Establishing a new consortium, MERGE, to investigate the genetics of male breast cancer

The MERGE consortium will be supported, in the first instance, by funding from the NCI Confluence project. Confluence will pay for DNA extractions for samples that are sent to NCI for genotyping. They will also pay for genotyping and preliminary data quality control. Confluence cannot cover the cost of sample retrieval and preparation that is performed by any individual cohort.

Relative to female breast cancer (FBC), the genetic basis for male breast cancer (MBC) is poorly understood. Pathogenic mutations in BRCA2 and PALB2 are strongly associated with risk, particularly amongst men from high-risk families. Polygenic susceptibility is also an established risk factor and there appears to be a strong genetic correlation between MBC and hormone receptor-positive FBC. Polygenic risk scores (PRS) for FBC have been demonstrated to have predictive power for both sporadic disease and for disease in pathogenic mutation carriers. Therefore, risk stratification using a PRS may be feasible for men at high risk of developing breast cancer, such as BRCA2 mutation carriers. Furthermore, a subset of breast cancer susceptibility loci have been shown to confer significantly larger risk effects for MBC than FBC, suggesting sex-differentiated regulation or activity of genes in the causal pathways for breast cancer that are influenced by causal variants. It is likely therefore that detection and characterisation of additional risk loci for MBC will enhance the predictive power of genetic risk stratification models and may also lead to novel insights into the genes and biological pathway that underpin susceptibility to this rare disease.

In order to conduct future studies into the aetiology and pathology of MBC on a collaborative basis, we have established a new Male Breast Cancer Genetics Consortium (MERGE), co-led by Dr Nick Orr (Queen's University Belfast, UK) and Prof Laura Ottini (Sapienza University of Rome, Italy). MERGE will participate in the US National Cancer Institute Confluence Project, a large-scale collaborative effort to discover novel susceptibility loci for breast cancer by performing genetic analysis of at least 300,000 cases (female and male) and 300,000 controls. Participation in Confluence will not be prerequisite for membership of MERGE and individual cohorts may opt out of Confluence if they wish to do so. However, by collaborating with Confluence, MERGE will be able to support de novo genotyping of MBC cases and population matched controls, to create the largest dataset worldwide with which to study the genetics of predisposition to the disease.

The overall goals of the MERGE consortium are i) to identify germline variants that are associated with risk of MBC and ii) to comprehensively characterise differences and similarities between breast tumours in males and females.

In the first instance we aim to identify novel predisposition loci for MBC by performing genome-wide analysis of SNP genotypes in MBC cases and population-matched controls. We also aim to develop PRS models that have been optimised for MBC for risk stratification in high-risk individuals such as male BRCA2 pathogenic mutation carriers.

MBC cases and population-matched controls will be subject to genome-wide genotyping using a custom-designed genotyping array (Illumina Global Screening Array (GSA), plus custom content) at the NCI Division of Cancer Epidemiology and Genetics (DCEG) Cancer Genomics Research Laboratory (CGR). Note that participating cohorts may also contribute existing genotype data. Standard quality control procedures for genotyping data will be applied, including sample and SNP-level completion rate checks, heterozygosity assessment, sex verification, population structure assessment and SNP deviation from Hardy-Weinberg proportions. The analytic plan will involve standard single-SNP association testing. PRS for predicting breast cancer will be developed using standard methods.

Due to the rarity of MBC there is a paucity of studies worldwide with the requisite numbers of samples that are necessary for robust genetic association analysis. A cohort consortium approach is therefore warranted to enable further characterisation of the disease, both in terms of its aetiology and pathology.

The previous largest GWAS of MBC comprised 1,380 cases. For planning purposes, we collected information on available samples from studies that expressed an interest in participating in the Confluence project and identified at least 4,000 additional cases. We anticipate therefore that we will have between 3-4 fold more cases than previous studies with which to detect novel susceptibility loci for MBC. Because MBC is a rare disease we are imposing no minimum number of cases needed to participate in the proposed project.

Mandatory: case-control status
Not mandatory: diagnosis of second breast cancers; survival (age at diagnosis, follow-up time, cause of death)

Mandatory: Existing or new genome-wide genotype data

Mandatory: subject and sample IDs, family IDs, sex
Not mandatory: age (at diagnosis for cases, at enrollment for controls), ethnicity, family history, tumour ER/PR/HER2 status, histotype, grading and TNM status

Yes