Cancer is a genetic disease on both the germline and somatic levels. With advances in technology,
sequencing is becoming increasingly important in the fight against cancer, both for determining risk to develop
disease and for treatment decisions. For the past several years, my primary responsibility in Dr. Susan
Neuhausen’s unit has been the high-throughput sequencing of ovarian and breast cancer cases and healthy
controls using Illumina’s next generation sequencing (NGS) technology. Dr. Neuhausen has been studying
inherited pathogenic mutations in breast and ovarian cancers since 1992 when she was part of the team who
localized and identified BRCA1 and BRCA2. Since then, other genes have been identified but the combined
effect of all genes explains less than half of the genetic risk for breast cancer. Currently, little is known about
the role of additional genes in the progression of cancer, and even less is known about the effects of variants
within these genes. This lack of knowledge limits our ability to identify those individuals at high risk to develop
cancer for targeted prevention. We hope to identify a proportion of the missing genetic risk. To date, I have
performed targeted and whole exome sequencing of over a thousand breast and ovarian cancer samples. This
process requires creating libraries for Illumina’s sequencing platform. I have made several modifications to
significantly reduce costs—modifications that have been adapted by the Integrative Genomics Core (IGC) at
City of Hope. I am currently devoting my time to Dr. Neuhausen’s R01 CA184585. This grant is the first large
sequencing study to identify genes that predispose to breast cancer in Hispanics, and to use a combined
germline and somatic approach to identify pathogenic mutations. Based on what is known from our pilot
sequencing study, genome-wide association studies (GWAS), and BRCA mutation screening in Hispanics, we
will likely identify both novel genes and novel recurrent mutations. We have already identified a founder PALB2
mutation. I am responsible for the whole exome sequencing, and the later targeted sequencing. I am working
with the IGC to better identify large rearrangements and then I will test if the findings are correct. In addition to
identifying known pathogenic mutations, I perform molecular biology assays including: a) yeast-two-hybrid
analysis to examine the effects of missense mutations on protein-protein interactions; b) luciferase assays to
investigate the effects of 3’ and 5’ UTR mutations that may affect binding of microRNAs and transcription
factors to regulatory elements; and c) PCR and subcloning to assess effects of splicing variants. I also work
with collaborators to identify germline and somatic mutations. This Research Specialist award will allow me to
continue to provide my expertise in molecular biology for current and future NCI-funded genomic projects. I will
keep on developing and testing new methods to better achieve our goals. By discovering genes that cause
cancers and understanding the effects of the mutations, we can better identify individuals who are at high risk,
and ultimately can offer preventive options and more effective treatments at diagnosis.
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