Allelic imbalance in BRCA1 and BRCA2 gene expression is associated with an increased breast cancer risk.

The contribution of BRCA1 and BRCA2 to familial and non-familial forms of breast cancer has been difficult to accurately estimate because of the myriad of potential genetic and epigenetic mechanisms that can ultimately influence their expression and involvement in cellular activities. As one of these potential mechanisms, we investigated whether allelic imbalance (AI) of BRCA1 or BRCA2 expression was associated with an increased risk of developing breast cancer. By developing a quantitative approach utilizing allele-specific real-time PCR, we first evaluated AI caused by nonsense-mediated mRNA decay in patients with frameshift mutations in BRCA1 and BRCA2. We next measured AI for BRCA1 and BRCA2 in lymphocytes from three groups: familial breast cancer patients, non-familial breast cancer patients and age-matched cancer-free females. The AI ratios of BRCA1, but not BRCA2, in the lymphocytes from familial breast cancer patients were found to be significantly increased as compared to cancer-free women (BRCA1: 0.424 versus 0.211, P = 0.00001; BRCA2: 0.206 versus 0.172, P = 0.38). Similarly, the AI ratios were greater for BRCA1 and BRCA2 in the lymphocytes of non-familial breast cancer cases versus controls (BRCA1: 0.353, P = 0.002; BRCA2: 0.267, P = 0.03). Furthermore, the distribution of under-expressed alleles between cancer-free controls and familial cases was significantly different for both BRCA1 and BRCA2 gene expression (P < 0.02 and P < 0.02, respectively). In conclusion, we have found that AI affecting BRCA1 and to a lesser extent BRCA2 may contribute to both familial and non-familial forms of breast cancer.

[1]  C. Eng,et al.  Comparative genomic and functional analyses reveal a novel cis-acting PTEN regulatory element as a highly conserved functional E-box motif deleted in Cowden syndrome. , 2007, Human molecular genetics.

[2]  G. Giles,et al.  BRCA1 promoter deletions in young women with breast cancer and a strong family history: a population-based study. , 2007, European journal of cancer.

[3]  Xiaowei Chen,et al.  Intronic alterations in BRCA1 and BRCA2: effect on mRNA splicing fidelity and expression , 2006, Human mutation.

[4]  F. Slack,et al.  Oncomirs — microRNAs with a role in cancer , 2006, Nature Reviews Cancer.

[5]  Ligang Wu,et al.  MicroRNAs direct rapid deadenylation of mRNA. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[6]  P. Møller,et al.  The frequent BRCA1 mutation 1135insA has multiple origins: a haplotype study in different populations , 2006, BMC Medical Genetics.

[7]  R. Kryscio,et al.  BRCA1 expression in a large series of sporadic ovarian carcinomas: a Gynecologic Oncology Group study , 2005, International Journal of Gynecologic Cancer.

[8]  S. Neuhausen,et al.  Prevalence of BRCA Mutations and Founder Effect in High-Risk Hispanic Families , 2005, Cancer Epidemiology Biomarkers & Prevention.

[9]  Vesselin Baev,et al.  MicroInspector: a web tool for detection of miRNA binding sites in an RNA sequence , 2005, Nucleic Acids Res..

[10]  P. Buckland Allele-specific gene expression differences in humans. , 2004, Human molecular genetics.

[11]  T. Nikaido,et al.  Expression of BRCA1 protein in benign, borderline, and malignant epithelial ovarian neoplasms and its relationship to methylation and allelic loss of the BRCA1 gene , 2004, The Journal of pathology.

[12]  M. King,et al.  Breast and Ovarian Cancer Risks Due to Inherited Mutations in BRCA1 and BRCA2 , 2003, Science.

[13]  K. Buetow,et al.  Allelic variation in gene expression is common in the human genome. , 2003, Genome research.

[14]  J. Ivanovich,et al.  Germline PTEN promoter mutations and deletions in Cowden/Bannayan-Riley-Ruvalcaba syndrome result in aberrant PTEN protein and dysregulation of the phosphoinositol-3-kinase/Akt pathway. , 2003, American journal of human genetics.

[15]  S. Pinder,et al.  Prognostic significance of BRCA1 expression in sporadic breast carcinomas , 2003, The Journal of pathology.

