April E Deveaux1, Tyler A Allen2, Muthana Al Abo2, Xiaodi Qin3, Dadong Zhang3, Brendon M Patierno1, Lin Gu2, Jhanelle E Gray4, Chad V Pecot5, Holly K Dressman6, Shannon J McCall7, Rick A Kittles8, Terry Hyslop9, Kouros Owzar9, Jeffrey Crawford10, Steven R Patierno10, Jeffrey M Clarke10, Jennifer A Freedman11. 1. Department of Medicine, Division of Medical Oncology, Duke University School of Medicine, Durham, NC, 27710, USA. 2. Duke Cancer Institute, Duke University School of Medicine, Durham, NC, 27710, USA. 3. Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, 27710, USA. 4. Department of Thoracic Oncology, Moffitt Cancer Center, Tampa, FL, 33612, USA. 5. Department of Medicine, Division of Hematology/Oncology, University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, 27599, USA. 6. Duke Cancer Institute, Duke University School of Medicine, Durham, NC, 27710, USA; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, 27710, USA. 7. Department of Pathology, Duke University School of Medicine, Durham, NC, 27710, USA. 8. Department of Population Sciences, Division of Health Equities, City of Hope National Medical Center, Duarte, CA, 91010, USA. 9. Duke Cancer Institute, Duke University School of Medicine, Durham, NC, 27710, USA; Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, 27710, USA. 10. Department of Medicine, Division of Medical Oncology, Duke University School of Medicine, Durham, NC, 27710, USA; Duke Cancer Institute, Duke University School of Medicine, Durham, NC, 27710, USA. 11. Department of Medicine, Division of Medical Oncology, Duke University School of Medicine, Durham, NC, 27710, USA; Duke Cancer Institute, Duke University School of Medicine, Durham, NC, 27710, USA. Electronic address: jennifer.freedman@duke.edu.
Abstract
OBJECTIVES: Despite disparities in lung cancer incidence and mortality, the molecular landscape of lung cancer in patients of African ancestry remains underexplored, and race-related differences in RNA splicing remain unexplored. MATERIALS AND METHODS: We identified differentially spliced genes (DSGs) and differentially expressed genes (DEGs) in biobanked lung squamous cell carcinoma (LUSC) between patients of West African and European ancestry, using ancestral genotyping and Affymetrix Clariom D array. DSGs and DEGs were validated independently using the National Cancer Institute Genomic Data Commons. Associated biological processes, overlapping canonical pathways, enriched gene sets, and cancer relevance were identified using Gene Ontology Consortium, Ingenuity Pathway Analysis, Gene Set Enrichment Analysis, and CancerMine, respectively. Association with LUSC survival was conducted using The Cancer Genome Atlas. RESULTS: 4,829 DSGs and 267 DEGs were identified, including novel targets in NSCLC as well as genes identified previously to have relevance to NSCLC. RNA splicing events within 3 DSGs as well as 1 DEG were validated in the independent cohort. 853 DSGs and 29 DEGs have been implicated as potential drivers, oncogenes and/or tumor suppressor genes. Biological processes enriched among DSGs and DEGs included metabolic process, biological regulation, and multicellular organismal process and, among DSGs, ion transport. Overlapping canonical pathways among DSGs included neuronal signaling pathways and, among DEGs, cell metabolism involving biosynthesis. Gene sets enriched among DSGs included KRAS Signaling, UV Response, E2 F Targets, Glycolysis, and Coagulation. 355 RNA splicing events within DSGs and 18 DEGs show potential association with LUSC patient survival. CONCLUSION: These DSGs and DEGs, which show potential biological and clinical relevance, could have the ability to drive novel biomarker and therapeutic development to mitigate LUSC disparities.
