Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations.

BACKGROUND We have previously demonstrated that breast cancers associated with inherited BRCA1 and BRCA2 gene mutations differ from each other in their histopathologic appearances and that each of these types differs from breast cancers in patients unselected for family history (i.e., sporadic cancers). We have now conducted a more detailed examination of cytologic and architectural features of these tumors. METHODS Specimens of tumor tissue (5-microm-thick sections) were examined independently by two pathologists, who were unaware of the case or control subject status, for the presence of cell mitosis, lymphocytic infiltration, continuous pushing margins, and solid sheets of cancer cells; cell nuclei, cell nucleoli, cell necrosis, and cell borders were also evaluated. The resulting data were combined with previously available information on tumor type and tumor grade and further evaluated by multifactorial analysis. All statistical tests are two-sided. RESULTS Cancers associated with BRCA1 mutations exhibited higher mitotic counts (P = .001), a greater proportion of the tumor with a continuous pushing margin (P<.0001), and more lymphocytic infiltration (P = .002) than sporadic (i.e., control) cancers. Cancers associated with BRCA2 mutations exhibited a higher score for tubule formation (fewer tubules) (P = .0002), a higher proportion of the tumor perimeter with a continuous pushing margin (P<.0001), and a lower mitotic count (P = .003) than control cancers. CONCLUSIONS Our study has identified key features of the histologic phenotypes of breast cancers in carriers of mutant BRCA1 and BRCA2 genes. This information may improve the classification of breast cancers in individuals with a family history of the disease and may ultimately aid in the clinical management of patients.

[1]  D. Birnbaum,et al.  Novel indications for BRCA1 screening using individual clinical and morphological features , 1999, International journal of cancer.

[2]  J. Spratt.  Re: Variation in mammographic breast density by time in menstrual cycle among women aged 40-49 years. , 1999, Journal of the National Cancer Institute.

[3]  D. Birnbaum,et al.  BRCA1 and medullary breast cancer. , 1998, JAMA.

[4]  C. Tomasetto,et al.  The pS2/TFF1 trefoil factor, from basic research to clinical applications. , 1998, Biochimica et biophysica acta.

[5]  J. Thompson,et al.  BRCA1 mutations and breast cancer in the general population: analyses in women before age 35 years and in women before age 45 years with first-degree family history. , 1998, JAMA.

[6]  J Chang-Claude,et al.  Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. , 1998, American journal of human genetics.

[7]  H. Ruffner,et al.  BRCA1 is a cell cycle-regulated nuclear phosphoprotein. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[8]  D E Goldgar,et al.  Cancer risks in two large breast cancer families linked to BRCA2 on chromosome 13q12-13. , 1997, American journal of human genetics.

[9]  M. Stratton.  Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases , 1997, The Lancet.

[10]  Luke Hughes-Davies,et al.  Transcriptional activation functions in BRCA2 , 1997, Nature.

[11]  G. Eichele,et al.  Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2 , 1997, Nature.

[12]  A. Ashworth,et al.  Cloning, chromosomal mapping and expression pattern of the mouse Brca2 gene. , 1997, Human molecular genetics.

[13]  Yonghong Xiao,et al.  Association of BRCA1 with Rad51 in Mitotic and Meiotic Cells , 1997, Cell.

[14]  A. Berchuck,et al.  Cell cycle control of BRCA2. , 1996, Cancer research.

[15]  I. Verma,et al.  Transcriptional activation by BRCA1 , 1996, Nature.

[16]  J. Rommens,et al.  The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds , 1996, Nature Genetics.

[17]  M. King,et al.  Growth retardation and tumour inhibition by BRCA1 , 1996, Nature Genetics.

[18]  G M Lenoir,et al.  Hereditary breast cancer: Pathobiology, prognosis, and BRCA1 and BRCA2 gene linkage , 1996, Cancer.

[19]  Julian Peto,et al.  Identification of the breast cancer susceptibility gene BRCA2 , 1996, Nature.

[20]  B. Koller,et al.  Brca1 deficiency results in early embryonic lethality characterized by neuroepithelial abnormalities , 1996, Nature Genetics.

[21]  D. Birnbaum,et al.  Germ line mutation at BRCA1 affects the histoprognostic grade in hereditary breast cancer. , 1996, Cancer research.

[22]  C. Larsson,et al.  Mutation analysis of the BRCA2 gene in 49 site–specific breast cancer families , 1996, Nature Genetics.

[23]  B. Weber,et al.  Mouse Brca1: localization sequence analysis and identification of evolutionarily conserved domains. , 1995, Human molecular genetics.

[24]  D. Easton,et al.  Estimates of the gene frequency of BRCA1 and its contribution to breast and ovarian cancer incidence. , 1995, American journal of human genetics.

[25]  David L. Page,et al.  Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression , 1995, Nature Genetics.

[26]  Steven E. Bayer,et al.  A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. , 1994, Science.

[27]  U. Chetty,et al.  Breast cancer incidence, penetrance and survival in probable carriers of BRCA1 gene mutation in families linked to BRCA1 on chromosome 17q12–21 , 1994, The British journal of surgery.

[28]  S. Seal,et al.  Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. , 1994, Science.

[29]  A. Gentile,et al.  Medullary carcinoma of the breast. A multicenter study of its diagnostic consistency. , 1993, Archives of pathology & laboratory medicine.

[30]  J. Davies,et al.  Pathology reporting in breast cancer screening. Royal College of Pathologists Working Group. , 1991, Journal of clinical pathology.

[31]  M. King,et al.  Linkage of early-onset familial breast cancer to chromosome 17q21. , 1990, Science.

[32]  N. Breslow,et al.  Statistical methods in cancer research: volume 1- The analysis of case-control studies , 1980 .

[33]  P. Rosen,et al.  Medullary carcinoma of the breast. A clinicopathologic study with 10 year follow‐up , 1977, Cancer.

[34]  P. J. Huber.  The behavior of maximum likelihood estimates under nonstandard conditions , 1967 .

[35]  W. W. Richardson.  Medullary Carcinoma of the Breast , 1956, British Journal of Cancer.