Analysis Of Oncogenic Driver Mutations In Lung Squamous-Cell Carcinoma From Chinese Population

Lung cancer is still the leading cause of cancer-related mortality worldwide. As a common malignancy, the5-year survival rate of advanced non-small cell lung cancer(NSCLC) remains poor, about15%. NSCLC comprises three different subtypes:squamous-cell carcinoma, large-cell carcinoma and adenocarcinoma. The squamous-cell carcinoma accounts for40%of all cases of lung cancer. Compared with adenocarcinoma, the mutation rate of squamous-cell carcinoma is relatively low and whether squamous-cell carcinoma contains EGFR/KRAS mutation is still in controversy due to the inexplicit pathological descriptions of previous studies, which makes the screening of driver mutations in squamous-cell carcinoma difficult in clinical practice.This study was conducted basing on the debate and controversy in driver mutation research area of squamous-cell carcinoma. From2008-2011,310surgical resected lung squamous-cell carcinoma specimens were collected, including frozen tissues and corresponding FFPE tumor blocks in Fudan University Shanghai Cancer Center. All specimens were reviewed by two pathologists, and44specimens were found with obvious glandular component by morphological examination. TTF-1staining was conducted in266specimens with no obvious glandular component by morphological examination to find24specimens with focal or scattered positive TTF-1staining. CK7staining was continually conducted in240TTF-1negative specimens to find25specimens with focal or scattered positive CK7staining and215specimens with CK7negative staining. Meanwhile, all310specimens were either P63-positive or CK5/6-positive. The total specimens comprise95squamous-cell carcinomas with glandular component and215pure squamous-cell carcinomas. Subsequently, driver mutations testing were performed with cDNA sequencing, including EGFR, KRAS, BRAF, HER2, PIK3CA, AKT1, DDR2, EML4-ALK and KIF5B, CCDC6-RET fusions. The subgroup of specimens with glandular component was found with26mutations (26/95,27.4%), including11EGFR mutations,7KRAS mutations,1BRAF mutation,1HER2mutation,5PIK3CA mutations,2EML4-ALK fusions. And the group of pure squamous-cell carcinomas were found with10mutations(10/215,4.7%), including7PIK3CA mutations,1AKT1mutation,1DDR2mutation and1EGFR mutation. No KIF5B and CCDC6-RET fusions was found. EGFR and KRAS mutations were predominantly found in the subgroups of specimens with glandular component and related with glandular component. By conducting microdissection in4specimens with obvious glandular component, EGFR mutation heterogeneity were found in2specimens.Concludingly, a total of30%squamous-cell carcinoma specimens were found with glandular component with biomarker-assisted examination which is a precondition of driver mutation testing. The mutation spectrum of squamous-cell carcinomas with glandular component was similar to adenocarcinomas and predominantly found with EGFR, KRAS, BRAF, HER2, PIK3CA mutation and EML4-ALK fusion. While the pure squamous-cell carcinomas were lack of driver mutations and only AKT1, DDR2and PIK3CA testing should be performed. Considering the debate on heterogeneity in driver mutations, two component should be routinely included into analysis. For mutation-negative patients, metastatic lesions should be re-biopsied, examined and tested like the primaries. This study provided a clinical reference in targeted therapy screening with squamous-cell carcinomas.