BA2 - High-dimensional genotype in relation to breast cancer and WHI clinical trial interventions
Investigator Names and Contact Information
Ross Prentice (rprentic@whi.org)
Introduction/Intent
Breast cancer is among the three leading causes of cancer death in US women. At least 20%, perhaps as much as one-third of breast cancer is thought to be attributable to inherited factors. Breast cancer is a multifactorial polygenic disease and theoretical data, as well as results from previous studies, suggest that numerous common genetic variants resulting in moderate associations contribute substantially to overall occurrence of these cancers. The first stage of a genome-wide scan study using 360,000 common single nucleotide polymorphisms (SNPs) involving 1000 breast cancer cases and pair-matched controls has been completed, and a second stage involving 800 breast cancer cases and pair-matched controls, and 10,000 SNPs selected using first stage data, has also been completed using specimens from the WHI observational study. The study proposed here will provide an additional major study for the selection of breast cancer-related SNPs from among these 10,000, and will provide an opportunity to examine the effect of disease-related SNPs on the breast cancer hazard ratios arising from each component of the WHI clinical trial.
Recent advancements in genotyping technology have allowed genome-wide studies of this type to become feasible, and present a logical and critical next step to further explore the impact of genetic variants in this disease and to elucidate intervention effects in the WHI clinical trial. The SNP markers in the present study will be genotyped using the high-throughput Affymetrix GeneChip microarray platform with the chips already designed by Perlegen Sciences. The genotyping will be performed at the state-of-the-art facilities of Perlegen Sciences and the genotype, clinical outcome, and other research data will be analyzed in a collaborative fashion by investigators at the Fred Hutchinson Cancer Research Center and at Perlegen, with the help of WHI consultants. The elimination of false positive findings is a major consideration in high-dimensional genotyping studies of this type. For the multistage designs proposed the overall significance level will be chosen as 0.0000025 for breast cancer, leaving an expected total of only 0.9 false positive findings. Equally important, these studies will be sufficiently powered to establish moderate associations between genotypes and cancer risk, and to identify moderate associations between genotypes and WHI clinical trial intervention effects. We expect that results will identify new candidate pathways and help to elucidate the effects of interventions studied in the WHI clinical trial. These findings can also be expected to improve our understanding of the genetic susceptibility and molecular mechanisms of breast carcinogenesis, potentially leading to improved screening and preventive strategies for a very common cancer in postmenopausal women.
This proposal seeks to identify aspects of genotype that relate to the risk of breast cancer, and aspects of genotype that relate to the magnitude of intervention effects on breast cancer in the Women’s Health Initiative (WHI) randomized controlled clinical trial (CT). An ongoing genome-wide scan of breast cancer cases (as well as coronary heart disease and stroke cases) and matched controls in the WHI cohorts, being carried out as a collaborative study between Perlegen Sciences and the WHI, underlies the specific objectives as follows:
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To further assess the relationship between breast cancer risk and the 10,000 single nucleotide polymorphisms (SNPs) that have been identified in the first stage of the ongoing Perlegen-WHI collaborative study of breast cancer, through application to the 2,242 breast cancer cases in the WHI clinical trial, and to pair-matched controls, and
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To examine interactions of the effects of each of the four interventions studied in the WHI clinical trial (estrogen plus progestin; estrogen-alone; low-fat dietary pattern; calcium and vitamin D supplementation) with these 10,000 SNPs, using the same breast cancer cases and matched controls.
Results/Findings
Some of the publications related to this ancillary study are: 846, 1045, 1055, 1070, 1104. For a complete, up-to-date list of WHI papers related to this ancillary study, please use the searchable Papers section of this website.
