Alterations in a gene discovered last year by UT Southwestern Medical Center in Dallas scientists have been linked to breast, ovarian, and uterine cancers, the researchers reported in the February issue of Human Molecular Genetics.
Last year, Drs. Anne Bowcock and Richard Baer uncovered the BARD1 gene and found that its protein interacted with the protein of BRCA1, which is mutated in 40% to 50% of inherited cases of breast cancer.
New Gene May Play a Role in DNA Damage Control
“If BARD1 is mutated in tumors, even if only infrequently, the normal gene probably has an important function biologically,” said Dr. Bowcock, associate professor of pediatrics at UT Southwestern. Drs. Bowcock and Baer are the lead authors of the new study. Dr. Baer is professor of microbiology, and also holds the Sherry Wigley Crow Cancer Research Endowed Chair in honor of Robert Lewis Kirby, md, and the H. Lloyd and Willye V. Skaggs Professorship in medical research.
Of the 50 breast, 58 ovarian, and 60 uterine tumors analyzed, scientists found one BARD1 mutation in each group. The three different mutations occurred in the same region of the gene, which suggests that this gene, like BRCA1, may be involved in controlling cell division in response to deoxyribonucleic acid (DNA) damage. This “checkpoint” type of control normally allows a cell to repair damage to its DNA before replicating. If this mechanism is absent, there is an increased risk of tumor formation.
Gene Product Believed to Have Broad Function
The researchers believe that BARD1 mutations may play a role in both spontaneous and hereditary tumor development. Breast and uterine tumors associated with BARD1 mutations arose from new noninheritable mutations found only in the tumor cells, but the BARD1 mutations found in the ovarian tumors were inherited mutations.
“We believe that the product of the BARD1 gene may have a very broad function and belongs to a group of proteins that maintain the integrity of the genome called genome caretakers. Mutations in such proteins lead to tumors, and this is what we believe happens when there are mutations in BARD1,” Dr. Bowcock said.
To conduct this research, Drs. Bowcock and Baer had to uncover the BARD1 gene structure and design primers of corresponding DNA to look for genetic alterations. The primers now are available for others to use in tracking possible causes of breast, ovarian, and uterine cancers.
Other UT Southwestern investigators who collaborated in this research included To Hoa Thai, research associate in pediatrics; Dr. Fenghe Du, research fellow in pediatrics; Julia Tsou Tsan, research scientist in microbiology; Dr. Ying Jin, research fellow in microbiology; Anne Phung, research assistant in pediatrics; Monique Spillman, graduate student; Dr. Carolyn Muller, assistant professor of obstetrics and gynecology; Dr. Raheela Ashfaq, assistant professor of pathology; Dr. David Scott Miller, associate professor of obstetrics and gynecology and holder of the Dallas Foundation Chair in Gynecologic Oncology; and former faculty member Dr. Michael Mathis.
The Department of Molecular Biotechnology at the University of Washington School of Medicine also participated in the study.
The National Cancer Institute and the Department of Energy provided partial funding for the research.
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