Genomic landscape of clinically advanced KRAS wild-type pancreatic ductal adenocarcinoma

Frontiers in Oncology

Oncology

Daniel J. Zaccarini¹  Serenella Serinelli¹  Jeffrey S. Ross²  Natalie Danziger³  Richard Huang³  Tyler Janovitz³  Alina Basnet⁴  Stephen Graziano⁴  Prashanth Ashok Kumar⁴  Abirami Sivapiragasam⁴ 

[1] Department of Pathology, Upstate Medical University, Syracuse, NY, United States;Department of Pathology, Upstate Medical University, Syracuse, NY, United States;Foundation Medicine, Cambridge, MA, United States;Foundation Medicine, Cambridge, MA, United States;Upstate Cancer Center, Upstate Medical University, Syracuse, NY, United States;

关键词: pancreatic ductal adenocarcinoma;    KRAS;    KRAS;    genomic alterations;    targeted therapy;   

DOI  :  10.3389/fonc.2023.1169586

 received in 2023-02-19, accepted in 2023-06-07,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionKRAS mutation is a common occurrence in Pancreatic Ductal Adenocarcinoma (PDA) and is a driver mutation for disease development and progression. KRAS wild-type PDA may constitute a distinct molecular and clinical subtype. We used the Foundation one data to analyze the difference in Genomic Alterations (GAs) that occur in KRAS mutated and wild-type PDA.MethodsComprehensive genomic profiling (CGP) data, tumor mutational burden (TMB), microsatellite instability (MSI) and PD-L1 by Immunohistochemistry (IHC) were analyzed.Results and discussionOur cohort had 9444 cases of advanced PDA. 8723 (92.37%) patients had KRAS mutation. 721 (7.63%) patients were KRAS wild-type. Among potentially targetable mutations, GAs more common in KRAS wild-type included ERBB2 (mutated vs wild-type: 1.7% vs 6.8%, p <0.0001), BRAF (mutated vs wild-type: 0.5% vs 17.9%, p <0.0001), PIK3CA (mutated vs wild-type: 2.3% vs 6.5%, p <0.001), FGFR2 (mutated vs wild-type: 0.1% vs 4.4%, p <0.0001), ATM (mutated vs wild-type: 3.6% vs 6.8%, p <0.0001). On analyzing untargetable GAs, the KRAS mutated group had a significantly higher percentage of TP53 (mutated vs wild-type: 80.2% vs 47.6%, p <0.0001), CDKN2A (mutated vs wild-type: 56.2% vs 34.4%, p <0.0001), CDKN2B (mutated vs wild-type: 28.9% vs 23%, p =0.007), SMAD4 (mutated vs wild-type: 26.8% vs 15.7%, p <0.0001) and MTAP (mutated vs wild-type: 21.7% vs 18%, p =0.02). ARID1A (mutated vs wild-type: 7.7% vs 13.6%, p <0.0001 and RB1(mutated vs wild-type: 2% vs 4%, p =0.01) were more prevalent in the wild-type subgroup. Mean TMB was higher in the KRAS wild-type subgroup (mutated vs wild-type: 2.3 vs 3.6, p <0.0001). High TMB, defined as TMB > 10 mut/mB (mutated vs wild-type: 1% vs 6.3%, p <0.0001) and very-high TMB, defined as TMB >20 mut/mB (mutated vs wild-type: 0.5% vs 2.4%, p <0.0001) favored the wild-type. PD-L1 high expression was similar between the 2 groups (mutated vs wild-type: 5.7% vs 6%,). GA associated with immune checkpoint inhibitors (ICPIs) response including PBRM1 (mutated vs wild-type: 0.7% vs 3.2%, p <0.0001) and MDM2 (mutated vs wild-type: 1.3% vs 4.4%, p <0.0001) were more likely to be seen in KRAS wild-type PDA.

【 授权许可】

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Copyright © 2023 Ashok Kumar, Serinelli, Zaccarini, Huang, Danziger, Janovitz, Basnet, Sivapiragasam, Graziano and Ross