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Grant Details

Grant Number: 5R50CA211280-05 Interpret this number
Primary Investigator: Adamson, Aaron
Organization: Beckman Research Institute/City Of Hope
Project Title: Discovery and Characterization of Mutations in Breast and Ovarian Cancers
Fiscal Year: 2020


Abstract

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.



Publications

The RAD52 S346X variant reduces risk of developing breast cancer in carriers of pathogenic germline BRCA2 mutations.
Authors: Adamson A.W. , Ding Y.C. , Mendez-Dorantes C. , Bailis A.M. , Stark J.M. , Neuhausen S.L. .
Source: Molecular oncology, 2020 06; 14(6), p. 1124-1133.
EPub date: 2020-04-25.
PMID: 32175645
Related Citations

Pathogenic and likely pathogenic variants in PALB2, CHEK2, and other known breast cancer susceptibility genes among 1054 BRCA-negative Hispanics with breast cancer.
Authors: Weitzel J.N. , Neuhausen S.L. , Adamson A. , Tao S. , Ricker C. , Maoz A. , Rosenblatt M. , Nehoray B. , Sand S. , Steele L. , et al. .
Source: Cancer, 2019-08-15; 125(16), p. 2829-2836.
EPub date: 2019-06-17.
PMID: 31206626
Related Citations

Discovery of mutations in homologous recombination genes in African-American women with breast cancer.
Authors: Ding Y.C. , Adamson A.W. , Steele L. , Bailis A.M. , John E.M. , Tomlinson G. , Neuhausen S.L. .
Source: Familial cancer, 2018 04; 17(2), p. 187-195.
PMID: 28864920
Related Citations

The spectrum of genetic variants in hereditary pancreatic cancer includes Fanconi anemia genes.
Authors: Slavin T.P. , Neuhausen S.L. , Nehoray B. , Niell-Swiller M. , Solomon I. , Rybak C. , Blazer K. , Adamson A. , Yang K. , Sand S. , et al. .
Source: Familial cancer, 2018 04; 17(2), p. 235-245.
PMID: 28687971
Related Citations

Genetic Gastric Cancer Susceptibility in the International Clinical Cancer Genomics Community Research Network.
Authors: Slavin T. , Neuhausen S.L. , Rybak C. , Solomon I. , Nehoray B. , Blazer K. , Niell-Swiller M. , Adamson A.W. , Yuan Y.C. , Yang K. , et al. .
Source: Cancer genetics, 2017 Oct; 216-217, p. 111-119.
EPub date: 2017-08-17.
PMID: 29025585
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