Molecular characterization of lung squamous cell carcinoma tumors reveals therapeutically relevant alterations.

Asim Joshi,Amit Joshi,Nandini Menon,Vaishakhi Trivedi,Hitesh Kore,Vijay Patil,Pratik Chandrani,Vanita Noronha,Sanket Desai,Supriya Hait,Roma Sunder,Prajish Iyer,Kumar Prabhash,Anuradha Choughule,Rajiv Kumar,Amit Dutt,Rohit Mishra

doi:10.18632/oncotarget.27905

Abstract

Introduction: Unlike lung adenocarcinoma patients, there is no FDA-approved targeted-therapy likely to benefit lung squamous cell carcinoma patients.Materials and Methods: We performed survival analyses of lung squamous cell carcinoma patients harboring therapeutically relevant alterations identified by whole exome sequencing and mass spectrometry-based validation across 430 lung squamous tumors.Results: We report a mean of 11.6 mutations/Mb with a characteristic smoking signature along with mutations in TP53 (65%), CDKN2A (20%), NFE2L2 (20%), FAT1 (15%), KMT2C (15%), LRP1B (15%), FGFR1 (14%), PTEN (10%) and PREX2 (5%) among lung squamous cell carcinoma patients of Indian descent. In addition, therapeutically relevant EGFR mutations occur in 5.8% patients, significantly higher than as reported among Caucasians. In overall, our data suggests 13.5% lung squamous patients harboring druggable mutations have lower median overall survival, and 19% patients with a mutation in at least one gene, known to be associated with cancer, result in significantly shorter median overall survival compared to those without mutations. Conclusions: We present the first comprehensive landscape of genetic alterations underlying Indian lung squamous cell carcinoma patients and identify EGFR, PIK3CA, KRAS and FGFR1 as potentially important therapeutic and prognostic target.

Highlights

Unlike lung adenocarcinoma patients, there is no FDA-approved targeted-therapy likely to benefit lung squamous cell carcinoma patients
Non-small cell lung cancer (NSCLC), more common type of lung cancer, accounts for 85% of all lung cancers comprise of two major histological subtypes, adenocarcinoma and squamous cell carcinoma [2]
No approved targeted therapy regimens are available for lung squamous patients in spite of distinct genetic alterations identified in the tumor type, including alterations in TP53, PIK3CA, CDKN2A, MLL2, PTEN, KEAP1, NFE2L2,DDR2, FGFR1, PDGFRA, SOX2, and CCND1 [9,10,11,12,13,14,15]

Summary

Introduction

There is no FDA-approved targeted-therapy likely to benefit lung squamous cell carcinoma patients. Non-small cell lung cancer (NSCLC), more common type of lung cancer, accounts for 85% of all lung cancers comprise of two major histological subtypes, adenocarcinoma and squamous cell carcinoma [2]. Significant advances in the molecularly targeted therapies have been made to treat lung adenocarcinoma patients harboring mutant EGFR, ALK, RET, ROS1, BRAF, MET, NTRK-1 & 2, ERBB2, and FGFR3 [6,7,8]. No approved targeted therapy regimens are available for lung squamous patients in spite of distinct genetic alterations identified in the tumor type, including alterations in TP53, PIK3CA, CDKN2A, MLL2, PTEN, KEAP1, NFE2L2,DDR2, FGFR1, PDGFRA, SOX2, and CCND1 [9,10,11,12,13,14,15]. Most of the reported studies describe Caucasian, Chinese, Korean and Japanese population, with sparse information on the molecular profile of lung squamous patients of Indian origin that accounts for about 30% of Indian lung cancer disease [16]

Methods

Results

Conclusion