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Breast Cancer

The Center for Medical Genetics at NorthShore University HealthSystem (NorthShore) includes a broad spectrum of laboratory and clinical breast cancer research designed to bring rapid benefits to patient care. Funding from the National Institutes of Health, as well as the Susan G. Komen Breast Cancer Foundation and other major donors supports our breast cancer research initiatives.

Clinical Breast Cancer Research - Open to Enrollment 

Clinical Breast Cancer Research - Closed to Enrollment 

Laboratory Studies 

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Functional Assays of Genetic Instability in Breast and Ovarian Cancer and in Patients at High Genetic Risk

We are studying hereditary breast cancer by measuring the rate at which cells repair DNA damage.

Investigators

Study Principal Investigator: Jean J. Latimer, Ph.D. (University of Pittsburgh Cancer Institute)
NorthShore Site Principal Investigator: Wendy S. Rubinstein, M.D., Ph.D.

Capsule

The genetic material or DNA is the controlling element of each cell in our bodies. DNA repair is a defensive process which helps to prevent harmful changes from occurring to the genetic material of our cells. These harmful changes or mutations are what transform a normal cell into a tumor cell. Therefore, DNA repair is a process that helps to prevent cancer. When cancer occurs, one of the possible mechanisms is the failure of a DNA repair pathway. The BRCA1 and BRCA2 genes are involved in the repair of DNA damage; the loss of this gene function may lead to hereditary breast-ovarian cancer syndrome. The ability of cells to perform DNA repair can be measured using specific tests on living cells and on the DNA derived from these cells.

The capacity of cells to perform two types of DNA repair will be measured in normal tissue from patients at high genetic risk and normal tumor-adjacent tissue in patients who have breast and ovarian cancer. The capacity of white blood cells to perform two types of DNA repair will be measured as well.

One of the results of the failure of DNA repair is higher levels of mutation that can be detected in the blood using a test called the glycophorin A assay (GPA). We will utilize this blood test to determine whether the level of somatic mutation in the blood of patients correlates with the ability of the patient's tumor and/or non-tumor cells to perform DNA repair.

Study Participant Recruitment & Eligibility

Recruitment open

We are looking for men or women who are at high genetic risk for breast and ovarian cancer and are planning breast or ovarian surgery. Individuals under 75 who are newly diagnosed or who are having a preventative (prophylactic) mastectomy or oophorectomy are eligible.

We will ask you to donate about 2 tablespoons of blood before surgery and complete a short questionnaire about your eating habits, lifestyle and the types of job(s) you have had during the course of your life.

If interested in participating in this study, please call us for more specific information on eligibility 847.570.1029

Outcomes

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.

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.

Grant SG, Cerceo CM, Evdokimova VN, Das R, Auerbach A, Johnson R, Latimer JJ, and Rubinstein WS. (2004) "Elevated levels of somatic mutation in homozygotes and heterozygotes for inactivating mutations in the genes of the FA/BRCA pathway of DNA repair". Presented at the Sixth Annual Midwest DNA Repair Symposium, University of Kentucky, Lexington, Kentucky.

 

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PROSE Study of BRCA1 and BRCA2 Mutation Carriers

We are working to identify modifier genes and environmental factors that may contribute to the expression of cancer in BRCA1 and BRCA2 mutation carriers.

Investigators

Study Principal Investigators: Timothy Rebbeck, Ph.D. (University of Pennsylvania), Susan Neuhausen, Ph.D. (University of California at Irvine)
NorthShore Principal Investigator: Wendy S. Rubinstein, M.D., Ph.D.

Capsule

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.

Study Participant Recruitment & Eligibility

Recruitment open

You must be an NorthShore, Center for Medical Genetics patient who tested positive for either the BRCA1 or BRCA2 gene mutation. If you choose to participate you will be asked to fill out a questionnaire about your health and donate about two tablespoons of blood. If interested in participating in this study, please call us for more specific information on eligibility at 847-570-4652.

Outcomes

Studies from this large, multicenter cooperative research group involving over 3200 BRCA1 and BRCA2 carriers have shown that preventive breast surgery is effective, preventive ovarian surgery prevents both ovarian and breast cancers, and that short term use of hormones in BRCA carriers is safe following preventive removal of the ovaries. This group has also begun to shed light on lifestyle factors and genes which influence whether BRCA carriers develop cancer.

