Major Research Projects

The Northern California Family Registry for Breast Cancer

In 1995, the National Cancer Institute established the Breast Cancer Family Registry, an international consortium, for interdisciplinary and translational studies of the genetic epidemiology of breast cancer. http://epi.grants.cancer.gov/CFR/ The six collaborating family registries in the U.S.  (San Francisco Bay area, New York City, Philadelphia and Utah), Ontario, Canada and Melbourne/Sydney, Australia, have enrolled over 15,000 breast cancer families. Using common protocols and questionnaires, data and biospecimens have been collected for breast cancer patients and family members. Available resources include 1) interview data on family history of breast and other cancers; hormonal, lifestyle and other factors; dietary intake based on a food frequency questionnaire; and self-reported treatment information for individuals diagnosed with breast cancer; and 2) biospecimens, such as blood or mouthwash samples, and archived tumor tissue for individuals diagnosed with breast cancer. Registry participants have been followed-up annually in order to assess the occurrence of new cancers in the family. A more intensive follow-up was initiated in 2007.

The Northern California site covering the nine counties of the Greater San Francisco Bay area has recruited over 3,000 families, including 2,200 (73%) families from racial/ethnic minority groups. Recruitment of an additional 800 African-American and Hispanic families in continuing and has been expanded into the Sacramento area. Participating family members are kept informed through an annual newsletter (see below).

Principal Investigator: Esther M. John, Ph.D.

Co-Investigators: Dee W. West, Ph.D., NCCC and Stanford University; Alice S. Whittemore, Ph.D., Stanford University;

Collaborators: Alex Miron, Ph.D., Dana-Farber Cancer Institute; Patrick Bender, Ph.D., Coriell Institute

Funding: National Cancer Institute (U01 CA069417)

Collaborative Studies

The data and biospecimen resources from the six collaborating family registries are available to qualified researchers worldwide. Confidentiality is maintained by the assignment of a study identification number to each registry participant. No personal information such as names or contact information is shared with collaborating researchers. Applications to use the resources are reviewed by a Scientific Advisory Board (for information on application process, consult http://epi.grants.cancer.gov/CFR/). To date, the Advisory Board has approved over 100 research studies on a wide range of topics. Below is a listing of studies initiated by investigators at the Northern California site and collaborative studies the Northern California site has participated in.

BRCA1 and BRCA2 Mutations in Minority Families
Few studies have examined BRCA1 and BRCA2 mutations on breast cancer patients from racial/ethnic minority populations. The Northern California site of the Breast Cancer Family Registry has enrolled 2,200 minority families, which is a unique resource to study BRCA1 and BRCA2 mutations in specific racial/ethnic groups, including the spectrum of pathogenic mutations and unclassified variants, prevalence of mutations and variants, and penetrance. This study led by Dr. Esther M. John (National Cancer Institute, U01 CA069417) estimated the population-based prevalence of these mutations in non-Hispanic white, African-American, Hispanic, and Asian-American breast cancer patients and compare the estimates to those published for non-Hispanic white breast cancer patients enrolled in the registry. Work is on-going to validate BRCAPRO in minority populations, and estimate the penetrance of breast and other cancers among carriers.

Genetics of Breast Cancer in Blacks
African-American and African women experience a disproportionate burden of premenopausal breast cancer for reasons that remain unknown. The identification of persons carrying breast cancer susceptibility genes is a promising approach to understanding the etiology of the disease and developing more effective early detection and prevention strategies. This on-going study led by Dr. Funmi Olopade, University of Chicago (National Cancer Institute, R01 CA089085) will compare 1,000 breast cancer patients from Nigeria and 600 African-American breast cancer cases enrolled in the Northern California site of the Breast Cancer Family Registry with regard to the prevalence and spectrum of BRCA1 and BRCA2 mutations in the two populations of African descent. The study will also assess the association with polymorphisms in the UGTIA gene, and examine UGTIA polymorphisms as potential modifiers of breast cancer risk in carriers of BRCA1 or BRCA2 mutations.

