This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lakhani, S. R. Articles by Stratton, M. R. Search for Related Content PubMed PubMed Citation Articles by Lakhani, S. R. Articles by Stratton, M. R.

The Pathology of Familial Breast Cancer: Histological Features of Cancers in Families Not Attributable to Mutations in BRCA1 or BRCA2¹

Department of Histopathology, University College London Medical School, London WC1E 6JJ, United Kingdom [S. R. L., A. F.]; Sections of Cancer Genetics, Epidemiology, and Cell Biology and Experimental Pathology, Haddow Laboratories, Institute of Cancer Research, Surrey SM2 5NG, United Kingdom [B. A. G., J. P., M. R. S.]; Statistical Laboratory, Department of Pure Mathematics and Mathematical Statistics, Cambridge CB1 8RN, United Kingdom [A. A.]; Imperial Cancer Research Fund Genetic Epidemiology Laboratory, St. James University Hospital, Leeds LS9 7TF, United Kingdom [D. T. B.]; Laboratory of Cell Biology, University Hospital of Iceland, IS-121 Reykjavik, Iceland [R. B. B., V. E.]; Department of Genetics and Pathology, Leiden University, 2300 RA Leiden, the Netherlands [P. D., C. C.]; International Agency for Research on Cancer, 69372 Lyon, Cedex 08, France [G. L., D. G.]; CRC Genetic Epidemiology Unit, Strangeways Research Laboratories, Cambridge CB1 4RN [L. M., D. F. E.]; CRC Human Cancer Genetics Research Group, Addenbrookes Hospital, Cambridge CB2 2QQ, United Kingdom [B. A. J. P.]; Medical Genetics, Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen AB9 2ZD, United Kingdom [N. H.]; Cytogenetics and Molecular Genetics, Hunter Area Pathology Service, John Hunter Hospital, New Lambton, New South Wales, 2305 Australia [R. J. S.]; Centre Jean Perrin, Laboratoire D’Oncologie Moleculaire, BP 392-63011 Clermont-Ferrand, France [Y-J. B.]; Edinburgh Breast Unit, Western General Hospital, Edinburgh EH4 2XU, United Kingdom [E. S.]; Deutsches Krebsforschungszentrum, Divisions of Epidemiology and Molecular Genome Analysis, D-69120 Heidelberg, Germany [U. H., J. C-C.]; University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania 19104 [B. W.]; Genetic Epidemiology Branch, Bethesda, Maryland 20892-7372 [J. P. S.]; Genetic Epidemiology, Department of Medical Informatics, University of Utah, Salt Lake City, Utah 84108 [S. N.]; Department of Pathology, The University of Edinburgh Medical School, Edinburgh EH8 9AG, United Kingdom [T. J. A.]; Department of Pathology, University of Liverpool, Liverpool L69 3GA, United Kingdom [J. P. S.]; Departement d’Oncologie-Genetique et Laboratoire d’Anatomie et de Cytologie Pathologiques, INSERM CRI 9703, Institut Paoli-Calmettes, 13273 Marseille, Cedex 9, France [H. S., J. J.]; Peter MacCallum Cancer Institute, St. Andrews Place, Melbourne 3002, Victoria, Australia [D. V.]; Department of Pathology, University of Melbourne, Parkville, Victoria 3050, Australia [D. V.]; Centre Leon Bernard, Cedex 08, 69373 Lyon, France [C. L.]; School of Biological and Medical Sciences, University of St. Andrews, St. Andrews, Fife KY16 9TS, United Kingdom [C. M. S.]; Department of Medicine, Trinity College Medical School, St. James Hospital, Dublin 8, Ireland [P. A. D., W. O., R. M.]; Unite de Genetique Oncologique, Institut Curie, 75231 Paris, Cedex 05, France [D. S-L.]; The Netherlands Cancer Institute, Antoni van Leeuwenhoek Huis, 1066 CX Amsterdam, the Netherlands [M. J. v. d. V.]; Max-Delbruck-Centrum fur Moleculare Medizin, Tumorgenetik, 13122 Berlin, Germany [S. S.]; Daniel den Hoed Cancer Centre, Rotterdam, 3008AE the Netherlands [J. G. M. K.]; and Duke University Medical Centre, Durham, North Carolina 27710 [P. A. F.]