Publications

Gaudet MM, Kirchhoff T, Green T, Vijai J, Korn JM, Guiducci C, Segrè AV, McGee K, McGuffog L, Kartsonaki C, Morrison J, Healey S, Sinilnikova OM, Stoppa-Lyonnet D, Mazoyer S, Gauthier-Villars M, Sobol H, Longy M, Frenay M, GEMO Study Collaborators, Hogervorst FB, Rookus MA, Collée JM, Hoogerbrugge N, van Roozendaal KE; HEBON Study Collaborators, Piedmonte M, Rubinstein W, Nerenstone S, Van Le L, Blank SV, Caldés T, de la Hoya M, Nevanlinna H, Aittomäki K, Lazaro C, Blanco I, Arason A, Johannsson OT, Barkardottir RB, Devilee P, Olopade OI, Neuhausen SL, Wang X, Fredericksen ZS, Peterlongo P, Manoukian S, Barile M, Viel A, Radice P, Phelan CM, Narod S, Rennert G, Lejbkowicz F, Flugelman A, Andrulis IL, Glendon G, Ozcelik H; OCGN, Toland AE, Montagna M, D'Andrea E, Friedman E, Laitman Y, Borg A, Beattie M, Ramus SJ, Domchek SM, Nathanson KL, Rebbeck T, Spurdle AB, Chen X, Holland H; kConFab, John EM, Hopper JL, Buys SS, Daly MB, Southey MC, Terry MB, Tung N, Overeem Hansen TV, Nielsen FC, Greene MI, Mai PL, Osorio A, Durán M, Andres R, Benítez J, Weitzel JN, Garber J, Hamann U, Peock S, Cook M, Oliver C, Frost D, Platte R, Evans DG, Lalloo F, Eeles R, Izatt L, Walker L, Eason J, Barwell J, Godwin AK, Schmutzler RK, Wappenschmidt B, Engert S, Arnold N, Gadzicki D, Dean M, Gold B, Klein RJ, Couch FJ, Chenevix-Trench G, Easton DF, Daly MJ, Antoniou AC, Altshuler DM, Offit K, Sinilnikova OM, Stoppa-Lyonnet D, Mazoyer S, Gauthier-Villars M, Sobol H, Longy M, Frenay M, Sinilnikova O, Barjhoux L, Giraud S, Léone M, Mazoyer S, Stoppa-Lyonnet D, Gauthier-Villars M, Houdayer C, Moncoutier V, Belotti M, de Pauw A, Bressac-de-Paillerets B, Remenieras A, Byrde V, Caron O, Lenoir G, Bignon YJ, Uhrhammer N, Lasset C, Bonadona V, Hardouin A, Berthet P, Sobol H, Bourdon V, Noguchi T, Eisinger F, Coulet F, Colas C, Soubrier F, Coupier I, Peyrat JP, Fournier J, Révillion F, Vennin P, Adenis C, Rouleau E, Lidereau R, Demange L, Nogues C, Muller D, Fricker JP, Longy M, Sevenet N, Toulas C, Guimbaud R, Gladieff L, Feillel V, Leroux D, Dreyfus H, Rebischung C, Cassini C, Faivre L, Prieur F, Ferrer SF, Frénay M, Vénat-Bouvet L, Lynch HT, Hogervorst FB, Rookus MA, Collée JM, Hoogerbrugge N, van Roozendaal KE, Hogervorst FB, Verhoef S, Verheus M, van 't Veer LJ, van Leeuwen FE, Rookus MA, Collée M, van den Ouweland AM, Jager A, Hooning MJ, Tilanus-Linthorst MM, Seynaeve C, van Asperen CJ, Wijnen JT, Vreeswijk MP, Tollenaar RA, Devilee P, Ligtenberg MJ, Hoogerbrugge N, Ausems MG, van der Luijt RB, Aalfs CM, van Os TA, Gille JJ, Waisfisz Q, Meijers-Heijboer H, Gomez-Garcia EB, van Roozendaal CE, Blok MJ, Oosterwijk JC, van der Hout AH, Mourits MJ, Vasen HF, Spurdle AB, Chenevix-Trench G.  Common genetic variants and modification of penetrance of BRCA2-associated breast cancer. PLoS Genet, 2010; 6(10): e1001183.

