Combining data from segregation analyses and mutation screening studies, the established breast cancer susceptibility genes are responsible for an estimated 20%-25% of the genetic component of this disease. The genes and/or sequence variants responsible for the remaining genetic component of breast cancer risk have yet to be identified. Most of the current enthusiasm for SNPs and haplotype mapping are predicated on the assumption that common modest risk variants are most important. However, few candidate associations between common SNPs and breast cancer risk have been independently reproduced. Thus the central question of this study: What is the relative contribution of common (usually modest-risk) sequence variants vs. rare (potentially higher-risk) sequence variants to the genetic attributable fraction of breast cancer? U Using an ethnically diverse series of 1,250 genetically high-risk breast cancer cases and 1,250 frequency-matched population controls, we propose a novel study designed to make a direct comparison between the common disease/ common variant and common disease/ rare variant models of genetic susceptibility. The study has two arms. In the first, we will genotype the cases and controls with all of the common- sequence variants that are known, or are found over the course of this study by the breast cancer genetics research community, to predict increased risk of breast cancer. In the second arm, we will mutation screen the open reading frames of strong candidate susceptibility genes in both the cases and the controls. Analysis of the genotype and mutation screening data should provide an answer to the central study question. Our focus on early onset and familial cases will substantially increase power to detect risk conferred by deleterious sequence variants as compared to a study of similar size without these criteria, fl Results from this study are relevant to public health in three ways: (1) This study will provide a hypothesis test of genes, and mutations in them, that appear to confer moderately to dramatically increased risk of breast cancer. Measuring risk due to mutations in these genes is a key step that lies between initial indications that the gene plays a role in breast cancer susceptibility and bringing the gene into the clinical practice of cancer genetics. (2) Results from this study will bear on the future direction of clinical cancer genetics. The relative contribution that moderate risk versus modest risk sequence variants make to the attributable risk of breast cancer will have an impact on how the genetic information enters clinical practice. (3) Analysis of the genotype and mutation screening data will provide a comparison of risk attributable to the common variant and rare variant genetic models of cancer susceptibility. This is a question of major current interest and importance within the genetics research community. If we observe that the rare sequence variants account for as much or more risk than do common SNPs, it may be necessary to expand mutation screening from the realm of genetic epidemiology/ family studies into larger scale population-based studies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA121245-04
Application #
7891415
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Divi, Rao L
Project Start
2007-09-30
Project End
2012-07-31
Budget Start
2010-09-20
Budget End
2011-07-31
Support Year
4
Fiscal Year
2010
Total Cost
$459,385
Indirect Cost
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Park, Daniel J; Tao, Kayoko; Le Calvez-Kelm, Florence et al. (2014) Rare mutations in RINT1 predispose carriers to breast and Lynch syndrome-spectrum cancers. Cancer Discov 4:804-15
Tavtigian, Sean V; Chenevix-Trench, Georgia (2014) Growing recognition of the role for rare missense substitutions in breast cancer susceptibility. Biomark Med 8:589-603
Damiola, Francesca; Pertesi, Maroulio; Oliver, Javier et al. (2014) Rare key functional domain missense substitutions in MRE11A, RAD50, and NBN contribute to breast cancer susceptibility: results from a Breast Cancer Family Registry case-control mutation-screening study. Breast Cancer Res 16:R58
Le Calvez-Kelm, Florence; Oliver, Javier; Damiola, Francesca et al. (2012) RAD51 and breast cancer susceptibility: no evidence for rare variant association in the Breast Cancer Family Registry study. PLoS One 7:e52374
Park, D J; Lesueur, F; Nguyen-Dumont, T et al. (2012) Rare mutations in XRCC2 increase the risk of breast cancer. Am J Hum Genet 90:734-9
Nguyen-Dumont, Tu; Jordheim, Lars P; Michelon, Jocelyne et al. (2011) Detecting differential allelic expression using high-resolution melting curve analysis: application to the breast cancer susceptibility gene CHEK2. BMC Med Genomics 4:39
Tavtigian, Sean V; Hashibe, Mia; Thomas, Alun (2011) Tests of association for rare variants: case control mutation screening. Nat Rev Genet 12:224
Goldgar, David E; Healey, Sue; Dowty, James G et al. (2011) Rare variants in the ATM gene and risk of breast cancer. Breast Cancer Res 13:R73
Le Calvez-Kelm, Florence; Lesueur, Fabienne; Damiola, Francesca et al. (2011) Rare, evolutionarily unlikely missense substitutions in CHEK2 contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutation-screening study. Breast Cancer Res 13:R6
Nguyen-Dumont, Tú; Calvez-Kelm, Florence Le; Forey, Nathalie et al. (2009) Description and validation of high-throughput simultaneous genotyping and mutation scanning by high-resolution melting curve analysis. Hum Mutat 30:884-90

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