Breast cancers arising in carriers of mutations in the breast cancer susceptibility genes, BRCA1 and BRCA2, differ histologically from each other and from breast cancers unselected for a family history. However, a substantial proportion of families with multiple cases of breast cancer is not attributable to these two genes (non-BRCA1/2 families). We have now characterized the pathology of 82 breast cancers from non-BRCA1/2 families. Breast cancers in non-BRCA1/2 families were of lower grade (P = 0.0018), showed fewer mitoses (P < 0.0001), less nuclear pleomorphism (P = 0.0014), less lymphocytic infiltrate (P < 0.0001), a lesser extent of the tumor with a continuous pushing margin (P = 0.004), a lesser extent of the tumor composed of solid sheets of cells (P = 0.0047), less necrosis (P = 0.002), and were more likely to be of invasive lobular type (P = 0.0003) than breast cancers arising in BRCA1 mutation carriers. In comparison with BRCA2 tumors, non-BRCA1/2 tumors were lower grade (P = 0.017) and exhibited less pleomorphism (P = 0.01) and more tubule formation (P = 0.05). In comparison with control breast cancers unselected for a family history of the disease, non-BRCA1/2 tumors were of significantly lower grade (P = 0.001), showed less pleomorphism (P = 0.0002), and had a lower mitotic count (P = 0.003). The results indicate that non-BRCA1/2 breast cancers differ histologically from both BRCA1 and BRCA2 breast cancers and are overall of lower grade. They also suggest that non-BRCA1/2 breast cancers differ from nonfamilial breast cancers, but these differences may be attributable to various types of bias.

This article has been cited by other articles:

				A. B. Spurdle, S. R. Lakhani, S. Healey, S. Parry, L. M. Da Silva, R. Brinkworth, J. L. Hopper, M. A. Brown, D. Babikyan, G. Chenevix-Trench, et al. Clinical Classification of BRCA1 and BRCA2 DNA Sequence Variants: The Value of Cytokeratin Profiles and Evolutionary Analysis--A Report From the kConFab Investigators J. Clin. Oncol., April 1, 2008; 26(10): 1657 - 1663. [Abstract] [Full Text] [PDF]

				K. Aaltonen, C. Blomqvist, R.-M. Amini, H. Eerola, K. Aittomaki, P. Heikkila, and H. Nevanlinna Familial Breast Cancers without Mutations in BRCA1 or BRCA2 Have Low Cyclin E and High Cyclin D1 in Contrast to Cancers in BRCA Mutation Carriers Clin. Cancer Res., April 1, 2008; 14(7): 1976 - 1983. [Abstract] [Full Text] [PDF]

				S. Schrading and C. K. Kuhl Mammographic, US, and MR Imaging Phenotypes of Familial Breast Cancer Radiology, January 1, 2008; 246(1): 58 - 70. [Abstract] [Full Text] [PDF]

				S Masciari, N Larsson, J Senz, N Boyd, P Kaurah, M J Kandel, L N Harris, H C Pinheiro, A Troussard, P Miron, et al. Germline E-cadherin mutations in familial lobular breast cancer J. Med. Genet., November 1, 2007; 44(11): 726 - 731. [Abstract] [Full Text] [PDF]

				W. F. Anderson, R. M. Pfeiffer, G. M. Dores, and M. E. Sherman Comparison of age distribution patterns for different histopathologic types of breast carcinoma. Cancer Epidemiol. Biomarkers Prev., October 1, 2006; 15(10): 1899 - 1905. [Abstract] [Full Text] [PDF]

				C. Cybulski, B. Gorski, T. Huzarski, T. Byrski, J. Gronwald, T. Debniak, D. Wokolorczyk, A. Jakubowska, E. Kowalska, O. Oszurek, et al. CHEK2-Positive Breast Cancers in Young Polish Women. Clin. Cancer Res., August 15, 2006; 12(16): 4832 - 4835. [Abstract] [Full Text] [PDF]

