Environmental Factor, February 2008, National Institute of Environmental Health Sciences
With IRB OK, Researchers Launch New Breast Cancer Study
By Eddy Ball
February 2008
Investigators Clarice Weinberg, Ph.D. and Dale Sandler, Ph.D., had reason to celebrate on January 18 when they learned that the NIEHS Institutional Review Board (IRB) had given final approval for launching their new study of breast cancer, known as the Two Sister Study. Building on the large Sister Study 
(http://www.sisterstudy.org/English/index1.htm) cohort they have been recruiting since 2004, the investigators secured a commitment for three years of funding for the new study in 2007 and now plan to begin recruiting for the new study.
As Weinberg explained, “This study will use a family approach to elucidate the combined roles of genes and environmental factors in causing young-onset breast cancer, and in influencing the long-term prognosis and general health of women following treatment for breast cancer.” For this study, “young-onset” means age 50 or younger.
The study will attempt to recruit about 2,000 women with young-onset breast cancer who are sisters of women already participating in the Sister Study. The investigators will invite any parents who are still living to contribute genetic data. It is being funded by a grant from Susan G. Komen for the Cure (http://cms.komen.org/komen/index.htm), which is also a partnering organization for the Sister Study.
The investigation is being led by Weinberg, NIEHS Biostatistics Branch chief and principal investigator, and Sandler, Epidemiology Branch chief and co-investigator. Other investigators include Jack Taylor, M.D., Ph.D., Stephanie London, M.D., and Lisa DeRoo, Ph.D., of the Epidemiology Branch, and Min Shi, Ph.D., of the Biostatistics Branch. As a companion to the larger Sister Study, the new study builds upon the strengths of the larger prospective study of the etiology of breast cancer but uses a family-based approach.
According to Weinberg, the subjects will include about 2,000 families with one daughter with breast cancer and another daughter without breast cancer, who meet enrollment criteria. Families to be selected will all have a daughter who developed breast cancer before the age of 50 and during the past three years and another daughter who is already in the Sister Study. Participants will provide saliva (for DNA) and dust samples, information about family and lifestyle, and details about their breast cancer diagnosis and treatment. The affected sisters will also be asked to give permission for release of medical records and tumor tissue blocks.
Any of their living parents who are willing to participate will be asked to provide saliva samples for extraction of DNA. The plan is to genotype more than 1,500 markers on some 150 candidate genes and to use statistical methods to identify causative (or protective) genetic variants that tend to be over- or under-transmitted to offspring who later develop breast cancer. Maternal genetic effects and parent-of-origin effects can also be studied with this design, something the larger cohort study will not be able to do.
Looking to the future, Weinberg said, “I’m hoping that we’ll be able to afford to do a genome-wide association study for Two Sisters, where we look at maybe 500,000 SNP markers across the genome.” The archived DNA will serve as a resource for future tests of new candidate genes uncovered in ongoing whole genome scans and could potentially be employed in studies of gene-gene interactions and acquired epigenetic modifications.
Exposures related to risk will be identifiable from the comparison of the affected and unaffected sisters. The family structure will then provide a powerful basis for characterizing the combined effects of genetic and non-genetic risk factors.
The young-onset cases enrolled in the Two Sister Study will be merged with the incident cases diagnosed in the larger Sister Study during follow-up. Together, they will form a cohort of breast cancer survivors. The investigators hope to secure funding to follow these survivors for up to ten years to identify factors that influence prognosis and general health following treatment.
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