Breast Cancer Risk Modifiers in BRCA Mutation Carriers
Women who carry mutations in BRCA1 or BRCA2 genes have an increased risk of developing breast cancer. Lifetime breast cancer risks have been estimated at 40-80% in such mutation carriers. Thus, some 20-60% of carriers live to advanced ages without developing breast cancer, suggesting that other genes or personal attributes may modify carriers' risks. This study led by Dr. Alice Whittemore, Stanford University (National Cancer Institute, R01 CA097359) examined whether five modifiable characteristics modify risk in carriers, including oral contraceptive use, alcohol consumption, cigarette smoking, medical radiation, and physical activity.

Cancer Risk in Relatives of Breast Cancer Patients
Two on-going studies explore the risk of cancer in relatives of breast cancer patients who have an increased risk of breast cancer.

The first study led by Dr. Jennifer Lee, Stanford University pooled data from the Northern California site of the Breast Cancer Family Registry and the Family Registry for Ovarian Cancer and examined the incidence of breast and ovarian cancer in first-degree relatives of breast and ovarian cancer patients enrolled in these two family registries, and assessed whether the risks in relatives vary by the patient's cancer site, carrier status of predisposing genetic mutations, or age at cancer diagnosis.

The second study led by Dr. Gillian Dite, University of Melbourne, examined the incidence of breast and other cancers in first- and second-degree relatives of early-onset breast cancer patients (diagnosed under age 35 years) that are enrolled in the three population-based sites of the Breast Cancer Family Registry (Northern California, Ontario Canada, and Melbourne/Sydney Australia).

Case-control Analyses of Breast Cancer Risk Factors
This on-going study led by various investigators of the Breast Cancer Family Registry performed a series of population-based case-control analyses using data from the three population-based sites of the Breast Cancer Family Registry (Northern California, Ontario Canada, and Melbourne/Sydney Australia). Analyses focused on oral contraceptive use and early-onset breast cancer, and associations with ovarian cysts, diagnostic medical radiation, and physical activity.

The Role of the ATM Gene in Familial Breast Cancer
The role of the ATM (Ataxia telangiectasia mutated) gene in breast cancer predisposition is controversial. Studies of carriers of ATM mutations have indicated that females have on average a 4-7 fold increased risk of breast cancer, but mutation analysis of the ATM gene in unselected breast cancer cases has failed to find a convincingly increased frequency compared with controls. This on-going study led by Dr. Georgia Chenevix Trench, Queensland Medical Institute for Research, Australia (National Cancer Institute, R01 CA100352) pooled resources from the Breast Cancer Family Registry and KConFab, an Australian consortium, to estimate the penetrance and frequency of breast cancer-causing ATM mutations in almost 3,000 putative hereditary breast cancer families. The findings will have numerous clinical implications, including whether women in high-risk families should be routinely or selectively screened for ATM, as well as BRCA1 and BRCA2 mutations.

IGF Signaling Pathway and Breast Cancer Risk
The identification of genetic risk factors in pathways that are central to the regulation of cell proliferation is one of the avenues leading to a better understanding of the development and progression of cancer. As uncontrolled cell growth is a hallmark of cancer, genes involved in insulin-like growth factor (IGF) signaling may play an important role in breast cancer etiology. This on-going study led by Dr. Susan Neuhausen, University of California, Irvine (National Cancer Institute, R01 CA116494) will pool resources from the Breast Cancer Family Registry and kConFab, an Australian consortium, and perform a comprehensive analysis of genes involved in IGF signaling through an approach that combines multiple variants in a single gene to form haplotypes and examines interactions of multiple genes in this pathway. The findings from this study will provide information to more accurately assess breast cancer risk in women and to target women who could benefit from prevention strategies. Currently, chemotherapies are being directed to the IGF pathway and the results of this study could provide further targets, as well as assist in identifying the group of women who could particularly benefit from these new drugs.

