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Molecular characterisation of TP53 mutated squamous cell carcinomas of the lung to identify putative targets for
Vilde D Haakensen1,2, Anand Khadse1,3, Vandana Sandhu1,3,4
1Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
Abstract:
Personalised cancer treatment depends on identification of therapeutically relevant biological subgroups of patients for assessing effect of treatment and to discover new therapeutic options. By analyses in heterogeneous patient populations, the effects may be lost in noise. Squamous cell carcinoma of the lung is a major killer worldwide. Despite recent advances, mortality is high and response to therapies varies greatly from patient to patient. Target search in biologically relevant subgroups may identify treatment options not so far discovered. A total of 198 patients undergoing surgery for squamous cell carcinomas of the lung were included in the study. The tumours were analysed for copy number alterations (n = 152) and gene expression from tumour (n = 188) and normal lung (n = 21), with both data levels present in 140 patients. We studied alterations in tumours harbouring mutations in TP53 and in previously published gene expression subtypes. Genes with consistent alterations in both genomic levels were identified as putative biomarkers. Results were validated in TCGA. The most convincing biomarker in TP53 mutated squamous cell carcinomas of the lung was BIRC5 with amplification in 36% of mutated samples, 5% in wild-type samples and a 17%-fold change of expression between TP53 mutated tumours and normal lung tissue. BIRC5 was significantly altered in the classical and primitive subtypes. We suggest BIRC5 as a putative predictive biomarker and putative druggable target in squamous cell lung carcinomas harbouring TP53 mutation or classified as classical and primitive subtypes.
Insights
Identifying BIRC5 as a biomarker in TP53-mutated lung squamous cell carcinoma could personalize treatment. This finding may reveal new therapeutic options for this deadly cancer.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Personalized cancer treatment requires identifying patient subgroups for effective therapy.
- Lung squamous cell carcinoma (LSCC) has high mortality and variable treatment response.
- Analyzing biologically relevant subgroups may uncover novel therapeutic targets.
Purpose of the Study:
- To identify potential biomarkers and therapeutic targets in LSCC by analyzing genomic alterations.
- To investigate the role of TP53 mutations and gene expression subtypes in LSCC.
- To discover genes with consistent alterations across genomic levels as potential biomarkers.
Main Methods:
- Analysis of copy number alterations and gene expression in 198 LSCC patients.
- Focus on tumors with TP53 mutations and previously defined gene expression subtypes.
- Validation of identified biomarkers using TCGA data.
Main Results:
- BIRC5 amplification (36%) and increased expression (17-fold) were observed in TP53-mutated LSCC.
- BIRC5 alterations were significant in classical and primitive LSCC subtypes.
- BIRC5 showed consistent genomic alterations in TP53-mutated tumors.
Conclusions:
- BIRC5 is a potential predictive biomarker for LSCC with TP53 mutations.
- BIRC5 represents a potential druggable target for LSCC patients with TP53 mutations or specific subtypes.
- This study highlights the importance of subgroup analysis for personalized cancer therapy.
