BRCA1 Haploinsufficiency and Gene Expression
BRCA1 Haploinsufficiency and Gene Expression
The purpose of this study is to collect a blood sample from patients that may be used for
 research purposes. These blood samples will be used by researchers at this institution to
 study the causes of breast and ovarian cancer, and to better understand how these cancers
 develop. We are trying to discover differences in the ways cells work in women with a high
 genetic risk of developing breast or ovarian cancer. Early data suggest that some genes may
 be turned on or off in different ways based upon whether or not a woman has a high genetic
 risk of developing breast or ovarian cancer. The primary objective is to test the hypothesis
 that BRCA1 haploinsufficiency regulates gene expression on the X chromosome. This hypothesis
 will be tested by comparing the gene expression profiles of BRCA1 heterozygotes (cases) to an
 age-matched group of unaffected women who are not BRCA1 mutation carriers (controls).
The specific aim of this project is to test the hypothesis that BRCA1 haploinsufficiency
 regulates gene expression on the X chromosome. This hypothesis will be examined by
 determining if X chromosome gene expression profiles, derived from lymphocyte RNA, of BRCA1
 mutation carriers (cases) can be distinguished from an age-matched group of women who do not
 have BRCA1 mutations (controls). Neither cases nor controls will have a history of cancer.
 This investigation will provide valuable insight into the biologic function of BRCA1 and its
 role in breast and/or ovarian tumorigenesis. Blood samples from cases will be collected from
 patients who have previously undergone genetic counseling through the Clinical Genetics
 Service at MSKCC and tested positive for a germline mutation in BRCA1. Blood samples from
 controls will be obtained from two sources.

 First from specimens already collected under IRB Protocol #99-030, entitled "Collection of
 Tissue, Blood, and Cells to be Used for Studying the Causes, Prevention, Diagnosis, and
 Treatment of Breast Cancer (T. King, PI). Controls will also be collected from patients who
 have previously undergone genetic counseling through the Clinical Genetics Service at MSKCC
 and tested negative for germline mutations in BRCA1. Isolation of total RNA from blood will
 be performed using the PAXgene™ Blood RNA System. This study will use lymphocyte RNA samples
 from 50 individuals with BRCA1 mutations and 50 age-matched controls. Gene expression
 profiling will be performed in the Genomics Core Laboratory of MSKCC under the supervision of
 Agnes Viale, PhD. Class comparison analysis will be performed on the gene expression data in
 the Biostatistics Department under the supervision of Adam Olshen, PhD. It is anticipated
 that this study will be completed in approximately 1 year.
Inclusion Criteria:

 For acquisition of control specimens, samples already collected under IRB approved protocol
 99-030 will be used. This protocol was a tissue and blood acquisition protocol entitled
 "Collection of Tissue, Blood, and Cells to Be Used for Studying the Causes, Prevention,
 Diagnosis, and Treatment of Breast Cancer". Patients have already given consent and signed
 a research authorization for to use their blood specimens for this purpose. Controls will
 also be collected from patients who have previously undergone genetic counseling through
 the Clinical Genetics Service at MSKCC and tested negative for a germline mutations in
 BRCA1. These individuals will be approached and asked to donate a sample at the time of
 their results appointment. Blood samples from cases will be collected from patients who
 have tested positive for a germline mutation in BRCA1. These women will have been
 participants in MSKCC protocols such as 96-51 and 97-29, or tested at outside institutions
 and receiving followup care at MSKCC. Any patient with a presumed pathogenic mutation in
 BRCA1 will be eligible for inclusion.

 Exclusion Criteria:

 Subjects will be eligible without regard to age, racial, or ethnic status. Subjects with
 any personal history of cancer will be excluded. Attending physicians authorized to obtain
 informed consent may exercise discretion in excluding individuals for appropriate medical
 or other (e.g., minors, mentally impaired) reasons. Patients with an unclassified variant
 in BRCA1 will be excluded as the functional significance of these variations is unknown.