MUT-TP53 2.0: a novel versatile matrix for statistical analysis of TP53 mutations in human cancera

Soussi, Thierry; Hamroun, Dalil; Hjortsberg, Linn; Rubio-Nevado, Jean Michel; Fournier, Jean Louis; Béroud, Christophe

doi:10.1002/humu.21313

Cited by 26 publications

(20 citation statements)

References 17 publications

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“…Approximately 80% of these missense mutations were projected to generate an inactive or partially inactive p53 protein (Fig. 3B) as determined by TP53-MUT 2.00, an online tool that predicts the biological activity of known TP53 mutations (24). In addition, missense mutations were enriched in the 9 most commonly mutated "hotspot" TP53 codons (175, 179, 195, 220, 237, 245, 248, 273, and 282) in ovarian carcinomas according to the IARC database (21,22).…”

Section: Resultsmentioning

confidence: 99%

“…All missense biological background mutations were evaluated by MUT-TP53 2.00 (24). Using functional and statistical information derived from the UMD (Universal Mutation Database) p53 database, this matrix assesses the likely biological activity of each mutation and categorizes them as one of the following: "inactive," "partially active," or "no significant loss of activity.…”

Section: Methodsmentioning

confidence: 99%

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Ultra-deep sequencing detects ovarian cancer cells in peritoneal fluid and reveals somatic TP53 mutations in noncancerous tissues

Krimmel

Schmitt

Harrell

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

148

110

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Current sequencing methods are error-prone, which precludes the identification of low frequency mutations for early cancer detection. Duplex sequencing is a sequencing technology that decreases errors by scoring mutations present only in both strands of DNA. Our aim was to determine whether duplex sequencing could detect extremely rare cancer cells present in peritoneal fluid from women with highgrade serous ovarian carcinomas (HGSOCs). These aggressive cancers are typically diagnosed at a late stage and are characterized by TP53 mutations and peritoneal dissemination. We used duplex sequencing to analyze TP53 mutations in 17 peritoneal fluid samples from women with HGSOC and 20 from women without cancer. The tumor TP53 mutation was detected in 94% (16/17) of peritoneal fluid samples from women with HGSOC (frequency as low as 1 mutant per 24,736 normal genomes). Additionally, we detected extremely low frequency TP53 mutations (median mutant fraction 1/13,139) in peritoneal fluid from nearly all patients with and without cancer (35/37). These mutations were mostly deleterious, clustered in hotspots, increased with age, and were more abundant in women with cancer than in controls. The total burden of TP53 mutations in peritoneal fluid distinguished cancers from controls with 82% sensitivity (14/17) and 90% specificity (18/20). Age-associated, low frequency TP53 mutations were also found in 100% of peripheral blood samples from 15 women with and without ovarian cancer (none with hematologic disorder). Our results demonstrate the ability of duplex sequencing to detect rare cancer cells and provide evidence of widespread, low frequency, age-associated somatic TP53 mutation in noncancerous tissue.TP53 mutations | ultra-deep sequencing | ovarian cancer | clonal hematopoiesis | premalignant mutations T he detection of tumor-specific mutations in clinically accessible samples has enormous potential to transform cancer diagnostics, monitoring, and screening. However, a major limitation is insufficiently accurate sequencing methods. Conventional nextgeneration sequencing (NGS) technologies have a high false positive error rate, which precludes reliable detection of mutations at frequencies <1/100 (1). "Molecular tagging" of single-stranded DNA decreases the rate of false mutations to less than 1 per 10,000 sequenced nucleotides and has been successfully applied to the detection of mutant cancer DNA in a variety of clinical samples (2-6). However, this false positive error rate limits the specificity of this method in challenging situations in which ultra-deep sequencing is needed to detect extremely low frequency mutant molecules (e.g., <1/10,000), as is the case of ovarian cancer DNA in Pap smears (5). Because true mutations are indistinguishable from artifacts, compromised specificity leads to lower sensitivity and overall low diagnostic accuracy. Duplex sequencing is an NGS technology that employs molecular tagging of both strands of DNA independently. True mutations are defined as mutations that are present at the same...