Genetics Studies of Mammographic Density
The density of breast tissue, which reflects differences in breast tissue composition, is one of the strongest known risk factors for breast cancer. Women with high vs. low mammographic density have a 3-4 fold increased risk of developing breast cancer. Studies in twins have estimated that the heritability of mammographic density is high (63%). This on-going study led by Dr. Johanna Rommens, Hospital for Sick Children, Toronto, Canada (National Cancer Institute, R01 CA102659) attempts to identify the major genetic determinants of radiographically dense breast tissue, with the long-term goal of identifying susceptibility genes for breast cancer. Mammograms are being collected for sister pairs enrolled in the Breast Cancer Family Registry, including the Northern California site, for whom blood samples and interview data are already available. The mammogram will be digitized in order to determine mammographic density. In addition, blood samples are being collected for dizygotic twins for whom mammograms and epidemiologic data are available from previous studies conducted in Ontario and Australia. Based on resources for about 4,000 women, genome-wide linkage studies will be carried out to identify major loci for mammographic density, followed with refined mapping using both linkage and association analyses. Finally, the gene variants associated with mammographic density will be tested for associations with breast cancer. The long term objectives are to gain insight into breast biology and to assist in the prediction and diagnosis of breast cancer, and ultimately to provide for prevention strategies and more effective treatments.

Prognosis in BRCA1 Associated Breast Cancer
Hereditary breast cancer occurs at an earlier age, is more likely to be bilateral, and is more likely to be associated with other cancers than "sporadic" breast cancer. There is growing evidence that BRCA1 associated cancers have different pathologic characteristics and worse prognosis than "sporadic" breast cancers. This on-going study led by Dr. Pamela Goodwin, Cancer Care Ontario, Toronto Canada (National Cancer Institute, R01CA102740) will investigate the prognosis and pathologic characteristics of breast cancers occurring in women with germline mutations in BRCA1, compared to women with "sporadic" breast cancers. Distant recurrence and death will be assessed in relation to traditional prognostic factors, detailed clinical and treatment-related variables collected by medical record review, and specific molecular markers. 

Publications
The following list includes publications co-authored by investigators from the Northern California site of the Breast Cancer Family Registry (John, Whittemore, West), and collaborators from the Northern California Cancer Center and Stanford University. For a complete list of all publications using resources from the Breast Cancer Family Registry, please visit this website: http://epi.grants.cancer.gov/CFR/about_breast_pubs.html

Daly MB, Offit K, Li F, Glendon G, Yaker A, West DW, Koenig B, McCredie M, Venne V, Nayfield S, Seminara D. Participation in the Cooperative Family Registry for Breast Cancer studies: issues of informed consent. J Natl Cancer Inst 2000; 92(6):452-456.

Beck JC, Beiswanger CM, John EM, Satariano E, West DW. Successful transformation of cryopreserved lymphocytes: a resource for epidemiological studies. Cancer Epidemiol Biomarkers Prev 2001;10:551-54.

Thompson D, Szabo CI, Mangion J, Oldenburg RA, Odefrey F, Seal S, Barfoot R, Kroeze-Jansema K, Teare D, Rahman N, Renard H, Mann G, Hopper JL, Buys SS, Andrulis IL, Senie RT, Daly MB, West D, Ostrander EA, Offit K, Peretz T, Osorio A, Benitez J, Nathanson KL, Sinilnikova OM, Olah E, Bignon YJ, Ruiz P, Badzioch MD, Vasen HF, Futreal AP, Phelan CM, Narod SA, Lynch HT, Ponder BA, Eeles RA, Meijers-Heijboer H, Stoppa-Lyonnet D, Couch FJ, Eccles DM, Evans DG, Chang-Claude J, Lenoir G, Weber BL, Devilee P, Easton DF, Goldgar DE, Stratton MR; KConFab Consortium. Evaluation of linkage of breast cancer to the putative BRCA3 locus on chromosome 13q21 in 128 multiple case families from the Breast Cancer Linkage Consortium. Proc Natl Acad Sci U S A 2002;99(2):827-31.

Lin SS, Clarke CA, O'Malley CD, Le GM. Studying cancer incidence and outcomes in immigrants: methodological concerns. Am J Public Health 2002 Nov;92(11):1757-9.
  
Lin SS, O'Malley CD, Clarke CA, Le GM. Birthplace and survival among Asian women diagnosed with breast cancer in cancer registry data: the impact of selection bias (letter). Int J Epidemiol 2002 Apr;31(2):511-3.

Andrulis IL, Anton-Culver H, Beck J, Bove B, Boyd J, Buys S, Godwin AK, Hopper JL, Li F, Neuhausen SL, Ozcelik H, Peel D, Santella RM, Southey MC, van Orsouw NJ, Venter DJ, Vijg J, Whittemore AS, Cooperative Family Registry for Breast Cancer Studies. Comparison of DNA- and RNA-based methods for detection of truncating BRCA1 mutations. Hum Mutat 2002;20(1):65-73.
  
