Comparison between genotype and phenotype identifies a high‐risk population carrying BRCA1 mutations

Hereditary breast carcinomas constitute about 10% of all malignant mammary tumors, but the selection criteria to identify a high‐risk population carrying BRCA1 mutations are not yet well‐defined. We have collected 51 pedigrees of familial breast cancer, 16 pedigrees of familial breast and ovarian cancer, and 30 cases of early‐onset breast cancer (<35 years of age) without any family history of breast cancer. The index cases of the 97 selected families were further subdivided into three groups based on histopathological parameters: group A (n = 19) was characterized by tumor grade III, negative estrogen and progesterone receptors, and high proliferative rate; group B (n = 20) was characterized by grade I–II tumors, positive hormonal receptors, and low proliferative rate; and group C (n = 58) was not homogeneous for the histopathological criteria. The aim of our study was to evaluate, in patients with a family history of breast cancer or with early diagnosis of breast cancer, the incidence of BRCA1 mutation on the basis of tumor phenotype. We found the highest rate of BRCA1 mutations in group A (53%), and low frequencies in groups B (5%) and C (0%). Our data strongly indicate that an aggressive tumor phenotype in patients with a positive family history or early diagnosis identifies a population with high probability of carrying BRCA1 mutations. Genes Chromosomes Cancer 27:130–135, 2000. © 2000 Wiley‐Liss, Inc.

[1]  R. Houlston,et al.  Family history and risk of breast cancer. , 1992, Journal of medical genetics.

[2]  Anne M. Bowcock,et al.  Identification of a RING protein that can interact in vivo with the BRCA1 gene product , 1996, Nature Genetics.

[3]  Statement of the American Society of Clinical Oncology: genetic testing for cancer susceptibility, Adopted on February 20, 1996. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  M. Skolnick,et al.  Statement of the American Society of Clinical Oncology : Genetic testing for cancer susceptibility. Commentaries , 1996 .

[5]  J. Boyd,et al.  Molecular genetic evidence of the occurrence of breast cancer as an integral tumor in patients with the hereditary nonpolyposis colorectal carcinoma syndrome , 1996, Cancer.

[6]  G. Puca,et al.  Characterization and epitope mapping of a new panel of monoclonal antibodies to estradiol receptor , 1993, Steroids.

[7]  Screening for mutations in exon 11 of the BRCA1 gene in 70 Italian breast and ovarian cancer patients by protein truncation test. , 1996, Oncogene.

[8]  G. Bots,et al.  Lhermitte‐duclos disease and cowden disease: A single phakomatosis , 1991, Annals of neurology.

[9]  Patrick Dowd,et al.  Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families , 1994, Nature Genetics.

[10]  K Offit,et al.  BRCA1 sequence analysis in women at high risk for susceptibility mutations. Risk factor analysis and implications for genetic testing. , 1997, JAMA.

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

[12]  Daniel Birnbaum,et al.  Steroid receptors in hereditary breast carcinomas associated with BRCA1 or BRCA2 mutations or unknown susceptibility genes , 1999, Cancer.

[13]  P. Wingo,et al.  Family history and the risk of breast cancer. , 1985, JAMA.

[14]  M. Swift,et al.  Mortality and cancer incidence in 263 patients with ataxia-telangiectasia. , 1986, Journal of the National Cancer Institute.

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

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

[17]  J. Klijn,et al.  Rapid detection of BRCA1 mutations by the protein truncation test , 1995, Nature Genetics.

[18]  S. Friend,et al.  Recommendations on predictive testing for germ line p53 mutations among cancer-prone individuals. , 1992, Journal of the National Cancer Institute.

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

[20]  J. Olsen,et al.  Cancer risk in close relatives of women with early-onset breast cancer – a population-based incidence study , 1999, British Journal of Cancer.

[21]  H. Hanafusa,et al.  Evidence for a transcriptional activation function of BRCA1 C-terminal region. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[22]  D. Hanahan.  Studies on transformation of Escherichia coli with plasmids. , 1983, Journal of molecular biology.

[23]  H. Lynch,et al.  Natural history and age at onset of hereditary breast cancer , 1992, Cancer.

[24]  M. King,et al.  Founding BRCA1 mutations in hereditary breast and ovarian cancer in southern Sweden. , 1996, American journal of human genetics.

[25]  David W. Hosmer,et al.  Applied Logistic Regression , 1991 .

[26]  I. Ellis,et al.  Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. , 2002, Histopathology.

[27]  F. Collins,et al.  The complete sequence of the coding region of the ATM gene reveals similarity to cell cycle regulators in different species. , 1995, Human molecular genetics.

[28]  G. Lenoir,et al.  Identification of seven new BRCA1 germline mutations in Italian breast and breast/ovarian cancer families. , 1996, Cancer research.

[29]  H T Lynch,et al.  Familial association of carcinoma of the breast and ovary. , 1974, Surgery, gynecology & obstetrics.

[30]  L. Strong,et al.  Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. , 1990, Science.

[31]  G. Giles,et al.  The histologic phenotypes of breast carcinoma occurring before age 40 years in women with and without BRCA1 or BRCA2 germline mutations , 1998, Cancer.

[32]  K. Gatter,et al.  Monoclonal antibody Ki‐67: its use in histopathology , 1990, Histopathology.

[33]  M B Daly,et al.  Modification of BRCA1-associated breast cancer risk by the polymorphic androgen-receptor CAG repeat. , 1999, American journal of human genetics.

[34]  J. Birch.  The Li‐Fraumeni cancer family syndrome , 1990, The Journal of pathology.

[35]  M. King,et al.  Inheritance of human breast cancer: evidence for autosomal dominant transmission in high-risk families. , 1988, Proceedings of the National Academy of Sciences of the United States of America.