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. 2023 Jun 19:13:1169586.
doi: 10.3389/fonc.2023.1169586. eCollection 2023.

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

Prashanth Ashok Kumar  1 , Serenella Serinelli  2 , Daniel J Zaccarini  2 , Richard Huang  3 , Natalie Danziger  3 , Tyler Janovitz  3 , Alina Basnet  1 , Abirami Sivapiragasam  1 , Stephen Graziano  1 , Jeffrey S Ross  2   3
Affiliations

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

Prashanth Ashok Kumar et al. Front Oncol. .

Abstract

Introduction: KRAS 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.

Methods: Comprehensive genomic profiling (CGP) data, tumor mutational burden (TMB), microsatellite instability (MSI) and PD-L1 by Immunohistochemistry (IHC) were analyzed.

Results and discussion: Our 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.

Keywords: KRAS mutation; KRAS wild-type pancreatic cancer; genomic alterations; pancreatic ductal adenocarcinoma; targeted therapy.

PubMed Disclaimer

Conflict of interest statement

All Foundation Medicine co-authors disclose that they are employees of Foundation Medicine and own shares in Roche Holdings. Authors affiliated with Upstate have no conflict of interest to disclose.

Figures

Figure 1
Figure 1
Long tail plot of GA in KRAS Wild-Type PDA.
Figure 2
Figure 2
Long Tail Plot of GA in KRAS mutated PDA.
Figure 3
Figure 3
Distribution of major KRAS short variant alterations in 13,953 PDAs. Sample size is different from the cohort used in our study and includes earlier versions of the Foundation One CDx test with different/smaller bait sets.
Figure 4
Figure 4
(A) Hematoxylin and eosin: histology of the tumor. (B) IGV View of KRAS G12C mutation.
Figure 5
Figure 5
(A) Hematoxylin and eosin: histology of the tumor. (B) ERBB2 amplification at 148 copies.
See this image and copyright information in PMC

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