TP53 Mutations in Head and Neck Squamous Cell Carcinoma and Their Impact on Disease Progression and Treatment Response

Abstract

Recent studies describing the mutational landscape of head and neck squamous cell carcinoma (HNSCC) on a genomic scale by our group and others, including The Cancer Genome Atlas, have provided unprecedented perspective for understanding the molecular pathogenesis of HNSCC progression and response to treatment. These studies confirmed that mutations of the TP53 tumor suppressor gene were the most frequent of all somatic genomic alterations in HNSCC, alluding to the importance of the TP53 gene in suppressing the development and progression of this disease. Clinically, TP53 mutations are significantly associated with short survival time and tumor resistance to radiotherapy and chemotherapy in HNSCC patients, which makes the TP53 mutation status a potentially useful molecular factor for risk stratification and predictor of clinical response in these patients. In addition to loss of wild-type p53 function and the dominant-negative effect on the remaining wild-type p53, some p53 mutants often gain oncogenic functions to promote tumorigenesis and progression. Different p53 mutants may possess different gain-of-function properties. Therefore, mutant p53 is not just one protein but actually a variety of proteins that contribute to an exceptionally vast network of tumor-promoting processes. Herein we review the most up-to-date information about TP53 mutations available via The Cancer Genome Atlas-based analysis of HNSCC and discuss our current understanding of the potential tumor-suppressive role of p53, focusing on gain-of-function activities of p53 mutations. We also summarize our knowledge regarding use of the TP53 mutation status as a potential evaluation or stratification biomarker for prognosis and a predictor of clinical response to radiotherapy and chemotherapy in HNSCC patients. Finally, we discuss possible strategies for targeting HNSCCs bearing TP53 mutations.

High-Risk HPV, Biomarkers, and Outcome in Matched Cohorts of Head and Neck Cancer Patients Positive and Negative for HIV

“…By this indicator, only one of the HPV-positive tumors (UP1880, p16 score= 1) among the HIV-infected cases was not driven by the HPV16 viral DNA found in the tumor. Among the HPV-positive tumors from HIV-negative controls, one (UM2495) failed to express p16, and two others (UM1349 and UM 1803) expressed only low levels of p16, raising a question about whether the virus is a driver in these cases or if p16 has been completely or partially inactivated by other mechanisms such as methylation or copy loss (19–22). …”

“…Generally when TP53 is wild type, little or no TP53 protein expression is seen in the tumor; however, TP53 protein expression is often high in tumors with mutant TP53 (22). Among the HPV-positive tumors from HIV-positive cases, TP53 expression was low or moderate in all but one tumor (UM2359, p53 score= 12)).…”

TSPAN31 is a critical regulator on transduction of survival and apoptotic signals in hepatocellular carcinoma cells

“…Previous studies reported that mutations in the p53 gene and decreased p53 expression contributed to cancer progression . The expression of TSPAN2 and TSPAN12 was increased following the down‐regulation of p53.…”

A genetic variant within MDM4 3′UTR miRNA binding site is associated with HPV16‐positive tumors and survival of oropharyngeal cancer

“…While tumor HPV status remains one of the strongest biomarkers for predicting outcome of SCCOP, identification of novel and robust biomarkers for predicting HPV status in SCCOP is clinically useful. As HPV(+) SCCOP patients have heterogeneous clinical outcomes, 25 it is possible for physicians to optimize patient actually inactive or less active. 55,56 In another study, HPV16 E6 mediated degradation was dominant over MDM2 in cervical cancer.…”

“…[19][20][21][22][23] Thus, identifying molecular biomarkers which may lead to improved survival for patients with SCCOP is urgently needed. p53 as an important tumor suppressor plays a critical role in genome integrity and acts as "the guardian of genome" in many human cancers, especially in squamous cell carcinomas of the head and neck (SCCHN), 24,25 while mouse double minute 2 (MDM2) and 4 (MDM4) inhibit the tumor suppressor activity of p53 through the interaction between p53 and the two negative modulators. [26][27][28] MDM4 is an oncoprotein which negatively regulates the p53.…”