This is an archive of papers published by the staff and faculty of Fox Chase Cancer Center. For questions about content, please contact Talbot Research Library
Last updated on
Judd J , Abdel Karim N , Khan H , Naqash AR , Baca Y , Xiu J , VanderWalde AM , Mamdani H , Raez LE , Nagasaka M , Pai SG , Socinski MA , Nieva JJ , Kim C , Wozniak AJ , Ikpeazu C , de Lima Lopes G Jr , Spira AI , Korn WM , Kim ES , Liu SV , Borghaei H
Characterization of KRAS Mutation Subtypes in Non-small Cell Lung Cancer
Mol Cancer Ther. 2021 Sep 13
AbstractKRAS is the most commonly mutated oncogene in NSCLC and development of direct KRAS inhibitors has renewed interest in this molecular variant. Different KRAS mutations may represent a unique biologic context with different prognostic and therapeutic impact. We sought to characterize genomic landscapes of advanced, KRAS-mutated non-small cell lung cancer (NSCLC) in a large national cohort to help guide future therapeutic development.Molecular profiles of 17,095 NSCLC specimens were obtained using DNA next-generation sequencing of 592 genes (Caris Life Sciences) and classified on the basis of presence and subtype of KRAS mutations. Co-occurring genomic alterations, tumor mutational burden (TMB), and PD-L1 expression [22C3, tumor proportion score (TPS) score] were analyzed by KRAS mutation type.Across the cohort, 4,706 (27.5%) samples harbored a KRAS mutation. The most common subtype was G12C (40%), followed by G12V (19%) and G12D (15%). The prevalence of KRAS mutations was 37.2% among adenocarcinomas and 4.4% in squamous cell carcinomas. Rates of high TMB (≥10 mutations/Mb) and PD-L1 expression varied across KRAS mutation subtypes. KRAS G12C was the most likely to be PD-L1 positive (65.5% TPS ≥ 1%) and PD-L1 high (41.3% TPS ≥ 50%). STK11 was mutated in 8.6% of KRAS wild-type NSCLC but more frequent in KRAS-mutant NSCLC, with the highest rate in G13 (36.2%). TP53 mutations were more frequent in KRAS wild-type NSCLC (73.6%).KRAS mutation subtypes have different co-occurring mutations and a distinct genomic landscape. The clinical relevance of these differences in the context of specific therapeutic interventions warrants investigation.
Notes1538-8514 Judd, Julia Abdel Karim, Nagla Khan, Hina Naqash, Abdul Rafeh Orcid: 0000-0001-7622-720x Baca, Yasmine Xiu, Joanne VanderWalde, Ari M Orcid: 0000-0002-6842-2563 Mamdani, Hirva Orcid: 0000-0003-3874-8703 Raez, Luis E Orcid: 0000-0003-2669-5771 Nagasaka, Misako Orcid: 0000-0001-5308-615x Pai, Sachin Gopalkrishna Orcid: 0000-0002-6755-3895 Socinski, Mark A Nieva, Jorge J Orcid: 0000-0003-1605-4719 Kim, Chul Orcid: 0000-0003-0191-8684 Wozniak, Antoinette J Ikpeazu, Chukwuemeka de Lima Lopes, Gilberto Jr Spira, Alexander I Korn, W Michael Orcid: 0000-0002-0124-6841 Kim, Edward S Liu, Stephen V Orcid: 0000-0002-4852-3914 Borghaei, Hossein Journal Article United States Mol Cancer Ther. 2021 Sep 13. doi: 10.1158/1535-7163.MCT-21-0201.