Researchers Leverage p53 Expression to Identify TP53 Missense Mutations in MCL

Reporting on their findings in the British Journal of Haematology, researchers have used immunohistochemistry (IHC) to leverage p53 expression as an identifier of mantle cell lymphoma (MCL) patients carrying mutations in tumor protein p53 (TP53), an indicator of poor prognosis in the disease.

While survival has greatly increased for most patients with MCL in recent years thanks to new treatments, the subgroup of these patients with TP53 mutations still face a grim prognosis. The researchers argued that identifying patients with TP53 mutations could help guide alternative treatment selections for these patients, such as a chemotherapy-free option.

Using 11 missense mutation samples among 72 samples accessed from the population-based BLISS (Biobank of Lymphomas in Southern Sweden) cohort, the researchers found that using p53 expression carried a significantly high accuracy of identifying TP53 missense mutation. Of the 11 samples, 9 were p53 positive, resulting in an 82% accuracy rate, with sensitivity at 82% (9 of 11) and specificity at 100% (61 of 61).

To further confirm the efficacy of the method, the researchers also analyzed previously published sequencing data from 3 cohorts of patients from the Nordic MCL2 and MCL3 studies. In this data set, the researchers observed that leveraging p53 expression resulted in an accuracy rate of 71% with sensitivity at 75% (6 of 8) and specificity at 95% (58/61).

“Patients with MCL TP53 mutated cells have a median overall survival (OS) of 1.8 [years] compared to 12.7 years in patients with TP53 wild-type (WT) MCL tumours,” explained the researchers, reflecting on previous research. “Patients with mutated TP53 tumours also have a shorter progression-free survival and higher incidence of relapse, with hazard ratios (HRs) of 6.8 and 6.9 respectively, in a multivariate analysis including [MCL International Prognostic Index] and blastoid morphology.”

In the current study, the researchers observed similar findings. Analyses of the BLISS cohort showed that having TP53 aberrations carried a 3-fold increase in the risk of death. These patients had an OS of 1.4 years while patients with unmutated MCL had a median OS of 6.2 years.

Among the patients in the N-MCL2/3 studies, the risk of death was 8.8 times higher among patients with mutated MCL. The median OS was significantly lower for these patients, who had a median OS of 2.4 years compared with a median OS of 14 years for patients with TP53 WT tumors.

Based on the findings, the researchers explained that using IHC analysis of p53 could be used in several ways, including to identify patients with shorter OS and as a screening method to identify patients who would benefit from further genomic TP53 analysis.

“Targeted sequencing in routine clinical practice is not yet implemented, and selection of patients constitutes an approach to reduce the practical and financial burden of a patient-wide screening using next-generation sequencing,” wrote the researchers. “Using p53 as a surrogate marker has already been suggested for other malignancies with a similar accuracy of ~90%.”

According to the researchers, IHC allows visualization of a mutated subclone, which can be challenging to identify through sequencing because of low allele frequency. Because of this, the researchers argued “this makes IHC a relevant technique to screen larger areas and shape genomic analysis for more accurate study of mutations in cases with clearly heterogeneity and clones arising within the tumour.”

Reference:

Rodrigues JM, Hassan M, Freiburghaus C, et al. p53 is associated with high-risk and pinpoints TP53 missense mutations in mantle cell lymphoma. Br J Haematol. Published online August 4, 2020. doi: 10.1111/bjh.17023.