The PROSE Study of BRCA1 and BRCA2 Mutation Carriers
Aims: Women who carry mutations in the BRCA1 or BRCA2 genes are at an increased risk of developing breast and ovarian cancer at some point during their life. However, some mutation carriers develop cancer while others do not. The age of onset of cancer varies among different women who carry BRCA1/2 mutations as well. The purpose of this study is to shed light on the factors which increase the chances of cancer development in BRCA1/2 carriers and to learn which factors are protective. The overall study goal is to identify genes involved in DNA damage recognition and repair pathways that influence BRCA1/2-associated cancer risk. The NorthShore Center for Medical Genetics is collaborating with the University of Pennsylvania and the University of California Irvine, as well as other sites both nationally and internationally in this study.
Diagnosis: Women who have tested positive for a mutation in either the BRCA1 or BRCA2 genes
Principal Investigator: Peter J. Hulick, MD, MMSc
IRB Approval Number: EH05-340
Sponsor: The University of Pennsylvania
Contact: Interested patients should contact Tina Selkirk at 847.570.4652
Open to Enrollment: Yes

Susceptibility Gene Identification in Families with a Genetic Predisposition To Breast Cancer (The SIFT Study)
Aims: Individuals with a hereditary breast cancer syndrome whose causative gene is yet undiscovered must be clinically managed according to the familial cancer pattern. For such families, it is not currently possible to separate those relatives who are at increased risk and those who face average cancer risks. Thus, many individuals with hereditary cancer patterns of unknown etiology will undergo high-risk surveillance and preventative surgery which would not be warranted if their “true” genetic status could be discerned. Once the responsible gene mutation is known, it is possible to change the risk status for family members and provide more individualized management recommendations.
Diagnosis: Men and women who have a personal and/or family history of breast cancer who have a negative genetic test result
Principal Investigator: Peter J. Hulick, MD, MMSc
IRB Approval Number: EH09-008
Sponsor: NorthShore University HealthSystem
Contact: Interested patients should contact Tina Selkirk at 847.570.4652
Open to Enrollment: Yes

Functional Assays of Genetic Instability in Breast and Ovarian Cancer and in Patients at High Genetic Risk
Aims/Outcome: Our study showed normal DNA repair capacity, using a pathway called nucleotide excision repair, in cultured normal breast epithelial tissue and cultured blood lymphocytes from a BRCA1 carrier. Our study proves definitively that inactivation of BRCA1 through the inherited mutation does not intrinsically confer this type of genetic instability on normal breast tissues. These data suggest that the mechanism of genomic instability driving the carcinogenic process may be fundamentally different in hereditary and sporadic breast cancer. This may result in different susceptibilities to agents which cause genetic mutations, and a different pathway to cancer in sporadic vs. inherited breast cancer.
Diagnosis: Men or women who are at high genetic risk for breast and ovarian cancer and are planning breast or ovarian surgery
Principal Investigator: Wendy S. Rubinstein, MD, PhD
Open to Enrollment: No
Publications: Latimer JJ, Rubinstein WS, Johnson JM, Kanbour-Shakir A, Vogel VG, Grant SG. Haploinsufficiency for BRCA1 is associated with normal levels of DNA nucleotide excision repair in breast tissue and blood lymphocytes. BMC Medical Genetics 2005, 6:26.

Clinical Utility of Magnetic Resonance Imaging (MRI) for Early Detection of Breast Cancer in High-Risk Women
Aims/Outcomes: Our study resulted in two women being diagnosed with stage 1 breast cancer, both of whom had very small tumors that were not detected by mammogram or felt by physicians. There was no significant increase in stress while in the screening study. There was a low rate of “unnecessary” biopsies (three of 103 women), but 34% needed additional six month breast MRI, U/S, mammogram, and/or biopsy. 
Diagnosis: Women considered to be at high risk of developing breast cancer
Principal Investigator: Wendy S. Rubinstein, MD, PhD 
Open to Enrollment:  No
Publications: O’Neill, SM, Rubinstein, WS, Sener SF, Weissman SM, Newlin AC, West D, Ecanow D, Rademaker AW, Edelman RR. Psychological Impact of Recall in High-Risk Breast MRI Screening. Breast Cancer Research and Treatment, 2009; 115(2):365-71.