Whittemore AS, Gong G, John EM, McGuire V, Li F, Ostrow K, DiCioccio R, Felberg A, West D. Prevalence of BRCA1 mutation carriers among U.S. non-Hispanic whites. Cancer Epidemiol Biomarkers Prev 2004; 13(12):2078-83.

Whittemore AS, Balise RR, Pharoah PDP, DiCioccio RA, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab)4, Oakley-Girvan I, Ramus SJ, Daly M, Usinowicz MB, Garlinghouse-Jones K, Ponder BAJ, Buys S, Senie R, Andrulis I, John E, Hopper JL, Piver MS. Oral contraceptive use and ovarian cancer risk among carriers of BRCA1 or BRCA2 mutations. Br J Cancer 200

Whittemore AS. Estimating genetic association parameters from family data. Biometrika 2004;91:219-25.

Whittemore AS, Balise RR, Pharoah PD, Dicioccio RA, Oakley-Girvan I, Ramus SJ, Daly M, Usinowicz MB, Garlinghouse-Jones K, Ponder BA, Buys S, Senie RT, Andrulis I, John E, Hopper JL, Piver MS. Oral contraceptive use and ovarian cancer risk among carriers of BRCA1 or BRCA2 mutations. Br J Cancer 2004;91(11):1911-5.

John EM, Hopper JL, Beck JC, Knight JA, Neuhausen SL, Senie RT, Ziogas A, Andrulis IL, Anton-Culver H, Boyd N, Buys SS, Daly MB, O'Malley FP, Santella RM, Southey MC, Venne VL, Venter DJ, West DW, Whittemore AS, Seminara S, for the Breast Cancer Family Registry. The Breast Cancer Family Registry: an infrastructure for cooperative multinational, interdisciplinary and translational studies of the genetic epidemiology of breast cancer. Breast Cancer Research 2004; 6(4):R375-R389.

Gomez SL, Glaser SL. Quality of birthplace information obtained from death certificates for Hispanics, Asians, and Pacific Islanders. Ethn Dis 2004;14(2):292-5.
  
Ahsan H, Chen Y, Whittemore AS, Kibriya MG, Gurvich I, Senie RT, Santella RM. A family-based genetic association study of variants in estrogen-metabolism genes COMT and CYP1B1 and breast cancer risk. Breast Cancer Res Treat 2004;85(2):121-31.

Milne RL, Knight JA, John EM, Dite GS, Balbuena R, Ziogas A, Andrulis IL, West DW, Li FP, Southey MC, Giles GG, McCredie MR, Hopper JL, Whittemore AS. Oral contraceptive use and risk of early-onset breast cancer in carriers and noncarriers of BRCA1 and BRCA2 mutations. Cancer Epidemiol Biomarkers Prev 2005 Feb;14(2):350-6.

Gomez SL, Glaser SL. Quality of cancer registry birthplace data for Hispanics living in the United States. Cancer Causes Control 2005 Aug;16(6):713-23.

Ahsan H, Whittemore AS, Chen Y, Senie RT, Hamilton SP, Wang Q, Gurvich I, Santella RM. Variants in estrogen-biosynthesis genes CYP17 and Cyp19 and breast cancer risk: a family-based genetic association study. Breast Cancer Res 2005;7(1):R71-81.

Turner-Cobb JM, Bloor LE, Whittemore AS, West D, Spiegel D. Disengagement and social support moderate distress among women with a family history of breast cancer. Breast J 2006 Jan-Feb;12(1):7-15.

Spurdle AB, Antoniou AC, Duffy D, Kelemen L, Holland H, Peock S, Cook MR, Smith PL, Greene MH, Simard J, Plourde M, Southey M, Godwin A, Beck J, Miron A, Daly M, Santella R, Hopper J, John EM, Andrulis I, Durocher F, Struewing, JP, Easton DF, Chenevix-Trench G, Australian Breast Cancer Family Study, Australian Jewish Breast Cancer Study, Breast Cancer Family Registry, Interdisciplinary Health Research International Team on Breast Cancer Susceptibility, The Kathleen Cunningham Foundation Consortium for Research into Familial Breast Cancer, and Epidemiological Study of Familial Breast Cancer Study Collaborators. The AIB1 polyglutamine repeat does not modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev 2006 Jan;15(1):76-9.

