Specific TP53 mutations predict aggressive phenotype in head and neck squamous cell carcinoma: a retrospective archival study

Abstract

BackgroundHead and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy in the world in developed countries. Despite the intense research in the area of squamous cell carcinomas of head and neck (HNSCC), long-term survival rate has not changed significantly in this malignancy during recent decades.MethodsIn this study, we focused on TP53 mutations in specific regions, including DNA-binding surface, to determine whether mutations at specific locations of TP53 could be used to help in setting up prognosis and response to therapy of head and neck squamous cell carcinoma patients. We analysed TP53 mutations in 46 HNSCC by PCR-SSCP and sequencing and characterized how different TP53 mutations affect the patient outcome.ResultsTumours containing TP53 mutations in DNA-binding regions (L2, L3 and LSH motif) had a significantly poorer prognosis and response to radiotherapy than tumours outside those regions. Disease-specific 5-year survival of patients with TP53 mutations affecting DNA contacts was 43.5% while it was 77.8% (p < 0.05) in patients with TP53 mutations in other residues not involved in DNA contact. Moreover, nodal metastasis were more prevalent (although not statistically significantly) with TP53 mutations in DNA-binding surface regions. We noticed that the patients with TP53 mutations in L3/LSH motifs had a significantly poorer response (11.4% responding) to radiation than the patients with a wild type p53 (48.6%) or TP53 mutations outside the DNA-binding regions (40%) (p < 0.05).ConclusionsThese data indicate that a TP53 mutation in L2, L3 or LSH is worth pursuing as a marker for predicting prognosis and response to radiation among HNSCC patients.

Missense mutations in the TP53 DNA-binding domain predict outcomes in patients with advanced oral cavity squamous cell carcinoma

“…Truncating mutations are included in the group of disruptive mutations [8], which may likely have contributed to the unsatisfactory results obtained with this classification method in our cohort. In contrast, mutations in L2, L3 or LSH [7, 16, 23] and high-risk missense mutations according to the EAp53 [14, 15] were capable of identifying high-risk patients in a successful manner. We believe that this capacity may be attributed to the fact that they include a high proportion of a gain-of-function mutations [10].…”

“…Notably, TP53 mutations have been associated with a decreased response to both 5-fluorouracil [26] and radiotherapy [16]. Additionally, TP53 mutation subtypes may directly guide future targeted treatment.…”

“…It has been recently suggested that TP53 missense mutations occurring in evolutionary conserved residues are likely to confer a gain-of-function, ultimately predicting poor treatment response and a shorter survival in HNSCC patients [14, 15]. Other studies focusing on mutations occurring in the DBD or DBD-defined regions (e.g., L2, L3 and LSH) [7, 16] have reported their adverse prognostic significance, although conflicting results exist [7, 9, 16, 17]. Such discrepancies can be ascribed to small sample sizes or sequencing areas limited to exons 5−8.…”

Patient-derived tumour xenografts as models for oncology drug development

“…These results are consistent with previous findings demonstrating a correlation between TP53 mutations and a poor prognosis in patients with HNSCC and to neoadjuvant chemotherapy resistance. 66–68 A recent study tested the response to cetuximab against a large panel of PDTX cancer models including HNSCC; 27 of the eight HNSCC xenografts tested, five were responsive (63%), which was the highest response rate of any cancers tested. However, unlike the case for CRC and NSCLC, there was no correlation of response with mutations in KRAS , BRAF or NRAS , nor to amplification of receptors such as HER3 or MET.…”

Can radiological changes in lymph node volume during treatment predict success of radiation therapy in patients with locally advanced head and neck squamous cell carcinoma?

“…Radiotherapy (RT) is the mainstay of organ‐preserving treatment in locally advanced HNSCC, and the addition of concurrent chemotherapy improves overall survival, at the cost of increased toxicity . The advent of precision RT techniques, such as intensity‐modulated radiation therapy (IMRT), can reduce toxicity by reducing doses to normal structures …”