Identification of KRAS G12V associated clonal neoantigens and immune microenvironment in long-term survival of pancreatic adenocarcinoma

Chao Wang,Ying Yang,Wei Zhou,Fei Yuan,Ruyan Xie,Henghui Zhang,Jun Ji,Chenhong Peng,Chao Wu,Xianchao Guo,Lei Zhang,Min Shi,Jun Zhang

doi:10.1007/s00262-021-03012-4

Chao Wang, Ying Yang + Show 11 more

Open Access

https://doi.org/10.1007/s00262-021-03012-4

Copy DOI

Abstract

ObjectiveTo investigate the molecular characteristics in tumor immune microenvironment that affect long-term survival of patients with pancreatic adenocarcinoma (PAAD).MethodsThe tumor related genetic features of a female PAAD patient (over 13-year survival) who suffered from multiple recurrences and metastases, and six operations over one decade were investigated deeply. Genomic features and immune microenvironment signatures of her primary lesion as well as six metastatic tumors at different time-points were characterized.ResultsHigh-frequency clonal neoantigenic mutations identified in these specimens revealed the significant associations between clonal neoantigens with her prognosis after each surgery. Meanwhile, the TCGA and ICGC databases were employed to analyse the function of KRAS G12V in pancreatic cancer.ConclusionsThe genomic analysis of clonal neoantigens combined with tumor immune microenvironment could promote the understandings of personalized prognostic evaluation and the stratification of resected PAAD individuals with better outcome.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is one of the most notorious solid malignancies with the median overall survival (OS) less than 20 months after radical operation [1, 2]
The results showed that the pancreatic cancer patients belonging to K RAShigh expression group exhibited relatively shorter overall survival time (P = 0.0011, HR = 1.03, 95% CI: 1.01–1.05), shorter disease-specific survival time (P = 0.00045, HR = 1.04, 95% CI: 1.01–1.06), shorter disease-free interval time (P = 0.00089, HR = 1.06, 95% CI = 1.02–1.1) and shorter progression-free interval time (P = 0.0011, HR = 1.02, 95% CI = 1–1.04), compared with KRASlow expression group (Figure S1B-E)
Combining KRASG12V and TP53 wild-type (TP53WT) into consideration, we found that KRASG12V and TP53WT patients have significantly better prognosis compared with patients with other mutation types of KRAS and TP53WT in TCGA-pancreatic adenocarcinoma (PAAD) and ICGCPAAD cohorts (TCGA/KRASG12V&TP53WT: P = 0.017, ICGC/KRASG12V&TP53WT: P = 0.00068; Fig. 5e&f and additional Tables 4&5)

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is one of the most notorious solid malignancies with the median overall survival (OS) less than 20 months after radical operation [1, 2]. The factors affecting long-term survivors (LTSs) of PDAC are still poorly understood. Paniccia et al reported the survival data of 431 long-term survivors with over 10-year survival among 11,081 PDAC patients underwent radical pancreatectomy, indicating that the involvement status of lymph nodes, adjuvant chemotherapy, as well as the pathologic T stage acted as the predictive factors for LTSs [3]. The possibility of long-term survival in PDAC patients could not be excluded according to the positive nodes or the tumor size, which implied some unknown factors simultaneously affected LTSs beyond our knowledge. Sequencing analyses of 35 resected PDAC patients survived over 10 years revealed that no significant difference in somatic alterations between LTSs and control arms, suggested that the mutation status of common driver genes might not be the determinant of PDAC LTSs[5]

Methods

Results

Conclusion