Study Confirms Association of TP53 Mutations and ENE in Patients with Advanced OSCC

August 30, 2020

Researchers indicated that these findings suggest, “an ENE detection biomarker based on TP53 mutation detection would represent an enormous clinical benefit.”

A study published in Cancer confirmed the association between high-risk TP53 mutations and extranodal extension (ENE) in 2 distinct cohorts of advanced oral squamous cell carcinoma (OSCC), suggesting that these mutations may have a promising role as biomarkers.

In addition, high-risk TP53 mutations appeared to be an important modulator of oral cancer phenotype. Given this finding, researchers indicated that unveiling the molecular intricacies associated with each TP53 alteration will be critical in transforming TP53 into a useful clinical biomarker.

“Understanding the molecular consequences of different TP53 mutations is of utmost importance and the next necessary step toward enhancement of this classification system and its translation into an OSCC clinical biomarker,” the authors wrote.

Using 2 cohorts of patients with advanced OSCC, researchers sequenced the TP53 gene in 78 samples from 38 patients who were treated at a Brazilian institution and 40 patients who were treated at a US institution. TP53 mutations were classified according to an in-silico impact score (the evolutionary action score of p53 [EAp53]), which identifies mutations that have greater alterations of p53 protein function. Relevant findings were then validated in silico by analyzing 197 samples from patients with advanced OSCC from The Cancer Genome Atlas.

Overall, no differences were found with regard to clinical outcomes between patients with TP53-mutant and wild-type TP53 disease. However, patients who had tumors carrying high-risk TP53 mutations did have a significantly increased risk of developing ENE compared with patients who had wild-type TP53-bearing tumors. These findings were also validated among patients with advanced OSCC from The Cancer Genome Atlas cohort.

“For these patients, an ENE detection biomarker based on TP53 mutation detection would represent an enormous clinical benefit. However, to transform TP53 mutations into a clinically useful biomarker, it is necessary to further improve the understanding and classification of all its variants,” the authors noted. “Vast numbers of TP53 mutation classification algorithms have been developed, but their clinical value is still unproven.”

The researchers explained that a possible reason for this discrepancy is that most of these algorithms ignore the specific molecular background of each different tumor type. For example, though this study utilized the EAp53 system, which is calibrated to specifically work for head and neck squamous carcinomas, this system is limited to missense mutations, which does not score stop-codon, splice-site, and frameshift mutations.

Importantly, somatic mutations of the TP53 tumor-suppressor gene are the most common genomic alterations observed in patients with OSCC, occurring in approximately 80% of nonhuman papillomavirus-related cases. However, despite its association with decreased survival outcomes, the TP53 mutation is still not generally used in the management of patients with OSCC.

“Considering the relatively poor prognosis of patients with advanced OSCC, biomarkers that can accurately categorize patients according to their likelihood of treatment failure would be highly useful in guiding treatment decisions for the selection of patients who might fail standard treatments and potentially could benefit from alternative treatments in clinical trials,” the authors explained.

Reference:

Gleber-Netto FO, Neskey D, Flàvia de Mattos Costa A, et al. Functionally Impactful TP53 Mutations Are Associated With Increased Risk of Extranodal Extension in Clinically Advanced Oral Squamous Cell Carcinoma. Cancer. doi: 10.1002/cncr.33101