DNA strand with glowing markers

Squamous Cell Lung Cancer: Unlocking Genetic Secrets for Targeted Therapies

Soraya Malik in Health & Wellness July 2025 • 4 min read.

"A deep dive into the genetic landscape of squamous cell lung carcinoma (SqCLC) reveals new targets for precision medicine, offering hope for improved treatment strategies."

Lung cancer remains a leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) accounting for the majority of cases. Among NSCLCs, squamous cell lung carcinoma (SqCLC) represents a significant subtype, yet it has lagged behind in the era of targeted therapies that have transformed the treatment of adenocarcinoma.

Unlike adenocarcinoma, where mutations in genes like EGFR and ALK have led to the development of highly effective targeted drugs, SqCLC has lacked such clear-cut molecular targets. This disparity has driven researchers to delve deeper into the genetic profiles of SqCLC tumors, seeking vulnerabilities that can be exploited with new therapies.

Recent studies employing next-generation sequencing (NGS) have begun to unravel the complex genomic landscape of SqCLC, identifying recurrent mutations and copy number alterations in various genes. These findings hold promise for the development of personalized treatment strategies that can improve outcomes for patients with this challenging disease.

Decoding the Genetic Blueprint of SqCLC: What Did the Researchers Find?

A comprehensive study, published in Oncotarget in April 2016, meticulously analyzed the genetic profiles of 157 patients with surgically resected SqCLC. The researchers used NGS to identify mutations in 50 different genes, and fluorescence in situ hybridization (FISH) to detect copy number alterations (amplifications or deletions) in key genes. Immunohistochemistry (IHC) was used to assess the expression levels of proteins relevant to targeted therapy.

Here's a breakdown of the key findings:

Frequent Mutations: Somatic mutations were identified in 73.9% of the SqCLC cases examined.
Key Mutated Genes:
- TP53 (56.1%)
- CDKN2A (8.9%)
- PIK3CA (8.9%)
- KRAS (4.5%)
- EGFR (3.2%)
Copy Number Alterations: Significant gene copy number alterations were found in 75.8% of cases.
Key Genes with Copy Number Alterations:
- SOX2 amplification (31.2%)
- CDKN2A deletion (21.7%)
- PTEN deletion (16.6%)
- FGFR1 amplification (15.9%)
- EGFR amplification (14.0%)
- CCND1 amplification (14.0%)
- HER2 amplification (9.6%)
- PDGFRA amplification (7.6%)
Protein Expression: IHC analysis revealed the following protein expression patterns:
- VEGFR2 positive expression (80.5%)
- PD-L1 positive expression (47.2%)
- PTEN loss of expression (42.7%)
PD-L1 and Prognosis: Interestingly, positive expression of PD-L1 was associated with better disease-free survival (DFS), suggesting a potential role as a prognostic marker.

The study concluded that a remarkable 93.6% of SqCLC cases harbored at least one potentially druggable target based on these genetic and protein expression analyses.

The Future of SqCLC Treatment: Personalized Approaches on the Horizon

This study provides a crucial step forward in understanding the genetic complexity of SqCLC and identifying potential therapeutic targets. While further research is needed to translate these findings into clinical practice, the results suggest that personalized treatment strategies, tailored to the specific genetic alterations within each patient's tumor, hold great promise for improving outcomes in SqCLC. As new targeted agents and immunotherapies continue to be developed, comprehensive genomic profiling will play an increasingly important role in guiding treatment decisions and ultimately improving the lives of patients with this challenging disease.

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Everything You Need To Know

What is SqCLC, and why is it important to understand its genetic makeup?

SqCLC, or squamous cell lung carcinoma, is a significant subtype of non-small cell lung cancer (NSCLC). It's crucial to understand its genetic makeup because, unlike other NSCLC subtypes such as adenocarcinoma, effective targeted therapies have been lacking. Researchers are investigating the genetic profiles of SqCLC tumors to identify vulnerabilities that can be exploited with new therapies, ultimately aiming for personalized treatment strategies that can significantly improve patient outcomes. This approach contrasts with the successful targeted therapies available for other lung cancer types, such as those targeting EGFR and ALK mutations in adenocarcinoma.

Which genes are most frequently mutated in SqCLC, according to the study?

The study identified several frequently mutated genes in SqCLC. The most common mutation was in *TP53*, affecting 56.1% of cases. Other notable mutated genes included *CDKN2A* (8.9%), *PIK3CA* (8.9%), *KRAS* (4.5%), and *EGFR* (3.2%). These mutations represent potential targets for future therapies, highlighting the importance of genetic profiling in guiding treatment.

What are copy number alterations and which genes are commonly affected in SqCLC?

Copy number alterations refer to changes in the number of copies of a gene within a cell's DNA, such as amplification (increased copies) or deletion (decreased copies). In SqCLC, significant copy number alterations were found in 75.8% of cases. Key genes with copy number alterations include *SOX2* (amplification in 31.2% of cases), *CDKN2A* (deletion in 21.7%), *PTEN* (deletion in 16.6%), *FGFR1* (amplification in 15.9%), *EGFR* (amplification in 14.0%), *CCND1* (amplification in 14.0%), *HER2* (amplification in 9.6%), and *PDGFRA* (amplification in 7.6%). These alterations suggest potential targets for therapies designed to inhibit the amplified genes or restore the function of deleted ones.

How did the study use protein expression analysis and what were the key findings related to this?

The study utilized immunohistochemistry (IHC) to analyze protein expression levels in SqCLC tumors. The analysis revealed several key findings, including positive expression of VEGFR2 in 80.5% of cases, PD-L1 in 47.2%, and PTEN loss of expression in 42.7%. Notably, positive expression of PD-L1 was associated with better disease-free survival (DFS), suggesting it could serve as a prognostic marker. These protein expression patterns provide additional insights into the biology of SqCLC and help identify potential targets for therapies, such as those targeting the PD-L1 pathway.

What is the significance of the study's findings for the future of SqCLC treatment?

The study's findings are highly significant because they provide a deeper understanding of the genetic complexity of SqCLC and identify potential therapeutic targets. The study showed that a remarkable 93.6% of SqCLC cases harbored at least one potentially druggable target based on these genetic and protein expression analyses. This suggests that personalized treatment strategies, based on a patient's specific genetic profile, could significantly improve outcomes. The research emphasizes the need for comprehensive genomic profiling to guide treatment decisions and improve patient outcomes as new targeted agents and immunotherapies are developed.