M18 - Breast cancer post GWAS

Investigator Names and Contact Information

Sara Lindstroem (saralind@uw.edu)

Formerly David Hunter

Introduction/Intent

This post-GWA project "Discovery, Biology and Risk of Inherited Variants in Breast Cancer" is designed to systematically discover and fine map new genetic loci that influence breast cancer risk, explore their biological impact, and to begin to translate these findings into clinically useful tools to assess the risk associated with inheritance of multiple alleles and their potential interaction with each other and with established non-genetic risk factors. To do this we have assembled a multi-disciplinary team that includes the largest pre-existing Consortia researching the genetics of breast cancer, and computational biologists and basic scientists with a strong track record in the investigation of mechanisms by which genetic loci may influence breast cancer risk.

Overall Goals of the RFA:

Goal 1. To pursue promising scientific leads from initial Genome Wide Association Studies (GWAS) of cancer (exploiting previously generated "initial scan" GWAS data).

Goal 2. To accelerate and coordinate integrative post-GWAS discovery research, which could provide the basis for expediting clinical translation and public health dissemination of the findings.

Modification 1: Use leftover DNA samples for Oncochip at CIDR

Specific Aims for Mod 1:

1. Genotype approximately 600,000 variants in approximately 100,000 breast cancer cases and controls using a custom Illumina OncoChip. This OncoChip will include additional markers chosen because of the relevance to breast cancer, notably 38,000 markers chosen from the NHBGRI catalog of SNPs and for replication of cross-site meta-analysis. We will be able to complete this aim quickly (Years 1 and 2) because extracted DNA samples on these participants have already been assembled, and we have already established a pipeline for running Illumina Beadchips at CIDR and performing centralized genotype calling and quality control and assurance.

2. Conduct GWAS of breast cancer incidence. We aim to identify individual variants that are associated with risk of cancer generally, and with risk of particular subtypes (estrogen-receptor negative and triple-negative breast cancer).

3. Conduct GWAS of breast cancer survival. We aim to identify individual variants that are associated with cancer prognosis.

4. Validate proposed breast cancer markers. We aim to replicate all markers that have been suggestively or definitively associated with breast cancer incidence from the NHGRI catalog and for cross-site meta-analysis.

5. Fine-map known breast cancer loci. The OncoChip will contain many independent SNPs near all of the known breast cancer loci. Using these SNPs, we aim to carry out fine-mapping of known or suggestive breast cancer associated loci.

6. Conduct exploratory gene-environment, and gene-gene interaction analyses. We aim to identify additional variants associated with breast cancer by incorporating effect modification by established risk factors, including age at diagnosis and hormone therapy. We also aim to characterize the joint effects of newly identified risk variants and known risk factors by testing for gene-gene and gene-environment interaction.​