OBJECTIVES: Despite disparities in lung cancer incidence and mortality, the molecular landscape of lung cancer in patients of African ancestry remains underexplored, and race-related differences in RNA splicing remain unexplored. MATERIALS AND METHODS: We identified differentially spliced genes (DSGs) and differentially expressed genes (DEGs) in biobanked lung squamous cell carcinoma (LUSC) between patients of West African and European ancestry, using ancestral genotyping and Affymetrix Clariom D array. DSGs and DEGs were validated independently using the National Cancer Institute Genomic Data Commons. Associated biological processes, overlapping canonical pathways, enriched gene sets, and cancer relevance were identified using Gene Ontology Consortium, Ingenuity Pathway Analysis, Gene Set Enrichment Analysis, and CancerMine, respectively. Association with LUSC survival was conducted using The Cancer Genome Atlas. RESULTS: 4,829 DSGs and 267 DEGs were identified, including novel targets in NSCLC as well as genes identified previously to have relevance to NSCLC. RNA splicing events within 3 DSGs as well as 1 DEG were validated in the independent cohort. 853 DSGs and 29 DEGs have been implicated as potential drivers, oncogenes and/or tumor suppressor genes. Biological processes enriched among DSGs and DEGs included metabolic process, biological regulation, and multicellular organismal process and, among DSGs, ion transport. Overlapping canonical pathways among DSGs included neuronal signaling pathways and, among DEGs, cell metabolism involving biosynthesis. Gene sets enriched among DSGs included KRAS Signaling, UV Response, E2 F Targets, Glycolysis, and Coagulation. 355 RNA splicing events within DSGs and 18 DEGs show potential association with LUSC patient survival. CONCLUSION: These DSGs and DEGs, which show potential biological and clinical relevance, could have the ability to drive novel biomarker and therapeutic development to mitigate LUSC disparities.
Authors: Aravind Subramanian; Pablo Tamayo; Vamsi K Mootha; Sayan Mukherjee; Benjamin L Ebert; Michael A Gillette; Amanda Paulovich; Scott L Pomeroy; Todd R Golub; Eric S Lander; Jill P Mesirov Journal: Proc Natl Acad Sci U S A Date: 2005-09-30 Impact factor: 11.205
Authors: Matthew E Ritchie; Belinda Phipson; Di Wu; Yifang Hu; Charity W Law; Wei Shi; Gordon K Smyth Journal: Nucleic Acids Res Date: 2015-01-20 Impact factor: 16.971
Authors: Joshua D Campbell; Christopher Lathan; Lynette Sholl; Matthew Ducar; Mikenah Vega; Ashwini Sunkavalli; Ling Lin; Megan Hanna; Laura Schubert; Aaron Thorner; Nicholas Faris; David R Williams; Raymond U Osarogiagbon; Paul van Hummelen; Matthew Meyerson; Laura MacConaill Journal: JAMA Oncol Date: 2017-06-01 Impact factor: 31.777
Authors: Justin Goodwin; Michael L Neugent; Shin Yup Lee; Joshua H Choe; Hyunsung Choi; Dana M R Jenkins; Robin J Ruthenborg; Maddox W Robinson; Ji Yun Jeong; Masaki Wake; Hajime Abe; Norihiko Takeda; Hiroko Endo; Masahiro Inoue; Zhenyu Xuan; Hyuntae Yoo; Min Chen; Jung-Mo Ahn; John D Minna; Kristi L Helke; Pankaj K Singh; David B Shackelford; Jung-Whan Kim Journal: Nat Commun Date: 2017-05-26 Impact factor: 14.919
Authors: Bi-Dar Wang; Kristin Ceniccola; SuJin Hwang; Ramez Andrawis; Anelia Horvath; Jennifer A Freedman; Jacqueline Olender; Stefan Knapp; Travers Ching; Lana Garmire; Vyomesh Patel; Mariano A Garcia-Blanco; Steven R Patierno; Norman H Lee Journal: Nat Commun Date: 2017-06-30 Impact factor: 14.919
Authors: Steven S Coughlin; Patricia Matthews-Juarez; Paul D Juarez; Courtnee E Melton; Mario King Journal: Cancer Med Date: 2014-09-14 Impact factor: 4.452
Authors: Wenjun Yang; Hongliang Liu; Ruoxin Zhang; Jennifer A Freedman; Younghun Han; Rayjean J Hung; Yonathan Brhane; John McLaughlin; Paul Brennan; Heike Bickeboeller; Albert Rosenberger; Richard S Houlston; Neil E Caporaso; Maria Teresa Landi; Irene Brueske; Angela Risch; David C Christiani; Christopher I Amos; Xiaoxin Chen; Steven R Patierno; Qingyi Wei Journal: NPJ Precis Oncol Date: 2022-06-30
Authors: Muthana Al Abo; Terry Hyslop; Xiaodi Qin; Kouros Owzar; Daniel J George; Steven R Patierno; Jennifer A Freedman Journal: Genomics Date: 2021-03-08 Impact factor: 5.736