Tumor Protein p53 (TP53) Testing and Li-Fraumeni Syndrome

Sorrell, April; Espenschied, Carin R.; Culver, Julie O.; Weitzel, Jeffrey N.

doi:10.1007/s40291-013-0020-0

Cited by 90 publications

(40 citation statements)

References 144 publications

(193 reference statements)

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“…Interestingly, only germline mutations in women had predicted deleterious functional impact on p53 , whereas the mutations identified in men had predicted neutral impact on the protein. No evidence was found in the clinical profile of patients carrying these TP53 mutations to suggest Li-Fraumeni syndrome (37). Although women with MPM have TP53 mutations at a higher rate compared to men, no significant correlation of TP53 status was found to survival in this cohort.…”

Section: Discussionmentioning

confidence: 99%

Gender-Specific Molecular and Clinical Features Underlie Malignant Pleural Mesothelioma

et al. 2016

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Malignant pleural mesothelioma (MPM) is an aggressive cancer that occurs more frequently in men, but is associated with longer survival in women. Insight into the survival advantage of female patients may advance the molecular understanding of MPM and identify therapeutic interventions that will improve the prognosis for all MPM patients. In this study, we performed whole-genome sequencing of tumor specimens from 10 MPM patients and matched control samples to identify potential driver mutations underlying MPM. We identified molecular differences associated with gender and histology. Specifically, single-nucleotide variants of BAP1 were observed in 21% of cases, with lower mutation rates observed in sarcomatoid MPM (p<0.001). Chromosome 22q loss was more frequently associated with the epithelioid than that non-epitheliod histology (p=0.037), whereas CDKN2A deletions occurred more frequently in non-epithelioid subtypes among men (p=0.021) and were correlated with shorter overall survival for the entire cohort (p=0.002) and for men (p=0.012). Furthermore, women were more likely to harbor TP53 mutations (p=0.004). Novel mutations were found in genes associated with the integrin-linked kinase pathway, including MYH9 and RHOA. Moreover, expression levels of BAP1, MYH9, and RHOA were significantly higher in non-epithelioid tumors, and were associated with significant reduction in survival of the entire cohort and across gender subgroups. Collectively, our findings indicate that diverse mechanisms highly related to gender and histology appear to drive MPM.

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Section: Discussionmentioning

confidence: 99%

Gender-Specific Molecular and Clinical Features Underlie Malignant Pleural Mesothelioma

et al. 2016

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“…Half of patients with LFS develop at least one LFS-associated cancer before age 30, compared to a 1% incidence of cancer before age 30 in the general population [6]. The lifetime risk of cancer in LFS is estimated to be 73% for males and almost 100 % for females, with the increased risk of breast cancer accounting for the difference [7, 8].…”

Section: Discovery Of Li-fraumeni Syndrome and Identification Of P53 mentioning

confidence: 99%

Li–Fraumeni Syndrome Disease Model: A Platform to Develop Precision Cancer Therapy Targeting Oncogenic p53

Zhou

Gingold

et al. 2017

Trends in Pharmacological Sciences

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Li-Fraumeni syndrome (LFS) is a rare hereditary autosomal dominant cancer disorder. Germ-line mutations in TP53 are responsible for most cases of LFS. p53 is also the most commonly mutated gene in human cancers. Because inhibition of mutant p53 is considered a promising therapeutic strategy to treat these diseases, LFS provides a perfect genetic model to study p53 mutation-associated malignancies as well as screen potential compounds targeting oncogenic p53. In this review, we will briefly summarize the biology of LFS and the current understanding of oncogenic functions of mutant p53 in cancer development. We will discuss the strengths and limitations of current LFS disease models and touch on existing compounds targeting oncogenic p53 and in vitro clinical trials to develop new ones. Finally, we discuss how recently developed methodologies can be integrated into the LFS iPSC platform to develop precision cancer therapy.

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“…Breast cancer, sarcoma and brain, and adrenocortical carcinoma represent about 77–80% of LFS-associated tumors. Less frequent malignancies associated with LS include leukemia and lung, colorectal, skin, gastric, and ovarian cancer and these account for 15% of the tumors [ 62 ]. Nevertheless, these less frequent tumors are present in the general population; thus, their presence in LFS families could be because of chance.…”

Section: Tp53 and Li-fraumeni Syndromementioning

confidence: 99%

Hereditary Ovarian Cancer: Not OnlyBRCA1 and 2 Genes

Toss

Tomasello

Razzaboni

et al. 2015

BioMed Research International

197

118

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More than one-fifth of ovarian tumors have hereditary susceptibility and, in about 65–85% of these cases, the genetic abnormality is a germline mutation in BRCA genes. Nevertheless, several other suppressor genes and oncogenes have been associated with hereditary ovarian cancers, including the mismatch repair (MMR) genes in Lynch syndrome, the tumor suppressor gene, TP53, in the Li-Fraumeni syndrome, and several other genes involved in the double-strand breaks repair system, such as CHEK2, RAD51, BRIP1, and PALB2. The study of genetic discriminators and deregulated pathways involved in hereditary ovarian syndromes is relevant for the future development of molecular diagnostic strategies and targeted therapeutic approaches. The recent development and implementation of next-generation sequencing technologies have provided the opportunity to simultaneously analyze multiple cancer susceptibility genes, reduce the delay and costs, and optimize the molecular diagnosis of hereditary tumors. Particularly, the identification of mutations in ovarian cancer susceptibility genes in healthy women may result in a more personalized cancer risk management with tailored clinical and radiological surveillance, chemopreventive approaches, and/or prophylactic surgeries. On the other hand, for ovarian cancer patients, the identification of mutations may provide potential targets for biologic agents and guide treatment decision-making.

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Tumor Protein p53 (TP53) Testing and Li-Fraumeni Syndrome

Cited by 90 publications

References 144 publications

Gender-Specific Molecular and Clinical Features Underlie Malignant Pleural Mesothelioma

Gender-Specific Molecular and Clinical Features Underlie Malignant Pleural Mesothelioma

Li–Fraumeni Syndrome Disease Model: A Platform to Develop Precision Cancer Therapy Targeting Oncogenic p53

Hereditary Ovarian Cancer: Not OnlyBRCA1 and 2 Genes

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