Common Genetic Variation & Breast Cancer: A Genomic Approach

Institution: University of Southern California
Investigator(s): Christopher Haiman, Sc.D. -
Award Cycle: 2003 (Cycle IX) Grant #: 9KB-0006 Award: $462,925
Award Type: New Investigator Awards
Research Priorities
Etiology and Prevention>Prevention and Risk Reduction: ending the danger of breast cancer

Initial Award Abstract (2003)
DNA is the cellular blueprint of instructions passed on from generation to generation and encodes key biological elements called genes. Humans are 99.9% identical to each other at the level of their DNA. Distinguishing attributes, such as physical features, and a large part of disparity in susceptibility to developing disease are ascribed to the 0.1% difference in the DNA. The majority of these differences are in the form of single letter changes in the code of the DNA called single nucleotide polymorphisms and the majority of these changes are quite common. A number of genes have been linked with breast cancer and women carrying mutations in these genes have a substantially higher risk of developing the disease. Unfortunately, the mutations discovered to date are rare and, therefore, only account for a small fraction of breast cancer in the general population. It remains to be determined if polymorphisms in these genes alter a woman’s risk of breast cancer.

The central question we plan to answer is whether common variations in genes with established roles in breast cancer are associated with sporadic breast cancer risk. We are also interested in determining what percentage of the racial/ethnic variation in breast cancer risk may be explained by subtle differences in these genes. We propose to use a novel genetic (haplotype) approach that exploits the ancestral relationship between common variations in the DNA to identify genetic markers of sporadic breast cancer risk in a large-scale multiethnic epidemiologic study. (A haplotype is a combination of genotypes on the same chromosome that tend to be inherited as a group.)

This work will be carried out in a large multiethnic cohort study being conduct in Los Angeles and Hawaii comprised of African Americans, Latinas, Japanese, Whites and Hawaiians. We will comprehensively assess underlying differences in nucleotide sequence variation within candidate disease genes for each racial/ethnic group. This approach requires the evaluation of hundreds of variations across each gene. To do this we will use high-throughput genetic laboratory techniques. We will then evaluate differences in gene variation between cases and controls in a large-scale breast cancer case-control study within the cohort.

This study incorporates principles of both population genetics and epidemiology to unravel the genetic complexity of sporadic breast cancer. This is the first study to use these genetic (haplotype) research methods to explore common variation in these particular candidate breast cancer susceptibility genes in relation to breast cancer risk. An additional strength of this study is the ability to examine risk differences associated with common genetic variation between populations of diverse ancestral backgrounds.

Final Report (2006)
Over the past three years we have performed in-depth investigations of common genetic variation in established breast cancer susceptibility genes in relation to breast cancer risk. In these studies we utilized linkage disequilibrium-based genomic approaches to comprehensively survey genetic variation and test for associations with breast cancer risk among five racial and ethnic populations in the Multiethnic Cohort study. Genotyping of selected variations in the candidate genes ATM, BRCA1, BRCA2, TP53 and PTEN was conducted in a case-control study (cases, n = 1,715; controls, n = 2,502) comprised of African-American, Native Hawaiian, Japanese-American, Latino and White men and women from California (mainly Los Angeles) and Hawaii.

During year 1 we accomplished specific aim 1, which was to characterize the linkage-disequilibrium patterns for the candidate genes listed in the original proposal (this was performed for 5 of the 6 genes - all except LKB1). Because of the limited number of known single nucleotide polymorphisms (SNPs) across the LKB1 locus we were unable to study this gene by way of this particular genomic approach. Over the past two years we have also completed specific aim 2 which was the selection and genotyping of “tagging" SNPs for these five candidate genes in the case and control samples. To date we have published three manuscripts (one for each BRCA1, BRCA2 and PTEN) that describe our analyses and results. For these genes we observed extensive linkage disequilibrium patterns across each locus and for BRCA2 we found modest evidence of an association between a common haplotype pattern and breast cancer risk, whereas no relationship between SNPs or haplotypes in BRCA1 or PTEN were found to be significant predictors of risk. We have recently completed the analysis of tagging SNPs in both TP53 and ATM and our data suggest that genes do not contain markers of sporadic breast cancer risk. We plan to publish our findings for TP53 and ATM by the end of the year. Over this time period we also plan to test gene-gene interactions between all of the tagging SNPs in each of the five genes (aim 3).

We have continued our work in this area and over the last six months we have selected and genotyped tagging SNPs for an additional ~50 genes from DNA repair pathways that have been implicated in breast cancer carcinogenesis. We hope that this work will continue to help us understand the role of variation in DNA repair pathways genes in breast carcinogenesis.

Common variation in BRCA2 AND breast cancer risk: a haplotype-based analysis in the Multiethnic cohort.
Periodical:Human Molecular Genetics
Index Medicus: Hum Mol Genet
Authors: Matthew L. Freedman,Kathryn L. Penney,Daniel O. Stram,Loic Le Marchand, Joel N. Hirschhorn
Yr: 2004 Vol: 13 Nbr: 20 Abs: Pg:2431-2441