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Ultra-deep sequencing detects ovarian cancer cells in peritoneal fluid and reveals somatic TP53 mutations in noncancerous tissues

Krimmel

Schmitt

Harrell

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

148

110

View full text Add to dashboard Cite

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“…13) and obtained using the MUT-TP53 2.0 Excel spreadsheet tool (22), which was also used to perform comparison of our dataset with previous publications using the mean and 95% confidence interval (CI) of p53 activity as measured by transactivation with the WAF1 promoter. In the validation cohort, the mean of our study was À1.27 for EGFR-wt and À1.34 for EGFR-mut, compared with À1.26 and À1.29 in the two comprehensive NSCLC studies reported in the tool.…”

Section: Analysis Of Tp53 Mutationsmentioning

confidence: 99%

Nondisruptive p53 Mutations Are Associated with Shorter Survival in Patients with Advanced Non–Small Cell Lung Cancer

Molina-Vila

Bertrán-Alamillo

Gasco

et al. 2014

Clinical Cancer Research

134

149

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Purpose: TP53 mutations in early-stage non-small cell lung cancer (NSCLC) may be associated with worse survival but their prognostic role in advanced NSCLC is controversial. In addition, it remains unclear whether mutated patients represent a clinically homogeneous group.Experimental Design: We retrospectively examined TP53 mutations and outcome in a training cohort of 318 patients with stage IIIB-IV NSCLC: 125 epidermal growth factor receptor (EGFR) wild-type (wt) and 193 EGFR mutated (mut). An independent validation cohort of 64 EGFR-mut patients was subsequently analyzed. Mutations were classified as "disruptive" and "nondisruptive" according to their predicted degree of disturbance of the p53 protein structure and function.Results: In the training cohort, TP53 mutations were found in 43 of the 125 EGFR-wt patients (34.4%). Of these, 28 had nondisruptive TP53 mutations and a median overall survival (OS) of 8.5 months, compared with 15.6 months for the remaining 97 patients (P ¼ 0.003). In the EGFR-mut group, TP53 mutations were found in 50 of the 193 patients (25.9%). The OS for the 26 patients with TP53 nondisruptive mutations was 17.8 months versus 28.4 months for the remaining 167 patients (P ¼ 0.04). In the validation cohort, the 11 patients with nondisruptive TP53 mutations had a median OS of 18.1 months compared with 37.8 months for the 53 remaining patients (P ¼ 0.006). In multivariate analyses, nondisruptive TP53 mutations had an independent, significant association with a shorter OS.Conclusions: Nondisruptive mutations in the TP53 gene are an independent prognostic factor of shorter survival in advanced NSCLC.

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“…25,26 The frequency (number of reported mutations in all cancers) and predicted TP53 residual activity was retrieved from the 2007_R1 release of the UMD_TP53 Mutation database (http://p53.free.fr). 27 Known polymorphisms in the TP53 gene were treated as being TP53 wild type.…”

Section: Analysis Of Tp53 Mutationsmentioning

confidence: 99%

Inactivation of TP53 correlates with disease progression and low miR-34a expression in previously treated chronic lymphocytic leukemia patients

Dufour

Palermo

Zellmeier

et al. 2013

Blood

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Key Points• Only a complete disruption of TP53 function increases the risk for disease progression in previously treated CLL patients.• MiR-34a expression significantly correlates with the predicted TP53 activity in previously treated CLL patients with TP53 abnormalities.In chronic lymphocytic leukemia (CLL) patients, disruptions of the TP53 tumor suppressor pathway by 17p13 deletion (del17p), somatic TP53 mutations, or downregulation of microRNA-34a have been associated with a poor prognosis. So far, the impact of the various TP53 defects has not been evaluated in a large cohort of previously treated and relapsed CLL patients. Here, we present the results of TP53 gene sequencing and fluorescence in situ hybridization for del17p in a phase 3 clinical trial (REACH [Rituximab in the Study of Relapsed Chronic Lymphocytic Leukemia]). Of the 457 patients, 52 had TP53 mutations and 37 had del17p. In 24 (46%) of the TP53 mutated patients, no del17p was found and in 9 of the del17p patients, no TP53 mutation was identified. Based on a predicted proportion of TP53 disruption, a complete disruption of TP53 function, either by a combination of point mutations and/or del17p, was associated with a high risk for disease progression. Progressionfree survival of patients with a heterozygous TP53 mutation was not significantly different from patients with a completely intact TP53 locus. In addition, only a complete loss of TP53 function correlated with low microRNA-34a expression levels. This trial was registered at www.clinicaltrials.gov as #NCT00090051. (Blood. 2013;121(18):3650-3657)

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MUT-TP53 2.0: a novel versatile matrix for statistical analysis of TP53 mutations in human cancera

Cited by 26 publications

References 17 publications

Ultra-deep sequencing detects ovarian cancer cells in peritoneal fluid and reveals somatic TP53 mutations in noncancerous tissues

Ultra-deep sequencing detects ovarian cancer cells in peritoneal fluid and reveals somatic TP53 mutations in noncancerous tissues

Nondisruptive p53 Mutations Are Associated with Shorter Survival in Patients with Advanced Non–Small Cell Lung Cancer

Inactivation of TP53 correlates with disease progression and low miR-34a expression in previously treated chronic lymphocytic leukemia patients

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