HomeResearchIntramural ResearchResearch Branches at NHGRIGenome Technology Branch Brody Lab

Lawrence Brody, Ph.D. Molecular Genetics Section Senior Investigator Genome Technology Branch Head Molecular Pathogenesis Section B.S. Pennsylvania State University, 1982 Ph.D. Johns Hopkins University, 1991 (301) 496-7824 (301) 480-2592 lbrody@helix.nih.gov Building 50, Room 5306 50 South Dr, MSC 8004 Bethesda, MD 20892-8004 Selected Publications Breast Cancer Information Core Investigator Recruitment in Cancer Genetics

Dr. Brody investigates the genetics of breast cancer and neural tube defects. As head of GTB¿s Molecular Pathogenesis section, he is interested in studying genetic mutations that lead to perturbations in normal metabolic pathways and cause disorders such as cancer and birth defects.

His laboratory investigates mutations in 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, Dr. Brody¿s laboratory was among the first to report that women carrying BRCA1 or BRCA2 mutations have a higher risk of developing both breast and ovarian cancer than women without such mutations. His group also discovered an unusually high frequency of specific BRCA1 mutations in the Jewish population. They recently helped identify eight distinct protein-shortening mutations and another six rare variations of BRCA2 in a group of African-American breast and ovarian cancer patients.

His team is continuing to study these two populations to better understand the risk of cancer associated with specific mutations and is collecting information on all identified mutations in these two genes worldwide. Currently, more than 2,000 distinct BRCA1 and BRCA2 mutations have been identified. Because women with BRCA1 mutations account for only five percent of all breast cancer cases diagnosed every year, there is a growing scientific consensus that not all BRCA mutations carry the same risk of cancer.

Dr. Brody¿s group also is investigating how normal BRCA genes help maintain healthy cells. The group demonstrated that the normal BRCA1 protein regulates key effectors that control the G2/M DNA damage checkpoint, a cell-cycle checkpoint that prevents cells with genomic damage from entering mitosis and reproducing. The carboxyl terminus of BRCA1 contains two motifs found in several DNA-repair and cell-cycle checkpoint proteins. Dr. Brody¿s laboratory demonstrated that these motifs also bind to a number of other nuclear proteins critical to DNA replication. This segment of BRCA1 also interacts with several histone deacetylases, proteins that modulate the transcriptional activity of genes leading to cell growth arrest, cellular differentiation, and apoptosis (programmed cell death).

Research has found that the amino terminus of BRCA1 is a RING finger protein, a class of proteins that have E3 ligase activity. E3 ligase catalyzes a key enzymatic 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 implicated in a range of illnesses, including cancer. Dr. Brody¿s team is working to identify all the molecules in the ubiquitination pathway that interact with BRCA1.

Dr. Brody¿s other major area of investigation is the genetics of neural tube defects (NTDs), one of the most common birth defects in the United States. Spina bifida, the most common NTD, results in the exposure of the spinal cord through an opening in the vertebrae. It often is corrected by major surgery, but it still can lead to life-long medical complications, including paralysis. A better understanding of the root causes of NTDs, therefore, is needed.

Dr. Brody¿s laboratory is collaborating with researchers at Trinity College in Dublin, Ireland- a country with an historically high rate of NTDs- and at the National Institute of Child Health and Human Development at NIH to identify genes controlling NTD risk in a large series of affected Irish families. This team has identified human genetic variants in the majority of the genes encoding the constituents of folate, vitamin B12, and homocysteine metabolic pathways. The team also established that perturbations of the folate metabolic pathways account for a large fraction of NTD cases.

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Last Updated: August 1, 2008