Browsing by Subject "Li-Fraumeni syndrome"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    LFSPROShiny: An Interactive R/Shiny App for Prediction and Visualization of Cancer Risks in Families With Deleterious Germline TP53 Mutations
    (American Society of Clinical Oncology, 2024) Nguyen, Nam H.; Dodd-Eaton, Elissa B.; Peng, Gang; Corredor, Jessica L.; Jiao, Wenwei; Woodman-Ross, Jacynda; Arun, Banu K.; Wang, Wenyi; Medical and Molecular Genetics, School of Medicine
    Purpose: LFSPRO is an R library that implements risk prediction models for Li-Fraumeni syndrome (LFS), a genetic disorder characterized by deleterious germline mutations in the TP53 gene. To facilitate the use of these models in clinics, we developed LFSPROShiny, an interactive R/Shiny interface of LFSPRO that allows genetic counselors (GCs) to perform risk predictions without any programming components and further visualize the risk profiles of their patients to aid the decision-making process. Methods: LFSPROShiny implements two models that have been validated on multiple LFS patient cohorts: a competing risk model that predicts cancer-specific risks for the first primary and a recurrent-event model that predicts the risk of a second primary tumor. Starting with a visualization template, we keep regular contact with GCs, who ran LFSPROShiny in their counseling sessions, to collect feedback and discuss potential improvement. On receiving the family history as input, LFSPROShiny renders the family into a pedigree and displays the risk estimates of the family members in a tabular format. The software offers interactive overlaid side-by-side bar charts for visualization of the patients' cancer risks relative to the general population. Results: We walk through a detailed example to illustrate how GCs can run LFSPROShiny in clinics from data preparation to downstream analyses and interpretation of results with an emphasis on the utilities that LFSPROShiny provides to aid decision making. Conclusion: Since December 2021, we have applied LFSPROShiny to over 100 families from counseling sessions at the MD Anderson Cancer Center. Our study suggests that software tools with easy-to-use interfaces are crucial for the dissemination of risk prediction models in clinical settings, hence serving as a guideline for future development of similar models.
  • Thumbnail Image
    Item
    Li-Fraumeni Syndrome Patient-derived LFS50 Progression Cell Series as an Experimental Model for Breast Cancer Prevention Research
    (Office of the Vice Chancellor for Research, 2013-04-05) Phatak, Amruta R.; Herbert, Brittney-Shea
    Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with germline mutations in the tumor suppressor gene TP53. Breast cancer (BC) is the most common tumor amongst women with LFS, who have increased risk for premenopausal BC before age 40 and a lifetime risk of 49% by the age of 60. Non-malignant, human mammary epithelial cells (HMECs) were derived from the contralateral breast tissue of LFS patient (LFS50) undergoing BC surgery. The LFS50 HMEC progression series comprises of pre-immortal (HME50), spontaneously immortalized (HME50-5E), hTERT-immortalized (HME50hTERT or HME50hT), and tumorigenic (HMET) which can be modeled to represent breast cancer progression. Gene expressions of the LFS50 series were profiled using HG-U133_Plus_2 Affymetrix chip. By hierarchical clustering, the LFS50 cells were observed to have significant differential expression of genes and ANOVA results revealed that EMT-related genes (e.g., epithelial membrane protein 3, p= 6.84911E-19; E-cadherin, p= 8.66098E-19; and Keratin 5, p= 9.73095E-19) to be the most differentially expressed amongst the LFS50 cells. Ingenuity Pathway Analysis (IPA) confirmed that Ecadherin and Keratin 5 were the top most differentially expressed genes as well as G2/M DNA Damage Checkpoint Regulation (p= 2.67E-05), Estrogen-mediated S-phase Entry (p=3.32E-04) Mitotic Roles of Polo-Like Kinase (p=5.5E-04) as few of the top canonical pathways. Furthermore, to identify the type of breast cancer that LFS50 series could model, the triple negative breast cancer (TNBC) subtyping database tool predicted that each of the LFS50 strains could be classified as a different subtype. Finally, as a proof of principle for drug targeting, treatment of the LFS50 series with PRIMA-1, a p53 rescue drug, using 3D cultures resulted in a reduction in acini size of the pre-invasive LFS50 cells (p<0.05). Therefore, this progression series can serve as a resource for drug target discovery and breast cancer prevention research.
  • Thumbnail Image
    Item
    Modeling cancer predisposition: Profiling Li-Fraumeni syndrome patient-derived cell lines using bioinformatics and three-dimensional culture models
    (2015-10-07) Phatak, Amruta Rajendra; Herbert, Brittney-Shea; Liu, Yunlong; Mendonca, Marc S.; Wells, Clark D.
    Although rare, classification of over 200 hereditary cancer susceptibility syndromes accounting for ~5-10% of cancer incidence has enabled the discovery and understanding of cancer predisposition genes that are also frequently mutated in sporadic cancers. The need to prevent or delay invasive cancer can partly be addressed by characterization of cells derived from healthy individuals predisposed to cancer due to inherited "single-hits" in genes in order to develop patient-derived samples as preclinical models for mechanistic in vitro studies. Here, we present microarray-based transcriptome profiling of Li-Fraumeni syndrome (LFS) patient-derived unaffected breast epithelial cells and their phenotypic characterization as in vitro three-dimensional (3D) models to test pharmacological agents. In this study, the epithelial cells derived from the unaffected breast tissue of a LFS patient were cultured and progressed from non-neoplastic to a malignant stage by successive immortalization and transformation steps followed by growth in athymic mice. These cell lines exhibited distinct transcriptomic profiles and were readily distinguishable based upon their gene expression patterns, growth characteristics in monolayer and in vitro 3D cultures. Transcriptional changes in the epithelial-to-mesenchymal transition gene signature contributed to the unique phenotypes observed in 3D culture for each cell line of the progression series; the fully transformed LFS cells exhibited invasive processes in 3D culture with disorganized morphologies due to cell-cell miscommunication, as seen in breast cancer. Bioinformatics analysis of the deregulated genes and pathways showed inherent differences between these cell lines and targets for pharmacological agents. After treatment with small molecule APR-246 that restores normal function to mutant p53, we observed that the neoplastic LFS cells had reduced malignant invasive structure formation from 73% to 9%, as well as an observance of an increase in formation of well-organized structures in 3D culture (from 27% to 91%) by stereomicroscopy and confocal microscopy. Therefore, the use of well-characterized and physiologically relevant preclinical models in conjunction with transcriptomic profiling of high-risk patient derived samples as a renewable laboratory resource can potentially guide the development of safer and more effective chemopreventive approaches.