MUTATION MAPPING IN NON-SMALL CELL LUNG CANCER; A META-ANALYSIS BY GEOGRAPHY AND HISTOLOGY (MUTMAP)

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Abstract

Background

This study comprises a meta-analysis of publicly available and newly generated mutation data in non-small-cell lung cancer patients to identify differences between histological subtypes and geographical populations. Gene mutation frequencies, along with two-gene coincidence data have been collated. We call this analysis a MutMap.

Methods

Publications reporting mutation data on two or more genes, in histologically and geographically defined populations, were identified. Assessments of single-gene mutation frequencies and two-gene mutation co-occurrences were carried out in Western and Eastern adenocarcinoma and squamous cell carcinoma populations.

Results

In total, 21 studies were identified. Data from AstraZeneca and the Guangdong Lung Cancer Institute were included in the meta-analysis. Mutation data were collated for eight genes (EGFR, KRAS, TP53, LKB1, BRAF, PIK3CA, PTEN and ERBB2). Adenocarcinoma cases contained more mutations than squamous cases. The most commonly mutated gene was TP53; however, mutation frequencies varied between geographical regions and between histologies. Mutations in EGFR were common (46.3%) in Eastern adenocarcinoma patients but rarer in Western cases (14.8%). Conversely, KRAS mutations were more common in Western adenocarcinoma patients (25.7%) than Eastern cases (11.2%). Mutations in LKB1 were also more common in Western patients. Mutations in PTEN were common in Eastern squamous samples (9.8%).

Results

Mutation co-occurrence in two genes was also examined. Mutations in EGFR and KRAS were exclusive to each other. In addition, in Western adenocarcinoma patients, mutations in both EGFR and LKB1 occurred significantly less often than would be expected by chance. There were several two-gene mutation co-occurrences which were detected at levels ≥5% of the NSCLC population, e.g. TP53 with either KRAS or EGFR in adenocarcinoma.

Conclusions

Overall, this study expands on the view that mutation prevalence in NSCLC is complex, with variation between histological subtypes and geographical populations. Mutation co-occurrence may also be a factor in future treatment paradigms as segments ≥5% of NSCLC possess both activating oncogenic driver mutations and mutations in tumour suppressor genes.

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