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Updated: Jul 6, 2025
Comparative Lesions Analysis Through a Targeted Sequencing Approach
Published on: November 5, 2019
Digging into the NGS Information from a Large-Scale South European Population with Metastatic/Unresectable Pancreatic
Dimitrios C Ziogas1, Eirini Papadopoulou2, Helen Gogas1
1First Department of Internal Medicine, Laikon General Hospital, School of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece.
Abstract:
Despite ongoing oncological advances, pancreatic ductal adenocarcinoma (PDAC) continues to have an extremely poor prognosis with limited targeted and immunotherapeutic options. Its genomic background has not been fully characterized yet in large-scale populations all over the world. Methods: Replicating a recent study from China, we collected tissue samples from consecutive Greek patients with pathologically-confirmed metastatic/unresectable PDAC and retrospectively investigated their genomic landscape using next generation sequencing (NGS). Findings: From a cohort of 409 patients, NGS analysis was successfully achieved in 400 cases (56.50% males, median age: 61.8 years). Consistent with a previous study, KRAS was the most frequently mutated gene in 81.50% of tested samples, followed by TP53 (50.75%), CDKN2 (8%), and SMAD4 (7.50%). BRCA1/2 variants with on-label indications were detected in 2%, and 87.50% carried a variant associated with off-label treatment (KRAS, ERBB2, STK11, or HRR-genes), while 3.5% of the alterations had unknown/preliminary-studied actionability (TP53/CDKN2A). Most of HRR-alterations were in intermediate- and low-risk genes (CHEK2, RAD50, RAD51, ATM, FANCA, FANCL, FANCC, BAP1), with controversial actionability: 8% harbored a somatic non-BRCA1/2 alteration, 6 cases had a high-risk alteration (PALB2, RAD51C), and one co-presented a PALB2/BRCA2 alteration. Elevated LOH was associated with HRR-mutated status and TP53 mutations while lowered LOH was associated with KRAS alterations. Including TMB/MSI data, the potential benefit from an NGS-oriented treatment was increased from 1.91% to 13.74% (high-MSI: 0.3%, TMB > 10 muts/MB: 12.78%). TMB was slightly increased in females (4.75 vs. 4.46 muts/MB) and in individuals with age > 60 (4.77 vs. 4.40 muts/MB). About 28.41% showed PD-L1 > 1% either in tumor or immune cells, 15.75% expressed PD-L1 ≥ 10%, and only 1.18% had PD-L1 ≥ 50%. This is the largest depiction of real-world genomic characteristics of European patients with PDAC, which offers some useful clinical and research insights.
Insights
This study analyzed the genomic landscape of 400 Greek pancreatic ductal adenocarcinoma (PDAC) patients using next-generation sequencing (NGS). Findings reveal common mutations like KRAS and TP53, with potential for NGS-guided treatments in 13.74% of cases.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis and limited treatment options.
- The genomic landscape of PDAC is not fully characterized globally.
- Understanding PDAC genomics is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the genomic landscape of Greek PDAC patients.
- To identify actionable mutations for potential targeted or immunotherapeutic strategies.
- To replicate and expand upon previous PDAC genomic studies.
Main Methods:
- Collected tissue samples from 409 Greek patients with metastatic/unresectable PDAC.
- Performed next-generation sequencing (NGS) on 400 patient samples.
- Analyzed gene mutations, including KRAS, TP53, CDKN2A, SMAD4, BRCA1/2, and HRR-genes, alongside TMB, MSI, and PD-L1 expression.
Main Results:
- KRAS (81.50%) and TP53 (50.75%) were the most frequent mutations.
- Actionable variants (on-label or off-label) were found in 89.50% of patients.
- Potential benefit from NGS-oriented treatment increased to 13.74% when including TMB/MSI data; PD-L1 expression varied, with 28.41% showing >1%.
Conclusions:
- This study provides the largest genomic profile of European PDAC patients to date.
- Identified a significant proportion of patients with actionable mutations, suggesting potential for NGS-guided therapy.
- Genomic insights can inform clinical decisions and future research for PDAC treatment.
