Ashok Kumar Prashanth, Serinelli Serenella, Zaccarini Daniel J, Huang Richard, Danziger Natalie, Janovitz Tyler, Basnet Alina, Sivapiragasam Abirami, Graziano Stephen, Ross Jeffrey S
Upstate Cancer Center, Upstate Medical University, Syracuse, NY, United States.
Department of Pathology, Upstate Medical University, Syracuse, NY, United States.
Front Oncol. 2023 Jun 19;13:1169586. doi: 10.3389/fonc.2023.1169586. eCollection 2023.
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.
Comprehensive genomic profiling (CGP) data, tumor mutational burden (TMB), microsatellite instability (MSI) and PD-L1 by Immunohistochemistry (IHC) were analyzed.
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.
KRAS突变在胰腺导管腺癌（PDA）中很常见，是疾病发生和进展的驱动突变。KRAS野生型PDA可能构成一种独特的分子和临床亚型。我们使用Foundation one数据来分析KRAS突变型和野生型PDA中发生的基因组改变（GA）的差异。
分析了综合基因组图谱（CGP）数据、肿瘤突变负担（TMB）、微卫星不稳定性（MSI）以及通过免疫组织化学（IHC）检测的PD-L1。
我们的队列中有9444例晚期PDA患者。8723例（92.37%）患者存在KRAS突变。721例（7.63%）患者为KRAS野生型。在潜在可靶向突变中，KRAS野生型中更常见的GA包括ERBB2（突变型与野生型：1.7%对6.8%，p<0.0001）、BRAF（突变型与野生型：0.5%对17.9%，p<0.0001）、PIK3CA（突变型与野生型：2.3%对6.5%，p<0.001）、FGFR2（突变型与野生型：0.1%对4.4%，p<0.0001）、ATM（突变型与野生型：3.6%对6.8%，p<0.0001）。在分析不可靶向GA时，KRAS突变组中TP53（突变型与野生型：80.2%对47.6%，p<0.0001）、CDKN2A（突变型与野生型：56.2%对34.4%，p<0.0001）、CDKN2B（突变型与野生型：28.9%对23%，p =0.007）、SMAD4（突变型与野生型：26.8%对15.7%，p<0.0001）和MTAP（突变型与野生型：21.7%对18%，p =0.02）的百分比显著更高。ARID1A（突变型与野生型：7.7%对13.6%，p<0.0001）和RB1（突变型与野生型：2%对4%，p =0.01）在野生型亚组中更普遍。KRAS野生型亚组的平均TMB更高（突变型与野生型：2.3对3.6，p<0.0001）。高TMB（定义为TMB>10 mut/mB，突变型与野生型：1%对6.3%，p<0.0001）和非常高TMB（定义为TMB>20 mut/mB，突变型与野生型：0.5%对2.4%，p<0.0001）有利于野生型。两组之间的PD-L1高表达相似（突变型与野生型：5.7%对6%）。与免疫检查点抑制剂（ICPI）反应相关的GA，包括PBRM1（突变型与野生型：0.7%对3.2%，p<0.0001）和MDM2（突变型与野生型：1.3%对4.4%，p<0.0001）在KRAS野生型PDA中更可能出现。
