Oncotarget: Lung squamous cell carcinoma tumors reveal therapeutic alterations

Oncotarget published "Molecular characterization of lung squamous cell carcinoma tumors reveals therapeutically relevant alterations" which reported that unlike lung adenocarcinoma patients, there is no FDA-approved targeted-therapy likely to benefit lung squamous cell carcinoma patients.

The authors 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.

They report a mean of 11.6 mutations/Mb with a characteristic smoking signature along with mutations in TP53, CDKN2A, NFE2L2, FAT1, KMT2C, LRP1B, FGFR1, PTEN and PREX2 among lung squamous cell carcinoma patients of Indian descent.

In overall, the 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.

They 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.

Dr. Amit Dutt and Dr. Kumar Prabhash said, "Lung cancer is the leading cause of cancer-related deaths across the globe with more than 1.7 million deaths annually."

"Lung cancer is the leading cause of cancer-related deaths across the globe with more than 1.7 million deaths annually."

Non-small cell lung cancer, a more common type of lung cancer, accounts for 85% of all lung cancers comprising two major histological subtypes, adenocarcinoma and squamous cell carcinoma.

The adenocarcinoma of the lung arises mostly in patients with no previous significant tobacco exposure, while the squamous subtype is found almost exclusively in former or current smokers with relatively higher overall mutational load.

However, 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.

Figure 4: Overall survival in lung squamous tumors with distinct gene alterations. Kaplan-Meier plots of overall survival (in days) in lung squamous tumors with mutations in (A) Druggable genes and (B) any gene are shown. The orange and green lines denote mutated and wild-type patients respectively. The dotted lines indicate median overall survival of the respective groups. P-value is indicated on the top right corner of the plots. The number of patients and median survival in each group is mentioned in the table below.

Moreover, 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.

In this study, the authors sought to describe the first genetic landscape of alterations underlying 430 Indian lung squamous genomes and uncover the prevalence of known targetable somatic alterations using next generation sequencing followed by validation using mass spectrometry.

The Dutt/Prabhash Research Team concluded in their Oncotarget Research Output, "we present a striking variation of genetic heterogeneity among lung squamous cell carcinoma patients of Indian descent. The findings from this study extend the scope of the ongoing umbrella clinical trials such as the Lung-MAP master protocol that aims to evaluate multiple targeted therapeutic strategies in lung squamous cell carcinoma patients and the AACR Project GENIE database collaborative project [29, 39]. A systematic exploration of these target genes in lung squamous cell carcinoma patients and variability across ethnicity could further extend our insights into the etiology of lung squamous cancer."

DOI - https://doi.org/10.18632/oncotarget.27905

Full text - https://www.oncotarget.com/article/27905/text/

Correspondence to - Amit Dutt - adutt@actrec.gov.in and Kumar Prabhash - kprabhash1@gmail.com

Keywords - lung squamous carcinoma, genetic alterations, druggable mutations, whole exome sequencing, mass spectrometry

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