p53 is associated with high‐risk and pinpointsTP53missense mutations in mantle cell lymphoma

Abstract

Survival for patients diagnosed with mantle cell lymphoma (MCL) has improved drastically in recent years. However, patients carrying mutations in tumour protein p53 (TP53) do not benefit from modern chemotherapybased treatments and have poor prognosis. Thus, there is a clinical need to identify missense mutations through routine analysis to enable patient stratification. Sequencing is not widely implemented in clinical practice for MCL, and immunohistochemistry (IHC) is a feasible alternative to identify high-risk patients. The aim of the present study was to investigate the accuracy of p53 as a tool to identify patients with TP53 missense mutations and the prognostic impact of overexpression and mutations in a Swedish population-based cohort. In total, 317 cases were investigated using IHC and 255 cases were sequenced, enabling analysis of p53 and TP53 status among 137 cases divided over the two-cohort investigated. The accuracy of predicting missense mutations from protein expression was 82%, with sensitivity at 82% and specificity at 100% in paired samples. We further show the impact of p53 expression and TP53 mutations on survival (hazard ratio of 3Á1 in univariate analysis for both), and the association to risk factors, such as high MCL International Prognostic Index, blastoid morphology and proliferation, in a population-based setting.

Infiltration of CD163‐, PD‐L1‐ and FoxP3‐positive cells adversely affects outcome in patients with mantle cell lymphoma independent of established risk factors

“…Information on Ki-67, p53 and morphology was available for most patients, while TP53 mutational status was only available for a sub-set of patients. 9,37 The MIPI was available for the NLG-MCL2/3 cohorts, but only for a limited fraction of the SLR patients, reducing the number of included patients in fully adjusted analyses.…”

Bilateral auricular nodules: A peculiar presentation of systemic mantle cell lymphoma

“…TP53 mutated MCL is associated with resistance to traditional chemotherapy and increased relapse rates. 5 , 6 Although such cases have also been linked to blastoid cytology and high proliferation indices, morphology alone does not predict TP53 status. Thus, efficient proxies are needed when molecular analysis is unavailable or impractical.…”

“…The demonstration of p53 overexpression (>30% of nuclei) by IHC in tissue microarray has been advanced as a reliable surrogate for TP53 missense mutations in MCL, with 82% sensitivity and 100% specificity reported. 5 It is hypothesized that the mutant p53 protein is relatively stable compared with the wild-type protein, leading to intracellular accumulation demonstrable by IHC. Importantly, complete loss of p53 expression by IHC carries significant prognostic relevance, which exceeds any karyotype, fluorescence in situ hybridization, or immunohistochemical analysis.…”

Targeted genomic investigations in a population-based cohort of mantle cell lymphoma reveal novel clinically relevant targets

“…The most commonly mutated gene that harbored variants with driver potential was the ATM gene (Figure 5(A)). TP53 variants were all considered disrupting or deleterious by the algorithms (except for the frameshift insertion that has not been previously reported, detailed information is published [19]) and classified as predicted drivers. SMARCA4 gene variants and UBR5 mutations (6/7) were also among the predicted drivers in the cohort.…”