TY - JOUR
T1 - Lung-MAP Next-Generation Sequencing Analysis of Advanced Squamous Cell Lung Cancers (SWOG S1400)
AU - Kozono, David
AU - Hua, Xing
AU - Wu, Michael C.
AU - Tolba, Khaled A.
AU - Waqar, Saiama N.
AU - Dragnev, Konstantin H.
AU - Cheng, Haiying
AU - Hirsch, Fred R.
AU - Mack, Philip C.
AU - Gray, Jhanelle E.
AU - Kelly, Karen
AU - Borghaei, Hossein
AU - Herbst, Roy S.
AU - Gandara, David R.
AU - Redman, Mary W.
N1 - Publisher Copyright:
© 2024 International Association for the Study of Lung Cancer
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
KW - Mutually exclusive gene sets (MEGS)
KW - Next generation sequencing
KW - PARP4
KW - Squamous cell lung cancer
UR - http://www.scopus.com/inward/record.url?scp=85202478753&partnerID=8YFLogxK
U2 - 10.1016/j.jtho.2024.07.024
DO - 10.1016/j.jtho.2024.07.024
M3 - Article
C2 - 39111731
AN - SCOPUS:85202478753
SN - 1556-0864
VL - 19
SP - 1618
EP - 1629
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
IS - 12
ER -