[16]  John L Hopper,et al.  Familial risks, early-onset breast cancer, and BRCA1 and BRCA2 germline mutations. , 2003, Journal of the National Cancer Institute.

[17]  R. Buller,et al.  Inactivation of BRCA1 and BRCA2 in ovarian cancer. , 2002, Journal of the National Cancer Institute.

[18]  J. Pasqualini Breast cancer: Prognosis, Treatment and Prevention Published in July 2002 by Marcel Dekker Inc., New York, USA; Basel, Switzerland; 656 pages; ISBN: 0-8247-0712-5; US$ 165.00 , 2002, The Journal of Steroid Biochemistry and Molecular Biology.

[19]  Roland L. Dunbrack,et al.  BRCA-1, BRCA-2 and Hereditary Breast Cancer , 2002 .

[20]  Chun-Fang Xu,et al.  Germline BRCA1 promoter deletions in UK and Australian familial breast cancer patients: Identification of a novel deletion consistent with BRCA1:ψBRCA1 recombination , 2002, Human mutation.

[21]  E. Lai Micro RNAs are complementary to 3′ UTR sequence motifs that mediate negative post-transcriptional regulation , 2002, Nature Genetics.

[22]  G. Mátyás,et al.  Quantification of single nucleotide polymorphisms: A novel method that combines primer extension assay and capillary electrophoresis , 2002, Human mutation.

[23]  E. Rosen,et al.  Mutant BRCA1 genes antagonize phenotype of wild-type BRCA1 , 2001, Oncogene.

[24]  A. Berns,et al.  Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer , 2001, Nature Genetics.

[25]  R. Goldbohm,et al.  Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58 209 women with breast cancer and 101 986 women without the disease , 2001, The Lancet.

[26]  F. Amaldi,et al.  A somatic mutation in the 5′UTR of BRCA1 gene in sporadic breast cancer causes down-modulation of translation efficiency , 2001, Oncogene.

[27]  G. Iliakis,et al.  Deficiency of human BRCA2 leads to impaired homologous recombination but maintains normal nonhomologous end joining , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Curtis C. Harris,et al.  Genetic interactions between tumor suppressors Brca1 and p53 in apoptosis, cell cycle and tumorigenesis , 2001, Nature Genetics.

[29]  R. L. Baldwin,et al.  BRCA1 promoter region hypermethylation in ovarian carcinoma: a population-based study. , 2000, Cancer research.

[30]  P. Pharoah,et al.  Frequent loss of BRCA1 mRNA and protein expression in sporadic ovarian cancers , 2000, International journal of cancer.

[31]  J. Herman,et al.  Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. , 2000, Journal of the National Cancer Institute.

[32]  I. Bièche,et al.  Overexpression of BRCA2 gene in sporadic breast tumours , 1999, Oncogene.

[33]  G. Giles,et al.  BRCA1 mutations and other sequence variants in a population-based sample of Australian women with breast cancer , 1999, British Journal of Cancer.

[34]  M. King,et al.  Frequency of breast cancer attributable to BRCA1 in a population-based series of American women. , 1998, JAMA.

[35]  M. Skolnick,et al.  Identification of a 14 kb deletion involving the promoter region of BRCA1 in a breast cancer family. , 1997, Human molecular genetics.

[36]  D. Lashkari,et al.  Use of a fluorescent-PCR reaction to detect genomic sequence copy number and transcriptional abundance. , 1996, Genome research.

[37]  K. Livak,et al.  Real time quantitative PCR. , 1996, Genome research.

[38]  Sheila Seal,et al.  BRCA2 mutations in primary breast and ovarian cancers , 1996, Nature Genetics.

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

[40]  K. Livak,et al.  Oligonucleotides with fluorescent dyes at opposite ends provide a quenched probe system useful for detecting PCR product and nucleic acid hybridization. , 1995, PCR methods and applications.

[41]  M. Skolnick,et al.  BRCA1 mutations in primary breast and ovarian carcinomas. , 1994, Science.

[42]  A. Jemal,et al.  Cancer Statistics, 2007 , 2007, CA: a cancer journal for clinicians.

[43]  K. Nathanson,et al.  Adjusting the estimated proportion of breast cancer cases associated with BRCA1 and BRCA2 mutations: Public health implications , 2005, Genetics in Medicine.

[44]  K. Kinzler,et al.  Small changes in expression affect predisposition to tumorigenesis , 2002, Nature Genetics.