McGuire V, John EM, Felberg A, Haile RW, Boyd NF, Thomas DC, Jenkins MA, Milne RL, Daly MB, Ward J, Terry MB, Andrulis IL, Knight JA, Godwin AK, Giles GG, Southey M, West DW, Hopper JL, Whittemore AS, kConFab Investigators. No increased risk of breast cancer associated with alcohol consumption among carriers of BRCA1 and BRCA2 mutations ages <50 years. Cancer Epidemiol Biomarkers Prev 2006 Aug;15(8):1565-7.

Knight JA, John EM, Milne RL, Dite GS, Balbuena R, Shi EJ, Giles GG, Ziogas A, Andrulis IL, Whittemore AS, Hopper JL; Breast Cancer Family Registry. An inverse association between ovarian cysts and breast cancer in the Breast Cancer Family Registry. Int J Cancer 2006 Jan 1;118(1):197-202.
  
Lee JS, John EM, McGuire V, Felberg A, Ostrow KL, DiCioccio RA, Li FP, Miron A, West DW, Whittemore AS. Breast and ovarian cancer in relatives of cancer patients, with and without BRCA1 and BRCA2 mutations. Cancer Epidemiol Biomarkers Prev 2006 Feb;15(2):359-63.
  
Longacre TA, Ennis M, Quenneville LA, Bane AL, Bleiweiss IJ, Carter BA, Catelano E, Hendrickson MR, Hibshoosh H, Layfield LJ, Memeo L, Wu H, O'malley FP. Interobserver agreement and reproducibility in classification of invasive breast carcinoma: an NCI breast cancer family registry study. Mod Pathol 2006 Feb;19(2):195-207.

Gomez SL, Glaser SL. Misclassification of race/ethnicity in a population-based cancer registry (United States). Cancer Causes Control 2006 Aug;17(6):771-81.
  
Haile RW, Thomas DC, McGuire B, Felberg A, John EM, Milne RL, Hopper JL, Jenkins MA, Levine AJ, Daly MM, Buys SS, Senie RM, Andrulis IL, Knight JA, Godwin AK, Southey M, McCredie MRE, Giles GG, Andrews L, Tucker K, Miron A, Apicella C, Tesoriero A, Pike MC, kConFab Investigators, Whittemore AS. BRCA1 and BRCA2 mutation carriers, oral contraceptive use, and breast cancer before age 50. Cancer Epidemiol Biomarkers Prev 2006 Oct;15(10):1863-70. Epub 2006 Oct. 4.

Bernstein JL, Teraoka S, Southey MC, Jenkins MA, Andrulis IL, Knight JA, John EM, Lapinski RH, Wolitzer AL, Whittemore AS, West DW, Seminara D, Olson ER, Spurdle AB, Chenevix-Trench G, Giles GG, Hopper JL, Concannon P. Population-based estimates of breast cancer risks associated with ATM gene variants c.T7271T>G and c.1066-6T>G (IVS10-6T>G) from the Breast Cancer Family Registry. Human Mutation 2006;27(11):1122-8.
  
Bernstein JL, Teraoka SN, John EM, Andrulis IL, Knight JA, Lapinski R, Olson ER, Wolitzer AL, Seminara D, Whittemore AS, Concannon P. The CHEK 2*1100delC allelic variant and risk of breast cancer: screening results from the Breast Cancer Family Registry. Cancer Epidemiol Biomarkers Prev 2006 Feb;15(2):348-52.

Bane AL, Beck JC, Bleiweiss I, Buys SS, Catalano E, Daly MB, Giles G, Godwin AK, Hisbshoosh H, Hopper JL, John EM, Layfield L, Longacre T, Miron A, Senie R, Southey MC, West DW, Whittemore AS, Wu H, Andrulis IL, O'Malley FP. BRCA2 mutation-associated breast cancers exhibit a distinguishing phenotype based on morphology and molecular profiles from tissue microarrays. Am J Surg Pathol 2007;31(1):121-8.