				W. F. Anderson and R. Matsuno Breast cancer heterogeneity: a mixture of at least two main types? J Natl Cancer Inst, July 19, 2006; 98(14): 948 - 951. [Full Text] [PDF]

				F. Kamangar, G. M. Dores, and W. F. Anderson Patterns of Cancer Incidence, Mortality, and Prevalence Across Five Continents: Defining Priorities to Reduce Cancer Disparities in Different Geographic Regions of the World J. Clin. Oncol., May 10, 2006; 24(14): 2137 - 2150. [Abstract] [Full Text] [PDF]

				R. A. Oldenburg, K. Kroeze-Jansema, H. Meijers-Heijboer, C. J. van Asperen, N. Hoogerbrugge, I. van Leeuwen, H. F.A. Vasen, A.-M. Cleton-Jansen, J. Kraan, J. J. Houwing-Duistermaat, et al. Characterization of Familial Non-BRCA1/2 Breast Tumors by Loss of Heterozygosity and Immunophenotyping. Clin. Cancer Res., March 15, 2006; 12(6): 1693 - 1700. [Abstract] [Full Text] [PDF]

				G. Chenevix-Trench, S. Healey, S. Lakhani, P. Waring, M. Cummings, R. Brinkworth, A. M. Deffenbaugh, L. A. Burbidge, D. Pruss, T. Judkins, et al. Genetic and Histopathologic Evaluation of BRCA1 and BRCA2 DNA Sequence Variants of Unknown Clinical Significance Cancer Res., February 15, 2006; 66(4): 2019 - 2027. [Abstract] [Full Text] [PDF]

				P K Lovelock, S Healey, W Au, E Y M Sum, A Tesoriero, E M Wong, S Hinson, R Brinkworth, A Bekessy, O Diez, et al. Genetic, functional, and histopathological evaluation of two C-terminal BRCA1 missense variants J. Med. Genet., January 1, 2006; 43(1): 74 - 83. [Abstract] [Full Text] [PDF]

				E. Honrado, A. Osorio, J. Palacios, R. L. Milne, L. Sanchez, O. Diez, A. Cazorla, K. Syrjakoski, D. Huntsman, P. Heikkila, et al. Immunohistochemical Expression of DNA Repair Proteins in Familial Breast Cancer Differentiate BRCA2-Associated Tumors J. Clin. Oncol., October 20, 2005; 23(30): 7503 - 7511. [Abstract] [Full Text] [PDF]

				G. Jonsson, T. L. Naylor, J. Vallon-Christersson, J. Staaf, J. Huang, M. R. Ward, J. D. Greshock, L. Luts, H. Olsson, N. Rahman, et al. Distinct Genomic Profiles in Hereditary Breast Tumors Identified by Array-Based Comparative Genomic Hybridization Cancer Res., September 1, 2005; 65(17): 7612 - 7621. [Abstract] [Full Text] [PDF]

				S. R. Lakhani, J. S. Reis-Filho, L. Fulford, F. Penault-Llorca, M. van der Vijver, S. Parry, T. Bishop, J. Benitez, C. Rivas, Y.-J. Bignon, et al. Prediction of BRCA1 Status in Patients with Breast Cancer Using Estrogen Receptor and Basal Phenotype Clin. Cancer Res., July 15, 2005; 11(14): 5175 - 5180. [Abstract] [Full Text] [PDF]

				A. V. Bassarova, J. M. Nesland, T. Sedloev, W. Lilleby, S. L. Hristova, D. Y. Trifonov, and E. Torlakovic Simultaneous Bilateral Breast Carcinomas: A Category with Frequent Coexpression of HER-2 and ER-{alpha}, High Ki-67 and bcl-2, and Low p53 International Journal of Surgical Pathology, July 1, 2005; 13(3): 239 - 246. [Abstract] [PDF]

				F. Al-Mulla, M. Abdulrahman, G. Varadharaj, N. Akhter, and J. T. Anim BRCA1 Gene Expression in Breast Cancer: A Correlative Study between Real-time RT-PCR and Immunohistochemistry J. Histochem. Cytochem., May 1, 2005; 53(5): 621 - 629. [Abstract] [Full Text] [PDF]

