Functional Genomics Laboratory, Kolling Institute of Medical Research DAC - TP53 mutation data in ovarian cancer
Ontology highlight
ABSTRACT:
PROVIDER: EGAC00001000589 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:National reports have called for the introduction of research experiences throughout the undergraduate curriculum, but practical implementation at many institutions faces challenges associated with sustainability, cost, and large student populations. We describe a novel course-based undergraduate research experience (CURE) that introduces introductory-level students to research in functional genomics in a 3-credit, multisection laboratory class. In the Pathways over Time class project, students study the functional conservation of the methionine biosynthetic pathway between divergent yeast species. Over the five semesters described in this study, students (N = 793) showed statistically significant and sizable growth in content knowledge (d = 1.85) and in self-reported research methods skills (d = 0.65), experimental design, oral and written communication, database use, and collaboration. Statistical analyses indicated that content knowledge growth was larger for underrepresented minority students and that growth in content knowledge, but not research skills, varied by course section. Our findings add to the growing body of evidence that CUREs can support the scientific development of large numbers of students with diverse characteristics. The Pathways over Time project is designed to be sustainable and readily adapted to other institutional settings.
| S-EPMC6007769 | biostudies-literature
Project description: Not available
| S-BSST1126 | biostudies-other
Project description: Not available
| S-EPMC9090805 | biostudies-literature
Project description: Not available
| S-EPMC4694096 | biostudies-literature
Project description:BACKGROUND:Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome characterized by a very high lifetime cancer risk and an early age at diagnosis of a wide cancer spectrum. Precise estimates for the risk of first and subsequent cancers are lacking. METHODS:The National Cancer Institute's Li-Fraumeni Syndrome Study includes families meeting the diagnostic criteria for LFS or Li-Fraumeni-like syndrome, and individuals with a germline TP53 mutation, choroid plexus carcinoma, adrenocortical carcinoma, or ?3 cancers. Herein, we estimated the cumulative risk and annual hazards for first and second cancers among TP53 mutation carriers (TP53 positive [TP53+]) using MATLAB statistical software. RESULTS:This study evaluated 286 TP53+ individuals from 107 families. The cumulative cancer incidence was 50% by age 31 years among TP53+ females and 46 years among males, and nearly 100% by age 70 years for both sexes. Cancer risk was highest after age 20 years for females, mostly due to breast cancer, whereas among males the risk was higher in childhood and later adulthood. Among females, the cumulative incidence rates by age 70 years for breast cancer, soft tissue sarcoma, brain cancer, and osteosarcoma were 54%, 15%, 6%, and 5%, respectively. Among males, the incidence rates were 22%, 19%, and 11%, respectively, for soft tissue sarcoma, brain cancer, and osteosarcoma. Approximately 49% of those with 1 cancer developed at least another cancer after a median of 10 years. The average age-specific risk of developing a second cancer was comparable to that of developing a first cancer. CONCLUSIONS:The cumulative cancer risk in TP53?+?individuals was very high and varied by sex, age, and cancer type. Additional work, including prospective risk estimates, is needed to better inform personalized risk management. Cancer 2016;122:3673-81. © 2016 American Cancer Society.
| S-EPMC5115949 | biostudies-literature
Project description:The p53 tumor suppressor transcriptionally regulates a myriad of genes involved in cell cycle control, DNA repair, cell survival, and cell metabolism and represents one of the most well-studied inhibitors of tumorigenesis. Since the discovery of TP53 in 1979, somatic mutations have been shown to be extremely common; more than 50% of human cancers carry loss-of-function mutations in TP53. Inherited or germline TP53 mutations are rare and are involved in complex hereditary cancer predisposition disorders, and affected family members can develop diverse tumor types and multiple primary cancers at young ages. In Brazil, a fascinating history of p53 and cancer predisposition began in the year 2000 with identification of the TP53 p.R337H mutation in close association with the development of adrenocortical tumors. In these past 20 years, much has been learned about the genetics and biochemistry of this mutation, which is widespread in Brazil because of a founder effect. This review highlights the contributions of TP53 p.R337H research over the last 20 years, the findings of which have sparked passionate debate among researchers worldwide, to understanding cancer predisposition in Brazilian individuals and families.
