The goal of this project is to identify and characterize clinically actionable mutations in all known breast cancer genes so that they can be incorporated into clinical care. DNA samples from 3000 cases and 2000 ancestry matched controls will be sequenced for all known breast cancer genes. Germline mutations will be evaluated with respect to function and relative risk of breast cancer. The discovery and characterization of clinically actionable variants in breast cancer genes involves three aims.
In AIM 1, we will sequence all 18 known breast cancer genes in DNA samples from 3000 women with breast cancer and 2000 ancestry-matched controls. In parallel, we will similarly evaluate 6 new candidate genes for inherited breast cancer that have emerged from our independent family studies. For all characterizations, we will use our recently developed approach for simultaneous capture and multiplexed sequencing, to >300-fold median coverage, of exons, introns, regulatory, and flanking intergenic regions of breast cancer genes.
In AIM 2, we will identify all variants predicted to lead to loss of gene function, including truncating mutations (whether nonsense, frameshifts, disrupting CNV and so on), complete genomic deletions, and putatively damaging missense mutations. We will assess all variants for effect on gene function using bioinformatics tools. Variants with possible splice effects will be evaluated by RT-PCR of patient RNA and ex vivo minigenes. The most promising missense alleles will be tested experimentally for DNA damage response, loss of enzyme activity and other functional assays as appropriate.
In AIM 3, we will test the strength of association of breast cancer with each of the 24 genes, based on the combined frequency of unambiguous loss-of-function mutations in cases vs controls. Relative risks will be estimated for each gene. The challenge of integrating genomics into clinical care is timely now for inherited predisposition to breast cancer, because multiple causal genes are known, specialized breast screening modalities are available, risk- reducing surgery is effective, and treatment of breast cancer is influenced by the patient's genotype. The goal of this project is to provide the information and technology necessary for this translation.
The goal of this project is to characterize all known breast cancer genes to identify clinically actionable mutations so that they can be incorporated into clinical care. DNA samples from 3000 cases and 2000 ancestry matched controls will be sequenced for 24 known breast cancer genes. Mutations will be evaluated with respect to function and relative risk of breast cancer.
|Norquist, Barbara M; Brady, Mark F; Harrell, Maria I et al. (2018) Mutations in Homologous Recombination Genes and Outcomes in Ovarian Carcinoma Patients in GOG 218: An NRG Oncology/Gynecologic Oncology Group Study. Clin Cancer Res 24:777-783|
|Zheng, Yonglan; Walsh, Tom; Gulsuner, Suleyman et al. (2018) Inherited Breast Cancer in Nigerian Women. J Clin Oncol 36:2820-2825|
|Stewart, Mikaela D; Zelin, Elena; Dhall, Abhinav et al. (2018) BARD1 is necessary for ubiquitylation of nucleosomal histone H2A and for transcriptional regulation of estrogen metabolism genes. Proc Natl Acad Sci U S A 115:1316-1321|
|Lolas Hamameh, Suhair; Renbaum, Paul; Kamal, Lara et al. (2017) Genomic analysis of inherited breast cancer among Palestinian women: Genetic heterogeneity and a founder mutation in TP53. Int J Cancer 141:750-756|
|Bernards, Sarah S; Norquist, Barbara M; Harrell, Maria I et al. (2016) Genetic characterization of early onset ovarian carcinoma. Gynecol Oncol 140:221-5|
|Norquist, Barbara M; Harrell, Maria I; Brady, Mark F et al. (2016) Inherited Mutations in Women With Ovarian Carcinoma. JAMA Oncol 2:482-90|
|Churpek, Jane E; Marquez, Rafael; Neistadt, Barbara et al. (2016) Inherited mutations in cancer susceptibility genes are common among survivors of breast cancer who develop therapy-related leukemia. Cancer 122:304-11|
|Catucci, Irene; Casadei, Silvia; Ding, Yuan Chun et al. (2016) Haplotype analyses of the c.1027C>T and c.2167_2168delAT recurrent truncating mutations in the breast cancer-predisposing gene PALB2. Breast Cancer Res Treat 160:121-129|
|Pritchard, Colin C; Mateo, Joaquin; Walsh, Michael F et al. (2016) Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med 375:443-53|
|Shirts, Brian H; Pritchard, Colin C; Walsh, Tom (2016) Family-Specific Variants and the Limits of Human Genetics. Trends Mol Med 22:925-934|
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