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Updated: Jun 17, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Lung-MAP Next-Generation Sequencing Analysis of Advanced Squamous Cell Lung Cancers (SWOG S1400)
David Kozono1, Xing Hua2, Michael C Wu2
1Department of Radiation Oncology, Dana-Farber Brigham Cancer Center, Boston, Massachusetts.
Introduction:
Squamous cell cancer (SqCC) is a lung cancer subtype with few targeted therapy options. Molecular characterization, that is, by next-generation sequencing (NGS), is needed to identify potential targets. Lung Cancer Master Protocol Southwest Oncology Group S1400 enrolled patients with previously treated stage IV or recurrent SqCC to assess NGS biomarkers for therapeutic sub-studies.
Methods:
Tumors underwent NGS using Foundation Medicine's FoundationOne research platform, which sequenced the exons and/or introns of 313 cancer-related genes. Mutually exclusive gene set analysis and Selected Events Linked by Evolutionary Conditions across Human Tumors were performed to identify mutually exclusive and co-occurring gene alterations. Comparisons were performed with data on 495 lung SqCC downloaded from The Cancer Genome Atlas. Cox proportional hazards models were used to assess associations between genetic variants and survival.
Results:
NGS data are reported for 1672 patients enrolled on S1400 between 2014 and 2019. Mutually exclusive gene set analysis identified two non-overlapping sets of mutually exclusive alterations with a false discovery rate of less than 15%: NFE2L2, KEAP1, and PARP4; and CDKN2A and RB1. PARP4, a relatively uncharacterized gene, showed three frequent mutations suggesting functional significance: 3116T>C (I1039T), 3176A>G (Q1059R), and 3509C>T (T1170I). When taken together, NFE2L2 and KEAP1 alterations were associated with poorer survival.
Conclusions:
As the largest dataset to date of lung SqCC profiled on a clinical trial, the S1400 NGS dataset establishes a rich resource for biomarker discovery. Mutual exclusivity of PARP4 and NFE2L2 or KEAP1 alterations suggests that PARP4 may have an uncharacterized role in a key pathway known to impact oxidative stress response and treatment resistance.
Insights
Next-generation sequencing (NGS) identified mutually exclusive gene alterations in squamous cell lung cancer (SqCC). PARP4 alterations co-occurred with NFE2L2/KEAP1, suggesting a role in treatment resistance.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Squamous cell cancer (SqCC) is a lung cancer subtype with limited targeted therapy options.
- Molecular characterization via next-generation sequencing (NGS) is crucial for identifying therapeutic targets in SqCC.
- The Lung Cancer Master Protocol S1400 study aimed to identify biomarkers in previously treated stage IV or recurrent SqCC.
Purpose of the Study:
- To perform molecular characterization of SqCC using NGS.
- To identify potential therapeutic targets and biomarkers for SqCC.
- To analyze gene alterations and their association with survival in SqCC patients.
Main Methods:
- Tumor samples underwent NGS using Foundation Medicine's FoundationOne platform, analyzing 313 cancer-related genes.
- Mutually exclusive gene set analysis and Selected Events Linked by Evolutionary Conditions across Human Tumors were employed to identify gene alteration patterns.
- Comparisons were made with The Cancer Genome Atlas (TCGA) lung SqCC data, and Cox proportional hazards models assessed survival associations.
Main Results:
- NGS data from 1672 S1400 patients revealed two sets of mutually exclusive alterations: {NFE2L2, KEAP1, PARP4} and {CDKN2A, RB1}.
- PARP4 exhibited frequent mutations (I1039T, Q1059R, T1170I), suggesting functional significance.
- Alterations in NFE2L2 and KEAP1 were associated with poorer survival outcomes.
Conclusions:
- The S1400 NGS dataset represents the largest molecular profile of SqCC from a clinical trial, serving as a valuable resource for biomarker discovery.
- The mutual exclusivity between PARP4 and NFE2L2/KEAP1 alterations indicates a potential uncharacterized role for PARP4 in pathways affecting oxidative stress response and treatment resistance.