| S-EPMC7589304 | biostudies-literature
Project description:Genome-wide copy number variation was measured in TP53 mutation negative ovarian tumours. Analysis described in "Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary" (Ahmed et al., 2010)
2010-03-04 | GSE19416 | GEO
Project description:ObjectiveComparisons of The Cancer Genome Atlas (TCGA) with high grade serous ovarian cancer (HGSOC) cell lines used in research reveal that many common experimental models lack defining genomic characteristics seen in patient tumors. As cell lines exist with higher genomic fidelity to TCGA, this study aimed to evaluate the utility of these cell lines as tools for preclinical investigation.MethodsWe compared two HGSOC cell lines with supposed high genomic fidelity to TCGA, KURAMOCHI and OVSAHO, with the most commonly cited ovarian cancer cell line, SKOV3, which has poor genomic fidelity to TCGA. The lines were analyzed for genomic alterations, in vitro performance, and growth in murine xenografts.ResultsUsing targeted next generation sequencing analyses, we determined that each line had a distinct mutation profile, including alterations in TP53, and copy number variation of specific genes. KURAMOCHI and OVSAHO better recapitulated serous carcinoma morphology than SKOV3. All lines expressed PAX8 and stathmin, but KURAMOCHI and OVSAHO did not express CK7. KURAMOCHI was significantly more platinum sensitive than OVSAHO and SKOV3. Unlike SKOV3, KURAMOCHI and OVSAHO engrafted poorly in subcutaneous xenografts. KURAMOCHI and OVSAHO grew best after intraperitoneal injection in SCID mice and recapitulated miliary disease while SKOV3 grew in all murine systems and formed oligometastatic disease.ConclusionsThe research utility of HGSOC cell line models requires a comprehensive assessment of genomic as well as in vitro and in vivo properties. Cell lines with closer genomic fidelity to human tumors may have limitations in performance for preclinical investigation.
| S-EPMC4587360 | biostudies-literature
Project description:Platinum-based chemotherapy is the therapy of choice for epithelial ovarian cancer (EOC). Acquired resistance to platinum (PT) is a frequent event that leads to disease progression and predicts poor prognosis. To understand possible mechanisms underlying acquired PT-resistance, we have recently generated and characterized three PT-resistant isogenic EOC cell lines. Here, we more deeply characterize several PT-resistant clones derived from MDAH-2774 cells. We show that, in these cells, the increased PT resistance was accompanied by the presence of a subpopulation of multinucleated giant cells. This phenotype was likely due to an altered progression through the M phase of the cell cycle and accompanied by the deregulated expression of genes involved in M phase progression known to be target of mutant TP53. Interestingly, we found that PT-resistant MDAH cells acquired in the TP53 gene a novel secondary mutation (i.e., S185G) that accompanied the R273H typical of MDAH cells. The double p53S185G/R273H mutant increases the resistance to PT in a TP53 null EOC cellular model. Overall, we show how the selective pressure of PT is able to induce additional mutation in an already mutant TP53 gene in EOC and how this event could contribute to the acquisition of novel cellular phenotypes.
| S-EPMC7016977 | biostudies-literature
Project description:TP53 mutations are ubiquitous in high-grade serous ovarian carcinomas (HGSOC), and the presence of TP53 mutation discriminates between high and low-grade serous carcinomas and is now an important biomarker for clinical trials targeting mutant p53. p53 immunohistochemistry (IHC) is widely used as a surrogate for TP53 mutation but its accuracy has not been established. The objective of this study was to test whether improved methods for p53 IHC could reliably predict TP53 mutations independently identified by next generation sequencing (NGS). Four clinical p53 IHC assays and tagged-amplicon NGS for TP53 were performed on 171 HGSOC and 80 endometrioid carcinomas (EC). p53 expression was scored as overexpression (OE), complete absence (CA), cytoplasmic (CY) or wild type (WT). p53 IHC was evaluated as a binary classifier where any abnormal staining predicted deleterious TP53 mutation and as a ternary classifier where OE, CA or WT staining predicted gain-of-function (GOF or nonsynonymous), loss-of-function (LOF including stopgain, indel, splicing) or no detectable TP53 mutations (NDM), respectively. Deleterious TP53 mutations were detected in 169/171 (99%) HGSOC and 7/80 (8.8%) EC. The overall accuracy for the best performing IHC assay for binary and ternary prediction was 0.94 and 0.91 respectively, which improved to 0.97 (sensitivity 0.96, specificity 1.00) and 0.95 after secondary analysis of discordant cases. The sensitivity for predicting LOF mutations was lower at 0.76 because p53 IHC detected mutant p53 protein in 13 HGSOC with LOF mutations. CY staining associated with LOF was seen in 4 (2.3%) of HGSOC. Optimized p53 IHC can approach 100% specificity for the presence of TP53 mutation and its high negative predictive value is clinically useful as it can exclude the possibility of a low-grade serous tumour. 4.1% of HGSOC cases have detectable WT staining while harboring a TP53 LOF mutation, which limits sensitivity for binary prediction of mutation to 96%.
| S-EPMC5091634 | biostudies-literature