What is the connection between cancer and birth defects? Lawrence Brody, Ph.D., Senior Investigator, Genome Technology Branch, and Head, Molecular Pathogenesis Section, says they have more in common than meets the eye.
" The connection between the two areas of research in my lab requires an extremely technical explanation," said Dr. Brody, whose laboratory in the Genome Technolgy Branch at the National Human Genome Research Institute (NHGRI) investigates the genetics of breast cancer and neural tube defects (NTDs). "But there is growing evidence that perturbations in folate metabolism, which is implicated in NTDs, can play a role in cancer pathogenesis."
Dr. Brody says he has always been interested in the whole organism or the whole population approach to understanding the origins of health and disease rather than just one narrow area of research. That is why he wants to learn as much as possible about potential influences on cancer, particularly breast cancer.
His laboratory is investigating mutations in the two known breast-cancer-linked genes, breast cancer gene 1 (BRCA1) and breast cancer gene 2 (BRCA2), and their roles in inherited breast and ovarian cancer susceptibility. In 1994, in one of the early studies to provide a definitive link between specific genetic mutations and increased risk of cancer, Dr. Brody and his co-workers reported that women who carry mutations in BRCA1 or BRCA2 have a higher risk of developing both breast and ovarian cancer than women who do not have these genetic mutations.
Furthermore, Dr. Brody's laboratory discovered that specific BRCA1 mutations are present at an unusually high frequency (1 per 100) in the general Jewish population. His laboratory conducted the first study to directly test the DNA from volunteers who are outside cancer-prone families and to estimate the cancer risk associated with each genetic alteration. More recently, in collaboration with scientists at Howard University, Dr. Brody's laboratory identified eight distinct protein-truncating (shortening) mutations and another six rare variations of BRCA2 in a group of African Americans with breast or ovarian cancer.
Today, Dr. Brody's team continues to study these two populations to better understand the risk of cancer associated with specific mutations in the BRCA1 and BRCA2 genes. In addition, the team is collecting information on all identified mutations in these two genes worldwide. More than 2,000 distinct genetic mutations in BRCA1 and BRCA2 have been reported so far. Because women with BRCA1 mutations account for only 5 percent of all breast cancer cases diagnosed every year, there is growing consensus among scientists that not all BRCA mutations carry the same risk of cancer.
"There are a number of older individuals with deleterious BRCA1 and BRCA2 mutations who do not appear to have disease. There also are many mutations whose clinical consequences are unclear. Even the confirmed deleterious mutations do not guarantee that a carrier will develop cancer," he explained.
Dr. Brody's laboratory also is attempting to understand how normal, or wild-type, BRCA genes function to maintain healthy cells. Both BRCA1 and BRCA2 are tumor-suppressor genes that, when functioning normally, are believed to help repair damaged DNA (a process that also prevents tumor development). He and his co-workers have demonstrated that wild-type BRCA1 regulates key effectors that control the G2/M DNA damage checkpoint, a mechanism that prevents cells with genomic damage from entering mitosis. Wild-type BRCA1, therefore, appears to be involved in regulating the onset of mitosis and cell reproduction.
Wild-type BRCA1 protein, through its interactions with DNA replication proteins and histone deacetylases, appears to be important to normal cell growth and reproduction, according to Dr. Brody. The carboxyl terminus of BRCA1 contains two "motifs" found in several DNA repair and cell-cycle checkpoint proteins. These motifs have been shown to bind to a number of other nuclear proteins critical to DNA replication. His lab showed that this region interacts with two histone deacetylases, proteins involved in modulating the transcriptional activity of certain genes leading to cell growth arrest, cellular differentiation and apoptosis (programmed cell death).
Recent research also has uncovered an unsuspected and surprising role of the amino terminus of the BRCA1 protein, Dr. Brody explained. That's because this end of BRCA1 is a "RING finger" protein, a class of proteins known to have E3 ligase activity. E3 ligase catalyzes a key step in the ubiquitination pathway, a cellular pathway that recognizes misfolded proteins in the nucleus and targets them for degradation, thus keeping the cell functioning normally. Defects in the normal ubiquitination pathway are likely to cause a range of illnesses, including cancer, said Dr. Brody. Currently, his team is attempting to identify the proteins ubiquinated by BRCA1.
"What we are doing now is trying to decipher the targets of ubiquitination," said Dr. Brody. "We are excited about this avenue of research because soon we will be able to put a face on and assign a function to this extremely important gene."
As if all this were not enough, Dr. Brody also studies NTDs, one of the most common birth defects in the United States, occurring in approximately 1 in 1,000 live births. The most common type of NTDs - open NTDs - occurs when the brain or spinal cord, or both, are exposed at birth through an opening in the skull or vertebrae. Spina bifida, the most common open NTD, often requires surgery, and is often associated with life-long medical complications, including paralysis. A better understanding of the root causes of NTDs is a critical need for the medical community, said Dr. Brody.
Ireland has one of the highest rates of NTDs in the world, and Dr. Brody's laboratory is collaborating with researchers at Trinity College in Dublin and the Irish Health Research Board to search for genes controlling NTD risk. A large group of affected families from Ireland is participating in the study. To date, the team, which also includes investigators at the National Institute of Child Health and Human Development, NIH, has identified human genetic variants in most of the genes encoding the enzymes of the folate, vitamin B12, and homocysteine metabolic pathways. Recent investigation [bmj.bmjjournals.com] by this group has established that perturbations of one of these metabolic pathways account for a large fraction of NTD cases. The group also plans to measure the biochemical and functional consequences of these variants in experimental animal models as well as in affected patients.
" There is strong evidence the genes involved in these metabolic pathways are putative NTD genes," said Dr. Brody.
True to his nature, Dr. Brody wants to see the big picture when it comes to understanding folate metabolism, including its role in DNA repair. Folate, a water-soluble vitamin that is part of the vitamin B complex, plays an important role in methylation reactions and DNA/RNA synthesis. Perturbations in folate metabolism are likely to lead to aberrant cell growth, said Dr. Brody. In addition, a growing body of data indicate that low folate intake may increase the risk for a variety of cancers. A better understanding of the genetics of the folate metabolism pathway, therefore, is likely to have implications for a number of conditions besides NTDs, including cancer.
"Birth defects are the canary in a coal mine," explained Dr. Brody. "Genes that affect the fetus are most likely candidates for variation that may affect other adult diseases, including cancer. So, it is not too much of a stretch to envision our work in breast cancer genetics and folate metabolism beginning to overlap in the near future."
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Last Updated: March 13, 2012