Prognostic and Predictive Effect of TP53 Mutations in Patients with Non–Small Cell Lung Cancer from Adjuvant Cisplatin–Based Therapy Randomized Trials: A LACE-Bio Pooled Analysis

Ma, Xiaoli; Teuff, Gwénaël Le; Lacas, Benjamin; Tsao, Ming‐Sound; Graziano, Stephen L.; Pignon, Jean-Pierre; Douillard, Jean-Yves; Chevalier, Thierry Le; Seymour, Lesley; Filipits, Martin; Pirker, Robert; Jänne, Pasi A.; Shepherd, Frances A.; Brambilla, Élisabeth; Soria, Jean‐Charles; Hainaut, Pierre

doi:10.1016/j.jtho.2016.02.002

Cited by 80 publications

(76 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies have shown that in patients who received platinumbased adjuvant chemotherapy, the presence of mutant type TP53 showed a tendency for shorter survival compared to wild-type TP53, depending on the specific type of mutation. [11][12][13] Hence, the stronger prognostic value we observed for TP53 mutations in advanced stage NSCLC could be due to therapy resistance/failure, supported by the negative prognostic effect of TP53 mutations in the (neo)adjuvanttreated patients of our study population. The currently available data on the prognostic value of TP53 mutations, recently reviewed by Deben et al, 3 indicated the importance of subtype and tumor stage.…”

Section: Discussionsupporting

confidence: 67%

Deep sequencing of the TP53 gene reveals a potential risk allele for non–small cell lung cancer and supports the negative prognostic value of TP53 variants

et al. 2017

View full text Add to dashboard Cite

The TP53 gene remains the most frequently altered gene in human cancer, of which variants are associated with cancer risk, therapy resistance, and poor prognosis in several tumor types. To determine the true prognostic value of TP53 variants in non-small cell lung cancer, this study conducted further research, particularly focusing on subtype and tumor stage. Therefore, we determined the TP53 status of 97 non-small cell lung cancer adenocarcinoma patients using next generation deep sequencing technology and defined the prognostic value of frequently occurring single nucleotide polymorphisms and mutations in the TP53 gene. Inactivating TP53 mutations acted as a predictor for both worse overall and progression-free survival in stage II-IV patients and patients treated with DNA-damaging (neo)adjuvant therapy. In stage I tumors, the Pro-allele of the TP53 R72P polymorphism acted as a predictor for worse overall survival. In addition, we detected the rare R213R (rs1800372, minor allele frequency: 0.0054) polymorphism in 7.2% of the patients and are the first to show the significant association with TP53 mutations in non-small cell lung cancer adenocarcinoma patients (p = 0.003). In conclusion, Our findings show an important role for TP53 variants as negative predictors for the outcome of non-small cell lung cancer adenocarcinoma patients, especially for TP53 inactivating mutations in advanced stage tumors treated with DNA-damaging agents, and provide the first evidence of the R213R G-allele as possible risk factor for non-small cell lung cancer.

show abstract

Section: Discussionsupporting

confidence: 67%

Deep sequencing of the TP53 gene reveals a potential risk allele for non–small cell lung cancer and supports the negative prognostic value of TP53 variants

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Overall survival was also computed for this group and found not to be significantly different (p=0.35) (Figure 2). We then performed an analysis similar to the one done in lung cancer21 and, again, the site of TP53 mutation did not have an impact on first platinum-free interval or overall survival (p=0.34 and p=0.23, respectively) (Figure 2). Given the known impact of BRCA1/2 mutations on overall survival in high grade serous ovarian cancer, we analyzed the impact of these mutations in the 182 patients with TP53 mutations.…”

Section: Resultsmentioning

confidence: 99%

“…In lung cancer, a structure-effect TP53 classification scheme has been described based on the location, nature, and predicted function of the mutation 21. We used the same scheme to classify variants into four categories: non-missense mutations, missense DNA-binding motif mutations, missense non-DNA-binding motif mutations, and unclassified/wild type.…”

Section: Methodsmentioning

confidence: 99%

“…Mutations for each cluster were assigned to each of the six classification schemes as defined by coding effect, the IARC classification,20 Brachova et a l ,8 Kang et a l ,11 our hierarchal system, and the lung classification scheme 21. The chi-square test was performed for each scheme to compare differences in the type of mutations between the cluster with the worse survival and the union of the clusters with better survival.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

TP53 mutations in high grade serous ovarian cancer and impact on clinical outcomes: a comparison of next generation sequencing and bioinformatics analyses

