TP53 hot spot mutations in ovarian cancer: Selective resistance to microtubule stabilizers in vitro and differential survival outcomes from The Cancer Genome Atlas

Seagle, Brandon Luke L.; Yang, Chia Ping Huang; Eng, Kevin H.; Dandapani, Monica; Odunsi-Akanji, Oluwatosin; Goldberg, Gary L.; Odunsi, Kunle; Horwitz, Susan Band; Shahabi, Shohreh

doi:10.1016/j.ygyno.2015.04.039

Cited by 22 publications

(12 citation statements)

References 30 publications

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“…Mutations in the disruptive category were associated with shorter survival. Particular mutation hotspots (248, 273 and 175) were recently observed to influence chemotherapy sensitivity and overall survival in ovarian cancer[ 41 ]. Although the DNA binding and oligomerization domains of TP53 are usually treated separately, our interface mappings highlight that many amino acids involved in TP53 dimerization are within the DBD, a fact that has been reported previously[ 42 ].…”

Section: Resultsmentioning

confidence: 99%

Structure-Based Analysis Reveals Cancer Missense Mutations Target Protein Interaction Interfaces

2016

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Recently it has been shown that cancer mutations selectively target protein-protein interactions. We hypothesized that mutations affecting distinct protein interactions involving established cancer genes could contribute to tumor heterogeneity, and that novel mechanistic insights might be gained into tumorigenesis by investigating protein interactions under positive selection in cancer. To identify protein interactions under positive selection in cancer, we mapped over 1.2 million nonsynonymous somatic cancer mutations onto 4,896 experimentally determined protein structures and analyzed their spatial distribution. In total, 20% of mutations on the surface of known cancer genes perturbed protein-protein interactions (PPIs), and this enrichment for PPI interfaces was observed for both tumor suppressors (Odds Ratio 1.28, P-value < 10−4) and oncogenes (Odds Ratio 1.17, P-value < 10−3). To study this further, we constructed a bipartite network representing structurally resolved PPIs from all available human complexes in the Protein Data Bank (2,864 proteins, 3,072 PPIs). Analysis of frequently mutated cancer genes within this network revealed that tumor-suppressors, but not oncogenes, are significantly enriched with functional mutations in homo-oligomerization regions (Odds Ratio 3.68, P-Value < 10−8). We present two important examples, TP53 and beta-2-microglobulin, for which the patterns of somatic mutations at interfaces provide insights into specifically perturbed biological circuits. In patients with TP53 mutations, patient survival correlated with the specific interactions that were perturbed. Moreover, we investigated mutations at the interface of protein-nucleotide interactions and observed an unexpected number of missense mutations but not silent mutations occurring within DNA and RNA binding sites. Finally, we provide a resource of 3,072 PPI interfaces ranked according to their mutation rates. Analysis of this list highlights 282 novel candidate cancer genes that encode proteins participating in interactions that are perturbed recurrently across tumors. In summary, mutation of specific protein interactions is an important contributor to tumor heterogeneity and may have important implications for clinical outcomes.

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Section: Resultsmentioning

confidence: 99%

Structure-Based Analysis Reveals Cancer Missense Mutations Target Protein Interaction Interfaces

2016

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“…The number of mutated genes per sample ranged from 3 to 7 with a median of 4.5, identical with the number of mutations. Just two of the 37 revealed mutations were known cancer hotspots: TP53 p.G266V and TP53 p.R248Q, the latter actually in OC [ 22 ], and TP53 p.R248Q mutation has been reported to aggregate and to be associated with metastasis [ 23 ]. The most commonly altered genes were TP53 and BRCA1 with 6/8 and 5/8 events, respectively.…”

Section: Resultsmentioning

confidence: 99%

Next-Generation Sequencing-based genomic profiling of brain metastases of primary ovarian cancer identifies high number of BRCA-mutations

