Katherine L. Nathanson, MD

Dr. Nathanson's studies focus on multiple aspects of inherited breast cancer, particularly on inherited susceptibility to breast cancer in relation to the BRCA 1 and BRCA2 genes, and on "mystery" families with multiple incidences of breast cancer but no BRCA 1 or BRCA2 mutation. Dr. Nathanson's team has performed large-scale sequencing on high-risk breast cancer families and patients, who have either experienced several cases of cancer themselves or within their families. In some women, researchers have identified previously unknown causative mutations and variation in novel genes, which may be associated with disease. They are in the process of putting together a large collaborative project to validate the novel findings.

In 2012-2013, Dr. Nathanson's team will continue to do whole exome sequencing in high-risk families and women with multiple primary breast and ovarian cancers to further identify potential novel susceptibility genes associated with breast cancer. They are focusing on genes that encode proteins involved in the repair of DNA (the proteins encoded in most known breast cancer susceptibility genes participate in DNA damage sensing and repair). However, Dr. Nathanson will continue to examine variation across the genome, and in regions in which linkage has suggested that breast cancer susceptibility genes exist. In order to make sure that variation in these genes is truly associated with breast cancer risk, she and her team will use a targeted capture to screen women diagnosed with breast cancer before the age 45, who do not have mutations in BRCA1/2, and compare them to women who are "true negatives," meaning that they tested negative for a familial mutation in BRCA1/2, in order to determine if the gene is associated with an increase in breast cancer risk. They also will collaborate with other breast cancer researchers to increase the population size, and strengthen individual findings through collaborative efforts.

Mid-year Progress: Dr. Nathanson's team has performed whole exome (most of the coding regions in the genome) sequencing on high-risk breast cancer families and patients with breast and ovarian cancer, and targeted (specific genes) sequencing in women with early onset breast cancer before age 40. In women from high risk families and with multiple primary cancers, they have identified previously unknown causative mutations in genes associated with breast cancer susceptibly explaining the breast and/or ovarian cancer risk in the individual or family. The researchers also have identified variation in novel genes, which may be associated with cancer susceptibility. They are working together with other BCRF investigators to select genes, and put together a data set, for validation of these novel findings. In the women with breast cancer under age 40, Dr. Nathanson has found preliminarily that ~10% carry deleterious mutations (known to affect protein function), most in moderate penetrance genes. These results are of particular importance, as similar testing is being offered commercially. How to translate identification of moderate risk gene mutations into improvements in patient care is still unclear. This study is the first step in clinical translation, as scientists need to understand the range and types of mutations identified in women with different disease characteristics.

Bio:
Dr. Katherine Nathanson received her BS in Biology with Honors from Haverford College and her MD from the University of Pennsylvania School of Medicine. She then trained in Internal Medicine at the Beth Israel Hospital, Boston and did a fellowship in Genetics at the Children's Hospital of Philadelphia and the Hospital of the University of Pennsylvania. She is doubly boarded in Internal Medicine and Genetics. She completed her postdoctoral laboratory training with Dr. Barbara Weber in the University of Pennsylvania School of Medicine, focusing on breast cancer genetics.

Dr. Nathanson has had a long-standing interest in the genetics of breast cancer and her studies in breast cancer have focused on three areas. During her fellowship, she has led several studies that focused on characterizing BRCA1 and BRCA2 mutations in different patient populations for which she received the AFLAC Scholar-In-Training award. She also has participated in studies identifying genetic modifiers of penetrance in BRCA1 and BRCA2 mutation carriers, examining both candidate modifiers of penetrance with Dr. Timothy Rebbeck and using linkage based methods to identify novel modifiers of penetrance. She has participated in the Breast Cancer Linkage Consortium effort to identify novel genetic variants that increase susceptibility to breast cancer, such as CHEK2. Dr. Nathanson's current efforts continue these studies and have expanded to include characterization of breast cancer on a genomic level to identify both somatic and germline genetic changes important in breast cancer.