Mandilaras

Garg

Cabanero

et al. 2019

Int J Gynecol Cancer

View full text Add to dashboard Cite

ObjectiveMutations in TP53 are found in the majority of high grade serous ovarian cancers, leading to gain of function or loss of function of its protein product, p53, involved in oncogenesis. There have been conflicting reports as to the impact of the type of these on prognosis. We aim to further elucidate this relationship in our cohort of patients.Methods229 patients with high grade serous ovarian cancer underwent tumor profiling through an institutional molecular screening program with targeted next generation sequencing. TP53 mutations were classified using methods previously described in the literature. Immunohistochemistry on formalin-fixed paraffin embedded tissue was used to assess for TP53 mutation. Using divisive hierarchal clustering, we generated patient clusters with similar clinicopathologic characteristics to investigate differences in outcomes.ResultsSix different classification schemes of TP53 mutations were studied. These did not show an association with first platinum-free interval or overall survival. Next generation sequencing reliably predicted mutation in 80% of cases, similar to the proportion detected by immunohistochemistry. Divisive hierarchical clustering generated four main clusters, with cluster 3 having a significantly worse prognosis (p<0.0001; log-rank test). This cluster had a higher concentration of gain of function mutations and these patients were less likely to have undergone optimal debulking surgery.ConclusionsDifferent classifications of TP53 mutations did not show an impact on outcomes in this study. Immunohistochemistry was a good predictor for TP53 mutation. Cluster analysis showed that a subgroup of patients with gain of function mutations (cluster 3) had a worse prognosis.

show abstract

“…In addition, occurrence and/or co-occurrence of mutations in tumor suppressor genes like TP53 and STK11 with typical oncogene driver mutations in lung cancer have been suggested to have implications for prognosis and treatment response [30–32], which may be of complimentary clinical value. Our analysis of 533 consecutive NSCLCs screened during a single year showed considerable differences between histological subgroups in the proportion of cases harboring a known or suggested actionable variant, with adenocarcinomas having the greatest potential benefit from this type of analyses (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

Clinical framework for next generation sequencing based analysis of treatment predictive mutations and multiplexed gene fusion detection in non-small cell lung cancer

Lindquist¹,

Karlsson

Leveén³

et al. 2017

Oncotarget

View full text Add to dashboard Cite

Precision medicine requires accurate multi-gene clinical diagnostics. We describe the implementation of an Illumina TruSight Tumor (TST) clinical NGS diagnostic framework and parallel validation of a NanoString RNA-based ALK, RET, and ROS1 gene fusion assay for combined analysis of treatment predictive alterations in non-small cell lung cancer (NSCLC) in a regional healthcare region of Sweden (Scandinavia). The TST panel was clinically validated in 81 tumors (99% hotspot mutation concordance), after which 533 consecutive NSCLCs were collected during one-year of routine clinical analysis in the healthcare region (˜90% advanced stage patients). The NanoString assay was evaluated in 169 of 533 cases. In the 533-sample cohort 79% had 1-2 variants, 12% >2 variants and 9% no detected variants. Ten gene fusions (five ALK, three RET, two ROS1) were detected in 135 successfully analyzed cases (80% analysis success rate). No ALK or ROS1 FISH fusion positive case was missed by the NanoString assay. Stratification of the 533-sample cohort based on actionable alterations in 11 oncogenes revealed that 66% of adenocarcinomas, 13% of squamous carcinoma (SqCC) and 56% of NSCLC not otherwise specified harbored ≥1 alteration. In adenocarcinoma, 10.6% of patients (50.3% if including KRAS) could potentially be eligible for emerging therapeutics, in addition to the 15.3% of patients eligible for standard EGFR or ALK inhibitors. For squamous carcinoma corresponding proportions were 4.4% (11.1% with KRAS) vs 2.2%. In conclusion, multiplexed NGS and gene fusion analyses are feasible in NSCLC for clinical diagnostics, identifying notable proportions of patients potentially eligible for emerging molecular therapeutics.

show abstract

Prognostic and Predictive Effect of TP53 Mutations in Patients with Non–Small Cell Lung Cancer from Adjuvant Cisplatin–Based Therapy Randomized Trials: A LACE-Bio Pooled Analysis

Abstract: TP53 mutation had no prognostic effect but was marginally predictive for survival from ACT. In patients who received ACT, TP53 mutation tended to be associated with shorter survival than wild-type TP53.

Cited by 80 publications

References 41 publications

Deep sequencing of the TP53 gene reveals a potential risk allele for non–small cell lung cancer and supports the negative prognostic value of TP53 variants

Deep sequencing of the TP53 gene reveals a potential risk allele for non–small cell lung cancer and supports the negative prognostic value of TP53 variants

TP53 mutations in high grade serous ovarian cancer and impact on clinical outcomes: a comparison of next generation sequencing and bioinformatics analyses

Clinical framework for next generation sequencing based analysis of treatment predictive mutations and multiplexed gene fusion detection in non-small cell lung cancer

Contact Info

Product

Resources

About