Domchek SM, Friebel TM, Singer CF, Evans DG, Lynch HT, Isaacs C, Garber JE, Neuhausen SL, Matloff E, Eeles R, Pichert G, Van t'veer L, Tung N, Weitzel JN, Couch FJ, Rubinstein WS, Ganz PA, Daly MB, Olopade OI, Tomlinson G, Schildkraut J, Blum JL, Rebbeck TR. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA, 2010;304(9):967-975.

Antoniou AC, Wang X, Fredericksen ZS, McGuffog L, Tarrell R, Sinilnikova OM, Healey S, Morrison J, Kartsonaki C, Lesnick T, Ghoussaini M, Barrowdale D; EMBRACE, Peock S, Cook M, Oliver C, Frost D, Eccles D, Evans DG, Eeles R, Izatt L, Chu C, Douglas F, Paterson J, Stoppa-Lyonnet D, Houdayer C, Mazoyer S, Giraud S, Lasset C, Remenieras A, Caron O, Hardouin A, Berthet P; GEMO Study Collaborators, Hogervorst FB, Rookus MA, Jager A, van den Ouweland A, Hoogerbrugge N, van der Luijt RB, Meijers-Heijboer H, Gómez García EB; HEBON, Devilee P, Vreeswijk MP, Lubinski J, Jakubowska A, Gronwald J, Huzarski T, Byrski T, Górski B, Cybulski C, Spurdle AB, Holland H; kConFab, Goldgar DE, John EM, Hopper JL, Southey M, Buys SS, Daly MB, Terry MB, Schmutzler RK, Wappenschmidt B, Engel C, Meindl A, Preisler-Adams S, Arnold N, Niederacher D, Sutter C, Domchek SM, Nathanson KL, Rebbeck T, Blum JL, Piedmonte M, Rodriguez GC, Wakeley K, Boggess JF, Basil J, Blank SV, Friedman E, Kaufman B, Laitman Y, Milgrom R, Andrulis IL, Glendon G, Ozcelik H, Kirchhoff T, Vijai J, Gaudet MM, Altshuler D, Guiducci C; SWE-BRCA, Loman N, Harbst K, Rantala J, Ehrencrona H, Gerdes AM, Thomassen M, Sunde L, Peterlongo P, Manoukian S, Bonanni B, Viel A, Radice P, Caldes T, de la Hoya M, Singer CF, Fink-Retter A, Greene MH, Mai PL, Loud JT, Guidugli L, Lindor NM, Hansen TV, Nielsen FC, Blanco I, Lazaro C, Garber J, Ramus SJ, Gayther SA, Phelan C, Narod S, Szabo CI; MOD SQUAD, Benitez J, Osorio A, Nevanlinna H, Heikkinen T, Caligo MA, Beattie MS, Hamann U, Godwin AK, Montagna M, Casella C, Neuhausen SL, Karlan BY, Tung N, Toland AE, Weitzel J, Olopade O, Simard J, Soucy P, Rubinstein WS, Arason A, Rennert G, Martin NG, Montgomery GW, Chang-Claude J, Flesch-Janys D, Brauch H; GENICA, Severi G, Baglietto L, Cox A, Cross SS, Miron P, Gerty SM, Tapper W, Yannoukakos D, Fountzilas G, Fasching PA, Beckmann MW, Dos Santos Silva I, Peto J, Lambrechts D, Paridaens R, Rüdiger T, Försti A, Winqvist R, Pylkäs K, Diasio RB, Lee AM, Eckel-Passow J, Vachon C, Blows F, Driver K, Dunning A, Pharoah PP, Offit K, Pankratz VS, Hakonarson H, Chenevix-Trench G, Easton DF, Couch FJ.  A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population.  Nature Genetics, 2010 Oct;42(10):885-92.

