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Refined characterization of head and neck squamous cell carcinomas expressing a seemingly wild-type p53 protein
Katharina Leng1, Simone Schlien, Franz X Bosch
1Molekularbiologisches Labor, Universitäts-HNO-Klinik, Heidelberg, Germany.
Background:
A fraction of head and neck squamous cell carcinomas (HNSCC) reveal overexpression of the p53 protein although sequence analysis failed to detect mutations in the core region of the protein. The functional and clinical status of p53 in these tumors is unclear.
Methods:
In 31 HNSCC, allelic imbalances (AI) at TP53 and other chromosome 17 loci were analyzed by microsatellite marker analysis. Expression of p16(INK4a) protein was analyzed by immunohistochemistry. Seven tumors were re-examined for sequence alterations by the Affymetrix p53 GeneChip.
Results:
About 54.8% of these tumors showed AI at TP53; 41.9% showed loss of p16, an overlapping fraction of 35.5% demonstrated AI and p16 loss. Six of seven such tumors revealed heterozygous missense mutations.
Conclusions:
A large proportion of HNSCC with presumed wild-type p53 overexpression are false-negative cases. These results strengthen the established strong association of p53 protein overexpression with missense mutations. AI at TP53 and p16 loss are useful surrogate markers for genetic alterations of TP53 in HNSCC.
Insights
Many head and neck squamous cell carcinomas (HNSCC) with high p53 protein levels actually have mutations. Allelic imbalance at TP53 and p16 loss can indicate these genetic changes in HNSCC.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- A subset of head and neck squamous cell carcinomas (HNSCC) exhibit p53 protein overexpression without detectable mutations in the p53 core region.
- The functional and clinical significance of p53 in these specific HNSCC cases remains undetermined.
Purpose of the Study:
- To investigate the genetic status of p53 in HNSCC cases with p53 protein overexpression but no apparent mutations.
- To determine if allelic imbalance (AI) at TP53 and p16 loss serve as reliable indicators of TP53 genetic alterations in HNSCC.
Main Methods:
- Analysis of allelic imbalances (AI) at TP53 and chromosome 17 loci using microsatellite markers in 31 HNSCC.
- Immunohistochemical analysis of p16(INK4a) protein expression.
- Sequencing of the p53 gene using the Affymetrix p53 GeneChip in seven selected tumors.
Main Results:
- Allelic imbalance at TP53 was observed in 54.8% of tumors.
- Loss of p16 expression was detected in 41.9% of tumors.
- A combined 35.5% of tumors showed both AI at TP53 and p16 loss; six of these seven harbored heterozygous missense mutations.
Conclusions:
- A significant portion of HNSCC cases with presumed wild-type p53 overexpression are misclassified (false negatives).
- The findings reinforce the strong correlation between p53 protein overexpression and missense mutations.
- AI at TP53 and p16 loss are validated as effective surrogate markers for TP53 genetic alterations in HNSCC.
