297:Male; D015999:Multivariate Analysis; D009154:Mutation; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D012307:Risk Factors
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D014408:Biomarkers, Tumor
keywords: 8q24.21; BRCA1/2; Clinical-pathologic characteristics; Low-penetrance BC alleles; Male breast cancer; SNPs