Rebbeck TR, Mitra N, Domchek SM, Wan F, Chuai S, Friebel TM, Panossian S, Spurdle A, Chenevix-Trench G, kConFab, Singer C, Pfeiler G, Neuhausen SL, Lynch HT, Garber JE, Weitzel J, Isaacs C, Couch F, Narod SA, Rubinstein WS, Tomlinson G, Ganz PA, Olopade OI, Tung N, Blum JL, Greenberg RA, Nathanson KL, Daly MB. Modification of Ovarian Cancer Risk by BRCA1/2 Interacting Genes in a Multicenter Cohort of BRCA1/2 Mutation Carriers. DOI: 10.1158/0008.5472.CAN-09-0625. Cancer Research, 2009; 69(14):5801-5810.

Rebbeck TR. Kauff ND. Domchek SM. Meta-analysis of risk reduction estimates associated with risk reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers. Journal of the National Cancer Institute. 101(2): 80-7, 2009.

Rebbeck TR. Friebel T. Wagner T. Lynch HT. Garber JE. Daly MB. Isaacs C. Olopade OI. Neuhausen SL. van 't Veer L. Eeles R. Evans DG. Tomlinson G. Matloff E. Narod SA. Eisen A. Domchek S. Armstrong K. Weber BL. PROSE Study Group. Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. Journal of Clinical Oncology. 23(31):7804-10, 2005

Rubinstein WS. Surgical Management of BRCA1 and BRCA2 Carriers Slightly Sweetened. (Invited Editorial). Rebbeck TR et al., Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers. Journal of Clinical Oncology. 2005;23(31):772-774.

Rebbeck TR. Friebel T. Lynch HT. Neuhausen SL. van 't Veer L. Garber JE. Evans GR. Narod SA. Isaacs C. Matloff E. Daly MB. Olopade OI. Weber BL. Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. Journal of Clinical Oncology. 22(6):1055-62, 2004.

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The SIFT Registry for families with a history of breast cancer and negative genetic testing for breast cancer susceptibility genes

We are establishing a registry for families with a high risk of developing breast cancer where a causative gene has not been successfully identified. Our goal is to identify new breast cancer susceptibility genes that predispose to breast cancer in these families.

Investigators

Principal Investigator: Wendy S. Rubinstein, M.D., Ph.D.

Capsule

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.

“SIFT” stands for: Susceptibility Gene Identification in Families with a Genetic Predisposition to Breast Cancer

Study Participant Recruitment & Eligibility

Recruitment open

We are looking for men and women who have a personal and/or family history of breast cancer and are at least 18 years old. Eligibility requires that you or your family member has received negative genetic test results for one or more of the following genes: BRCA1, BRCA2, CHEK2, CDH1, PTEN, ATM, and/or p53. If additional clinical genetic testing was recommended for you and/or your relatives, then you would not be eligible to participate in this research study. Complete eligibility/exclusion criteria are discussed in more detail as part of the consenting process.

Participants will be asked to provide information about a family history of cancer and to provide documentation of negative genetic test results. We would ask you to donate about 3 tablespoons of blood and to have the blood sample analyzed for genetic changes that lead to a higher risk of breast cancer.

Participants will also have the choice to participate in several optional study activities: allowing study staff to obtain tissue from previous cancers for you or a family member; completing a questionnaire covering medical history, lifestyle habits and environmental exposures; allowing study staff to contact you periodically for updates to medical and family histories; contacting family members if they would like to participate in this study; and being interested in hearing about future research study opportunities in breast cancer research.

Clinical Utility of Magnetic Resonance Imaging (MRI) for Early Detection of Breast Cancer in High-Risk Women

We examined the procedural and emotional aspects of breast MRI screening in high-risk women.

Investigators

Principal Investigator: Wendy S. Rubinstein, M.D., Ph.D.
Co-Investigators: Suzanne M. O’Neill, Ph.D., Robert R. Edelman, M.D., Daniel West, M.D., David Ecanow, M.D., Amy H. Peterman, Ph.D., Erika Brinkmann M.D., Douglas E. Merkel, M.D., David P. Winchester, M.D., Alfred Rademaker, Ph.D.

Capsule

We investigated the use of magnetic resonance imaging (MRI) for early detection in high-risk women. MRI may detect breast cancer early and possibly find tumors that are missed by mammograms. Since MRI may identify suspicious areas of breast tissue that require additional breast biopsies with benign (non-cancerous) results, we looked at quality of life issues for high-risk women who may undergo frequent screenings and endure additional medical procedures. A total of 103 women were enrolled in this three-year study.