Computer Education for Breast Cancer Genetic Testing Take-Home Pilot
Aims/Outcomes: This study showed that computer-based education can be an effective way to inform patients about their risk of breast cancer and the pros and cons of genetic testing. This may help reduce unnecessary referrals to genetic counselors and reserve counseling for the high-risk patients who need it most.  The results suggest that the computer program may stand alone as an educational tool for low-risk patients when accompanied by appropriate follow-up by a qualified health professional. The computer program can be used as a supplement to standard genetic counseling for those at high risk. This may help free up precious counseling time to delve further into emotional issues and decision making about high-risk medical management.
Diagnosis: Women presenting for genetic counseling for hereditary breast and ovarian cancer syndrome
Principal Investigator: Wendy S. Rubinstein, MD, PhD
Open to Enrollment: No 
Publications: Green MJ, Peterson SK, Baker WM, Friedman LC, Harper GR, Rubinstein WS, Peters JA, Mauger DT. Use of an educational computer program before genetic counseling for breast cancer susceptibility: Effects on duration and content of counseling sessions. Genetics in Medicine. 2005;7(4):221-229.

Green MJ, Peterson SK, Baker WM, Friedman LC, Harper GR, Rubinstein WS, Mauger DT. Effect of a Computer-Based Decision Aid on Knowledge, Perceptions, and Intentions About Genetic Testing for Breast Cancer Susceptibility. A Randomized Controlled Trial. JAMA. 2004;292:442-452.

Rubinstein WS: Computer-Based Genetic Counseling. Letter to the Editor. JAMA. 1999;282:1719-1720.

Expression Profiling to Identify BRCA1 and BRCA2 Associated Breast Cancers
Aims/Outcomes: We have developed a new microarray test that can assess breast cancer biopsy material for evidence that a woman’s breast cancer was caused by an inherited mutation in the BRCA1 gene. Currently, about half of all BRCA1 and BRCA2 mutation carriers go unrecognized, because their family history is unrevealing. Testing the tumor with this technology is expected to be a much more cost-effective screen than gene testing the patient, and can help target gene testing to those individuals most likely to be positive. It also can help target testing to a particular gene (e.g. BRCA1) rather than two genes (BRCA1 and BRCA2), further reducing costs. This new approach also can help “fill in” family history, as it can be used to test tumors from deceased relatives. The test is highly sensitive (91%) and specific (83%), and the technique has worked in archival tumors stored in the pathology laboratory as long as 39 years. Once the test is developed for clinical use, any woman with breast cancer can find out if her cancer is hereditary and may be due to a BRCA1 gene mutation.
Diagnosis: Women with breast cancer who have a mutation in the BRCA1 gene
Principal Investigator: Wendy S. Rubinstein, MD, PHD
Open to Enrollment: No
Publications: None

Ashkenazi Jewish BRCA1/2 Founder Mutation analysis in tumor tissue
Aims: Ashkenazi Jewish founder mutations were correctly identified in all 62 specimens that were known to be positive for a founder mutation.  All specimens that were negative for a founder mutation were also correctly identified.
Diagnosis: Women with mutations in the BRCA1 or BRCA2 genes
Principal Investigator: Karen Kaul, MD, PhD and Kathy Mangold, PhD
Open to Enrollment: No
Publications: Mangold KA, Wang V, Weissman SM, Rubinstein WS, Kaul KL.  Detection of BRCA1 and BRCA2 Ashkenazi Jewish Founder Mutations in Formalin-Fixed Paraffin-Embedded Tissues Using Conventional PCR and Heteroduplex/Amplicon Size Differences.  Journal of Molecular Diagnostics, 2010; 12(1).

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