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Global gene expression profiling reveals a suppressed immune response pathway associated with 3q amplification in
Jun Qian1, Yong Zou1, Jing Wang2
1Thoracic Program at the Vanderbilt Ingram Cancer Center, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Nashville, TN, USA.
Abstract:
Chromosome 3q26-28 is a critical region of genomic amplification in non-small cell lung cancer (NSCLC), particularly lung squamous cell carcinomas (SCCs). No molecular therapeutic target has shown clinical utility for SCC, in contrast with adenocarcinomas of the lung. To identify novel candidate drivers in this region, we performed both Array Comparative Genomic Hybridization (array CGH, Agilent Human Genome CGH 244A oligo-microarrays) and Gene Expression Microarray (Agilent Human Gene Expression 4 × 44 K microarray) on 24 untreated lung SCC specimens. Using our previously published integrative genomics approach, we identified 12 top amplified driver genes within this region that are highly correlated and overexpressed in lung SCC. We further demonstrated one of the 12 top amplified driver Fragile X mental retardation-related protein 1 (FXR1) as a novel cancer gene in NSCLC and FXR1 executes its regulatory function by forming a novel complex with two other oncogenes, protein kinase C, iota ( PRKCI) and epithelial cell transforming 2 (ECT2) within the same amplicon in lung cancer cell. Here we report that immune response pathways are significantly suppressed in lung SCC and negatively associated with 3q driver gene expression, implying a potential role of 3q drivers in cancer immune-surveillance. In light of the attractive immunotherapy strategy using blockade of negative regulators of T cell function for multiple human cancer including lung SCC, our findings may provide a rationale for targeting 3q drivers in combination of immunotherapies for human tumors harboring the 3q amplicon. The data have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE40089.
Insights
Genomic amplifications in non-small cell lung cancer (NSCLC) squamous cell carcinoma (SCC) involve chromosome 3q drivers. These drivers, including FXR1, suppress immune responses, suggesting combined targeting with immunotherapy for better treatment outcomes.
Area of Science:
- Oncology
- Genomics
- Cancer Research
Background:
- Chromosome 3q26-28 amplifications are common in non-small cell lung cancer (NSCLC), especially lung squamous cell carcinomas (SCCs).
- Unlike lung adenocarcinomas, SCCs lack clinically validated molecular therapeutic targets.
- Identifying novel drivers in the 3q amplicon is crucial for developing targeted therapies for SCC.
Purpose of the Study:
- To identify novel amplified driver genes within the 3q26-28 region in lung SCC.
- To investigate the functional role of identified drivers, such as Fragile X mental retardation-related protein 1 (FXR1), in NSCLC.
- To explore the relationship between 3q driver gene expression and immune response pathways in lung SCC.
Main Methods:
- Array Comparative Genomic Hybridization (array CGH) and Gene Expression Microarray analysis were performed on 24 untreated lung SCC specimens.
- An integrative genomics approach was used to identify amplified and overexpressed genes within the 3q26-28 region.
- Protein-protein interactions were investigated to understand the functional complex of FXR1 with PRKCI and ECT2.
Main Results:
- Twelve top amplified driver genes in the 3q26-28 region were identified, showing high correlation and overexpression in lung SCC.
- Fragile X mental retardation-related protein 1 (FXR1) was confirmed as a novel cancer gene in NSCLC, forming a complex with PRKCI and ECT2.
- Immune response pathways were found to be significantly suppressed in lung SCC and negatively associated with 3q driver gene expression.
Conclusions:
- The 3q amplicon harbors multiple driver genes, including FXR1, PRKCI, and ECT2, which play a significant role in lung SCC development.
- Suppression of immune response pathways by 3q drivers suggests their involvement in cancer immune-surveillance evasion.
- Targeting 3q drivers in combination with immunotherapies may offer a novel therapeutic strategy for NSCLC patients with 3q amplicon.
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