Study Participant Recruitment & Eligibility

Recruitment closed

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 (3 of 103 women), but 34% needed additional 6 month breast MRI, U/S, mammogram, and/or biopsy.

Publication

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.

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Computer Education for Breast Cancer Genetic Testing Take-Home Pilot

We investigated ways to improve how patients are educated on matters faced during genetic counseling. We tested the effectiveness of using a CD-ROM computer program for patients to view before participating in a clinical visit.

Investigators

Study Principal Investigator: Michael Green, M.D. (Hershey Medical Center)

NorthShore Site Principal Investigator: Wendy S. Rubinstein, M.D., Ph.D.

Capsule

As more and more people seek genetic testing to learn their risks for hereditary diseases, the demands on genetic counseling services continue to grow. Only about 500 genetic counselors in the United States specialize in cancer genetics, most of them located near major urban centers.

There are risks that may result from learning about one’s genetic makeup. There is consensus that patients should be educated about genetic testing issues to prepare for their genetic counseling appointment. Such pre-appointment education includes the meaning of test results, the risks, benefits, alternatives to genetic testing, and the options for follow-up in the event of a positive test result. Pre-appointment education may allow patients more time to make an informed decision whether or not to undergo genetic testing. Dr. Michael Green and colleagues have developed a CD-ROM that provides general and specific information to individuals who are considering genetic testing for breast cancer. The long-term objective of this project is to improve patient understanding about breast cancer risk and genetic testing.

Study Participant Recruitment & EligibilityRecruitment

Closed

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 study was conducted at six medical centers across the country including NorthShore, and compared the use of an interactive, multimedia presentation with traditional one-on-one counseling. While knowledge increased in both groups, the researchers found that the computer program was more effective than genetic counseling for increasing knowledge among women at low risk of carrying a BRCA1 or BRCA2 mutation (a genetic predisposition to breast or ovarian cancer). However, genetic counseling was better at reducing the women’s anxiety and helping them have a more accurate understanding of their risk. In fact, education and counseling had a dissuading influence on low-risk women, who usually decided against genetic testing after learning more about it and about their level of genetic risk.

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.

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.

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Expression Profiling to Identify BRCA1 and BRCA2 Associated Breast Cancers

We are utilizing gene expression profiling to create a rapid, inexpensive test to detect hereditary breast cancer by looking at the genetic fingerprint of tumors that have an underlying mutation in the BRCA1 gene.

Investigators 

Principal Investigator: Wendy S. Rubinstein, M.D., Ph.D.
Co-Investigators: Karen Kaul, M.D., Ph.D., Henry T. Lynch, M.D., Xijin Ge, Ph.D., Lucyna W. Klatzco, Suzanne O'Neill, Ph.D.

Capsule

Gene expression profiling can assess the genetic fingerprint of cancer cells by examining the pattern of RNA expression of numerous genes at a time. We are developing a microarray gene chip that will be able to identify breast cancers caused by a BRCA1 gene mutation using breast tumor tissue obtained for a biopsy or at surgery. Breast cancers that arise in women with inherited BRCA1 mutations have a unique gene expression pattern that reflects the underlying mutation. We have accomplished analysis of BRCA1 tumors in archival materials. Gene expression profiling could lead to better identification of patients and families who have hereditary breast-ovarian cancer syndrome and help improve medical care in those families.

Study Participant Recruitment & Eligibility

Study does not require recruitment

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.

Publications

Rubinstein WS, Ge X, Kaul KL, Lynch HT. "Gene expression profiling of archival specimens distinguishes BRCA1-mutated from sporadic breast cancers". Presented as an abstract and platform presentation at the American Society of Human Genetics 56th Annual Meeting, New Orleans, LA October 9-13, 2006 

Rubinstein WS, Ge X, Kaul KL, Wang SM, Jafari N, Regner MA. "Gene Expression Profiling of BRCA1 Germline-Mutated Breast Carcinomas Supports Role of BRCA1 as a Stem Cell Regulator". Presented at the American Association for Cancer Research, Oncogenomics 2005: Dissecting Cancer Through Genome Research, San Diego, CA, February 2-6, 2005.