				J. Lorenzo Bermejo and K. Hemminki A population-based assessment of the clustering of breast cancer in families eligible for testing of BRCA1 and BRCA2 mutations Ann. Onc., February 1, 2005; 16(2): 322 - 329. [Abstract] [Full Text] [PDF]

				W. F. Anderson, K. C. Chu, S. Chang, and M. E. Sherman Comparison of Age-Specific Incidence Rate Patterns for Different Histopathologic Types of Breast Carcinoma Cancer Epidemiol. Biomarkers Prev., July 1, 2004; 13(7): 1128 - 1135. [Abstract] [Full Text] [PDF]

				J. Palacios, E. Honrado, A. Osorio, A. Cazorla, D. Sarrio, A. Barroso, S. Rodriguez, J. C. Cigudosa, O. Diez, C. Alonso, et al. Immunohistochemical Characteristics Defined by Tissue Microarray of Hereditary Breast Cancer Not Attributable to BRCA1 or BRCA2 Mutations: Differences from Breast Carcinomas Arising in BRCA1 and BRCA2 Mutation Carriers Clin. Cancer Res., September 1, 2003; 9(10): 3606 - 3614. [Abstract] [Full Text] [PDF]

				P. Osin, Y-J. Lu, J. Stone, T. Crook, R. S. Houlston, M. Gasco, B. A. Gusterson, and J. Shipley Distinct Genetic and Epigenetic Changes in Medullary Breast Cancer International Journal of Surgical Pathology, July 1, 2003; 11(3): 153 - 158. [Abstract] [PDF]

				I. Hedenfalk, M. Ringner, A. Ben-Dor, Z. Yakhini, Y. Chen, G. Chebil, R. Ach, N. Loman, H. Olsson, P. Meltzer, et al. Molecular classification of familial non-BRCA1/BRCA2 breast cancer PNAS, March 4, 2003; 100(5): 2532 - 2537. [Abstract] [Full Text] [PDF]

				L. F. A. Wessels, T. van Welsem, A. A. M. Hart, L. J. van't Veer, M. J. T. Reinders, and P. M. Nederlof Molecular Classification of Breast Carcinomas by Comparative Genomic Hybridization: a Specific Somatic Genetic Profile for BRCA1 Tumors Cancer Res., December 1, 2002; 62(23): 7110 - 7117. [Abstract] [Full Text] [PDF]

				A. Rosner, K. Miyoshi, E. Landesman-Bollag, X. Xu, D. C. Seldin, A. R. Moser, C. L. MacLeod, G. Shyamala, A. E. Gillgrass, and R. D. Cardiff Pathway Pathology : Histological Differences Between ErbB/Ras and Wnt Pathway Transgenic Mammary Tumors Am. J. Pathol., September 1, 2002; 161(3): 1087 - 1097. [Abstract] [Full Text] [PDF]

				S. R. Lakhani, M. J. van de Vijver, J. Jacquemier, T. J. Anderson, P. P. Osin, L. McGuffog, and D. F. Easton The Pathology of Familial Breast Cancer: Predictive Value of Immunohistochemical Markers Estrogen Receptor, Progesterone Receptor, HER-2, and p53 in Patients With Mutations in BRCA1 and BRCA2 J. Clin. Oncol., May 1, 2002; 20(9): 2310 - 2318. [Abstract] [Full Text] [PDF]

				I. Hedenfalk, D. Duggan, Y. Chen, M. Radmacher, M. Bittner, R. Simon, P. Meltzer, B. Gusterson, M. Esteller, M. Raffeld, et al. Gene-Expression Profiles in Hereditary Breast Cancer N. Engl. J. Med., February 22, 2001; 344(8): 539 - 548. [Abstract] [Full Text] [PDF]

				L. C. Verhoog, E. M. J. J. Berns, C. T. M. Brekelmans, C. Seynaeve, E. J. Meijers-Heijboer, and J. G. M. Klijn Prognostic Significance of Germline BRCA2 Mutations in Hereditary Breast Cancer Patients J. Clin. Oncol., November 1, 2000; 18(90001): 119s - 124. [Abstract] [Full Text] [PDF]