et al. 2017

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Ovarian cancer represents the most common gynaecological malignancy and has the highest mortality of all female reproductive cancers. It has a rare predilection to develop brain metastases (BM). In this study, we evaluated the mutational profile of ovarian cancer metastases through Next-Generation Sequencing (NGS) with the aim of identifying potential clinically actionable genetic alterations with options for small molecule targeted therapy. Library preparation was conducted using Illumina TruSight Rapid Capture Kit in combination with a cancer specific enrichment kit covering 94 genes. BRCA-mutations were confirmed by using TruSeq Custom Amplicon Low Input Kit in combination with a custom-designed BRCA gene panel. In our cohort all eight sequenced BM samples exhibited a multitude of variant alterations, each with unique molecular profiles. The 37 identified variants were distributed over 22 cancer-related genes (23.4%). The number of mutated genes per sample ranged from 3 to 7 with a median of 4.5. The most commonly altered genes were BRCA1/2, TP53, and ATM. In total, 7 out of 8 samples revealed either a BRCA1 or a BRCA2 pathogenic mutation. Furthermore, all eight BM samples showed mutations in at least one DNA repair gene. Our NGS study of BM of ovarian carcinoma revealed a significant number of BRCA-mutations beside TP53, ATM and CHEK2 mutations. These findings strongly suggest the implication of BRCA and DNA repair malfunction in ovarian cancer metastasizing to the brain. Based on these findings, pharmacological PARP inhibition could be one potential targeted therapeutic for brain metastatic ovarian cancer patients.Electronic supplementary materialThe online version of this article (doi:10.1007/s11060-017-2459-z) contains supplementary material, which is available to authorized users.

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“…In colon tumors, the two most frequent mutations in our cohort were contact mutations: point mutations of arginine 248 to glutamine (R248Q) and arginine 273 to cysteine (R273C). R273 mutations have been reported to show increased resistance to paclitaxel, cisplatin, and doxorubicin [36] , [37] , [38] . Patients with metastatic sarcoma or metastatic colorectal cancer who were positive for TP53 mutations in exons 5-8 (A159fs, R213*, R175H, H179R, H193R, V216M, G245S, and R273C) had better clinical outcomes (longer median progression-free disease and median overall survival) in response to treatment with pazopanib and vorinostat [39] .…”

Section: Discussionmentioning

confidence: 99%

Frequency of Somatic TP53 Mutations in Combination with Known Pathogenic Mutations in Colon Adenocarcinoma, Non–Small Cell Lung Carcinoma, and Gliomas as Identified by Next-Generation Sequencing

et al. 2018

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The tumor suppressor gene TP53 is the most frequently mutated gene in human cancer. It encodes p53, a DNA-binding transcription factor that regulates multiple genes involved in DNA repair, metabolism, cell cycle arrest, apoptosis, and senescence. TP53 is associated with human cancer by mutations that lead to a loss of wild-type p53 function as well as mutations that confer alternate oncogenic functions that enable them to promote invasion, metastasis, proliferation, and cell survival. Identifying the discrete TP53 mutations in tumor cells may help direct therapies that are more effective. In this study, we identified the frequency of individual TP53 mutations in patients with colon adenocarcinoma (48%), non–small cell lung carcinoma (NSCLC) (36%), and glioma/glioblastoma (28%) at our institution using next-generation sequencing. We also identified the occurrence of somatic mutations in numerous actionable genes including BRAF, EGFR, KRAS, IDH1, and PIK3CA that occurred concurrently with these TP53 mutations. Of the 480 tumors examined that contained one or more mutations in the TP53 gene, 219 were colon adenocarcinomas, 215 were NSCLCs, and 46 were gliomas/glioblastomas. Among the patients positive for TP53 mutations diagnosed with colon adenocarcinoma, 50% also showed at least one mutation in pathogenic genes of which 14% were BRAF, 33% were KRAS, and 3% were NRAS. Forty-seven percent of NSCLC patients harboring TP53 mutations also had a mutation in at least one actionable pathogenic variant with the following frequencies: BRAF: 4%, EGFR: 10%, KRAS: 28%, and PIK3CA: 4%. Fifty-two percent of patients diagnosed with glioma/glioblastoma with a positive TP53 mutation had at least one concurrent mutation in a known pathogenic gene of which 9% were CDKN2A, 41% were IDH1, and 11% were PIK3CA.

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TP53 hot spot mutations in ovarian cancer: Selective resistance to microtubule stabilizers in vitro and differential survival outcomes from The Cancer Genome Atlas

Cited by 22 publications

References 30 publications

Structure-Based Analysis Reveals Cancer Missense Mutations Target Protein Interaction Interfaces

Structure-Based Analysis Reveals Cancer Missense Mutations Target Protein Interaction Interfaces

Next-Generation Sequencing-based genomic profiling of brain metastases of primary ovarian cancer identifies high number of BRCA-mutations

Frequency of Somatic TP53 Mutations in Combination with Known Pathogenic Mutations in Colon Adenocarcinoma, Non–Small Cell Lung Carcinoma, and Gliomas as Identified by Next-Generation Sequencing

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