Rubinstein WS, Kaul KL, Jafari N, Wang SM, Ge X, Dyke P, Latimer JJ. “Expression Profiling to Identify BRCA1-associated breast cancers.” Presented at Session I of the 12th SPORE Investigators’ Workshop, Baltimore, M.D., July 10-13, 2004.

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Susan G. Komen Study of Familial DCIS and Invasive Breast Cancer

We are engaged in research to identify genetic determinants of breast cancer and create a comprehensive risk evaluation measure by applying gene expression profiling to the study of Familial DCIS and Invasive Breast Cancer.

Investigators

Principal Investigator: Wendy S. Rubinstein, M.D., Ph.D.
Co-Investigators: Xijin Ge, Ph.D., Robert A. Goldschmidt, M.D., Karen L. Kaul, M.D., Ph.D.

Capsule

It is important to develop ways to identify women at increased risk of breast cancer in order to focus early detection and prevention efforts on these individuals. Through gene expression profiling we are able to enrich for and identify candidate breast cancer susceptibility genes. About 15-20% of breast cancer occurs in familial clusters. The causes of familial breast cancer remain largely unexplained. It is thought that a broad mix of genetic and environmental risk factors contributes to familial breast cancer. We believe that the complexity of these risk factors explains why the discovery of familial breast cancer genes has been so elusive. Our strategy to circumvent this problem is to group tumors into smaller families or “molecular portraits.” We predict that shared patterns of gene expression are in part determined by the genetic predisposing factors that tumors of the same subtype share. We hypothesize that genes which cause familial breast cancer will be discernable among the larger set of genes which define breast cancer subtypes.

Study Participant Recruitment & Eligibility

Study does not require recruitment

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Bioinformatics study on BRCA1 transcriptional regulation mechanisms

We are working to determine the molecular reason why mutations in the BRCA1 gene lead primarily to overgrowth in breast and ovarian tissue and not other body tissue.

Investigators

Principal Investigator: Xijin Ge, Ph.D.
Co-Investigators: Wendy S. Rubinstein, M.D., Ph.D.

Capsule

The BRCA1 gene is expressed in many tissues and plays important roles in the maintenance of cells, DNA repair, and a variety of other molecular functions. Yet, mutations in the BRCA1 gene tend to lead only to breast tissue and ovarian tissue specific tumors. Inspired by recent work and our own preliminary data, we hypothesize BRCA1 is essential for the differentiation of breast stem cells into mature epithelial cells.

By analyzing transcriptome data on breast cancer, especially microarray-based expression profiles after inducible BRCA1 expression, SAGE-based cell-type specific gene expression in breast tissues, and our own microarray data of BRCA1-mutated and sporadic breast tumors, we can integrate various genomic annotation information to yield a large body of expression data. This large body of data provides a unique opportunity to study the molecular mechanism underlying breast tumor development. Our goal is to identify specific genes that mediate BRCA1’s function as a stem cell regulator.

Study Participant Recruitment & Eligibility

Study does not require recruitment

Outcomes

We have largely accomplished major computational analyses and our results lead to the proposal of a BRCA1 transcriptional network. Our analyses proposed candidate genes that might mediate the effects of BRCA1 in stem cell regulation.

Publications

In preparation

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Ashkenazi Jewish BRCA1/2 Founder Mutation analysis in tumor tissue

Using tissue block samples, we extracted DNA to perform mutation analysis for the Ashkenazi Jewish founder mutations.

Investigators

Karen L. Kaul, M.D., Ph.D. and Kathy A. Mangold, Ph.D.

Capsule

The most effective means to find a BRCA1/2 mutation in a family with a suggestive family history is to test an individual that has been affected by cancer.  When a mutation is identified in an affected family member, interpretation of results in other family members can be done more accurately. In many cases, the affected relative may be deceased, leaving only tissue samples for genetic analysis.  The purpose of this study was to determine how well Ashkenazi Jewish founder mutations could be detected from the DNA extracted from tissue blocks that are formalin-fixed paraffin-embedded..

We obtained tissue blocks from 100 anonymous individuals where BRCA1/2 mutation status was known, either positive or negative for a founder mutation.  Our method presents a procedure that can easily be implemented in many clinical laboratories.

Study Participant Recruitment & Eligibility

Study did not require recruitment

Outcomes

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.    

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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