Dataset Information

Common Susceptibility Loci for Male Breast Cancer.

ABSTRACT:

Background

The etiology of male breast cancer (MBC) is poorly understood. In particular, the extent to which the genetic basis of MBC differs from female breast cancer (FBC) is unknown. A previous genome-wide association study of MBC identified 2 predisposition loci for the disease, both of which were also associated with risk of FBC.

Methods

We performed genome-wide single nucleotide polymorphism genotyping of European ancestry MBC case subjects and controls in 3 stages. Associations between directly genotyped and imputed single nucleotide polymorphisms with MBC were assessed using fixed-effects meta-analysis of 1380 cases and 3620 controls. Replication genotyping of 810 cases and 1026 controls was used to validate variants with P values less than 1 × 10-06. Genetic correlation with FBC was evaluated using linkage disequilibrium score regression, by comprehensively examining the associations of published FBC risk loci with risk of MBC and by assessing associations between a FBC polygenic risk score and MBC. All statistical tests were 2-sided.

Results

The genome-wide association study identified 3 novel MBC susceptibility loci that attained genome-wide statistical significance (P < 5 × 10-08). Genetic correlation analysis revealed a strong shared genetic basis with estrogen receptor-positive FBC. Men in the top quintile of genetic risk had a fourfold increased risk of breast cancer relative to those in the bottom quintile (odds ratio = 3.86, 95% confidence interval = 3.07 to 4.87, P = 2.08 × 10-30).

Conclusions

These findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic etiology with FBC and identifying a fourfold high-risk group of susceptible men.

SUBMITTER: Maguire S

PROVIDER: S-EPMC8023850 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Publications

Common Susceptibility Loci for Male Breast Cancer.

Maguire Sarah S Perraki Eleni E Tomczyk Katarzyna K Jones Michael E ME Fletcher Olivia O Pugh Matthew M Winter Timothy T Thompson Kyle K Cooke Rosie R Trainer Alison A James Paul P Bojesen Stig S Flyger Henrik H Nevanlinna Heli H Mattson Johanna J Friedman Eitan E Laitman Yael Y Palli Domenico D Masala Giovanna G Zanna Ines I Ottini Laura L Silvestri Valentina V Hollestelle Antoinette A Hooning Maartje J MJ Novaković Srdjan S Krajc Mateja M Gago-Dominguez Manuela M Castelao Jose Esteban JE Olsson Hakan H Hedenfalk Ingrid I Saloustros Emmanouil E Georgoulias Vasilios V Easton Douglas F DF Pharoah Paul P Dunning Alison M AM Bishop D Timothy DT Neuhausen Susan L SL Steele Linda L Ashworth Alan A Garcia Closas Montserrat M Houlston Richard R Swerdlow Anthony A Orr Nick N

Journal of the National Cancer Institute 20210401 4

<h4>Background</h4>The etiology of male breast cancer (MBC) is poorly understood. In particular, the extent to which the genetic basis of MBC differs from female breast cancer (FBC) is unknown. A previous genome-wide association study of MBC identified 2 predisposition loci for the disease, both of which were also associated with risk of FBC.<h4>Methods</h4>We performed genome-wide single nucleotide polymorphism genotyping of European ancestry MBC case subjects and controls in 3 stages. Associat ...[more]

PMID: 32785646

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Project description:BackgroundGenome-wide association studies have discovered multiple genetic loci associated with breast cancer risk. Investigating these loci would be helpful to evaluate previous findings and identify causal variants for breast cancer. We evaluated index SNPs in 17 of these loci in a study of 1,511 cases and 1,454 controls of European descent.MethodsWe investigated the overall association with breast cancer and among subtypes defined as ER+ (estrogen receptor positive), ER- (estrogen receptor negative) and triple-negative breast cancer (TNBC). Combined effects of SNPs on breast cancer risk were assessed via a genetic risk score. We evaluated the contribution of both genetic variants and traditional risk factors to a breast cancer risk assessment model.ResultsFive of the 17 SNPs were significantly associated (P ≤ 0.05) with overall breast cancer in the same direction as previously reported: rs13387042 (2q35/TNP1), rs4973768 (3p24/SLC4A7), rs2046210 (6q25/ESR1), rs1219648 (10q26/FGFR2), and rs4784227 (16q12/TOX3). When stratified by breast cancer subtype, all five SNPs were associated (P < 0.05) with ER+ cancer, three with ER- cancer (rs13387042, rs1219648, and rs4784227), and one with TNBC (rs1219648). A GRS, based on those five significant SNPs, showed strong association with overall breast cancer with ORs (95 % CI) of 1.48 (1.22-1.79), 1.85 (1.52-2.25) and 2.26 (1.82-2.80), respectively, for each quartile, (P = 2.0 × 10(-15)). Traditional risk factors, including previous benign breast disease, breast cancer family history and parity, were significantly associated with breast cancer risk in the present study. These factors, together with the GRS, were used to build a breast cancer risk assessment model with a c statistic of 0.6321 from receiver operating characteristic analysis. The contribution of the GRS to the model was greater than prior benign breast disease, family history and parity with the c statistic change of 0.0374, 0.0324, 0.0103, 0.0012, respectively.ConclusionsOur study demonstrates that five SNPs were associated with overall breast cancer, with stronger association for ER+ than ER- cancer as previously reported, and suggests that a risk assessment model incorporating the GRS from five loci is useful in identifying women at high risk of breast cancer.

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Dataset Information

Common Susceptibility Loci for Male Breast Cancer.

Background

Methods

Results

Conclusions

Publications

Common Susceptibility Loci for Male Breast Cancer.

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