Terry MB, Knight JA, Zablotska L, Wang Q, John EM, Andrulis IL, Senie RT, Daly M, Ozcelik H, Briollais L, Santella RM. Alcohol metabolism, alcohol intake, and breast cancer risk: a sister-set analysis using the Breast Cancer Family Registry. Breast Cancer Res Treat 2007 Feb 1 [Epub ahead of print] (in press).

John EM, Phipps AI, Knight JA, Milne RL, Dite GS, Hopper JL, Andrulis IL, Southey M, Giles GG, West DW, Whittemore AS. Medical radiation exposure and breast cancer risk: Findings from the Breast Cancer Family Registry. Int J Cancer 2007;121:386-94.

Hong AL, Huo D, Kim HJ, Chen YS, Niu Q, Cummings SA, John EM, West DW, Whittemore AS, Das S, Olopade OI. UDP-Glucuronosyltransferase 1A1 gene polymorphisms and total bilirubin levels in an ethnically diverse cohort of women. Drug Metab Disposition 2007, 2007;35:1254-61.

Apicella C, Dowty JG, Dite GS, Jenkins MA, Senie R, Daly MB, Andrulis IL, John EM, Buys SS, Li FP, Glendon G, Chung W, Ozcelik H, Miron A, Kotar K, Southey MC, Foulkes W, Hopper JL. Validation study of the LAMBDA model for predicting the BRCA1 or BRCA2 mutation carrier status of North American Ashkenazi Jewish women. Clin Genet 2007, 72:87-97.

Breast Cancer Family Registry; Kathleen Cuningham Consortium for Research into Familial Breast Cancer (Australasia); Ontario Cancer Genetics Network (Canada). Smoking and risk of breast cancer in carriers of mutations in BRCA1 or BRCA2 aged less than 50 years. Breast Cancer Res Treat 2007 Oct 31; [Epub ahead of print]

John EM, Miron A, Gong G, Phipps AI, Felberg I, Li FP, West DW, Whittemore AS. Prevalence of pathogenic BRCA1 mutation carriers in five US racial/ethnic groups. JAMA 2007;298(24):2869-76.

Garner CP, Diny YC, John EM, Ingles SA, Olopade OF, Huo D, Adebamowo C, Ogundiran T, Neuhausen SL. Genetic variation in IGFBP2 and IGFBP5 is associated with breast cancer risk in populations of African descent. Hum Genet 2008; 123(3):247-55.

Kibriya MG, Jasmine F, Argos M, Andrulis IL, John EM, Chang-Claude J, Ahsan H. A genome-wide association study of early-onset breast cancer among BRCA1- and BRCA2-negative Caucasian women. Breast Cancer Res & Treatment 2008 May 8 [Epub ahead of print].

Rebbeck TR, Antoniou AC, Llopis TC, Nevanlinna H, Aittomaki K, Simard J, Spurdle AB, KConFab, Couch FJ, Pereira LH, Greene MH, Andrulis IL, Ontario Cancer Genetics Network, Pasche B, Kaklamani V, Breast Cancer Family Registry, Hamann U, Szabo C, Peock S, Cook M, Harrington PA, Dondaldson A, Male AM, Gardiner CA, Gregory H, Side LE, Robinson AC, Emmerson L, Ellis I, EMBRACE, Peyrat JP, Fournier J, Vennin P, Adenis C, Muller D, Fricker JP, Longy M, Sinilnikova OM, Stoppa-Lyonnet D, GEMO, Schmutzler RK, Versmold B, Engel C, Meindle A, Kast K, Schaefer D, Froster UG, Chenevix-Trench G, Easton DF. No association of TGFB1 L10P genotypes and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a multi-center cohort study. Breast Cancer Res Treat 2008; Jun 4. [Epub ahead of print]

Neuhausen SL, Ozcelik H, Southey MC, John EM, Godwin AK, Chung W, Iriondo-Perez J, Miron A, Santella RM, Whittemore AS, Andrulis IL, Buys SS, Daly MB, Hopper JL, Seminara D, Senie RT, Terry MB, for the Breast Cancer Family Registry. BRCA1 and BRCA2 mutation carriers in the Breast Cancer Family Registry: an open resource for collaborative research. Breast Cancer Res & Treatm 2008 Aug 14. [Epub ahead of print]

To learn more about FRBC, read our newsletters:

Back to Research Programs page.