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J Med Genet 42:633-638 doi:10.1136/jmg.2004.030049
  • Original article

Identification and characterization of missense alterations in the BRCA1 associated RING domain (BARD1) gene in breast and ovarian cancer

  1. M K Sauer1,
  2. I L Andrulis1,2,3
  1. 1Fred A. Litwin Center for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada
  2. 2Department of Laboratory Medicine and Pathobiology, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada
  3. 3Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada
  1. Correspondence to:
 Dr M K Sauer
 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Ave, Toronto, Ontario, M5G 1X5, Canada; monicamshri.on.ca
  • Received 14 December 2004
  • Accepted 7 February 2005
  • Revised 4 February 2005

Abstract

Background: BRCA1 associated RING domain protein (BARD1) was originally identified due to its interaction with the RING domain of BRCA1. BARD1 is required for S phase progression, contact inhibition and normal nuclear division, as well as for BRCA1 independent, p53 dependent apoptosis.

Methods: To investigate whether alterations in BARD1 are involved in human breast and ovarian cancer, we used single strand conformation polymorphism analysis and sequencing on 35 breast tumours and cancer cell lines and on 21 ovarian tumours.

Results: Along with the G2355C (S761N) missense mutation previously identified in a uterine cancer, we found two other variants in breast cancers, T2006C (C645R) and A2286G (I738V). The T2006C (C645R) mutation was also found in one ovarian tumour. A variant of uncertain consequence, G1743C (C557S), was found to be homozygous or hemizygous in an ovarian tumour. Eleven variants of BARD1 were characterised with respect to known functions of BARD1. None of the variants appears to affect localisation or interaction with BRCA1; however, putative disease associated alleles appear to affect the stability of p53. These same mutations also appear to abrogate the growth suppressive and apoptotic activities of BARD1.

Conclusions: These activities allowed us to identify one of the rare variants (A2286G; I738V) as a neutral polymorphism rather than a detrimental mutation, and suggested that G1743C (C557S) is not a polymorphism but may contribute to the cancer phenotype.

Footnotes

  • This study was supported by a Terry Fox Program Project Grant, a grant from the NCI to the Ontario site of the Cooperative Family Registry for Breast Cancer Studies (U01 CA69467) and by Cancer Care Ontario.

  • Competing interests: none declared

  • All necessary ethics committee approvals were secured for this study.