Proteogenomic analysis reveals Arp 2/3 complex as a common molecular mechanism in high risk pancreatic cysts and pancreatic cancer

Sep 23, 2026

Proteogenomic analysis investigates how benign pancreatic cysts may progress to pancreatic cancer (PC), focusing on intraductal papillary mucinous neoplasms (IPMNs). Using genome-wide association studies (GWAS), the study identifies significant variants linked to benign cysts and variants distinguishing PC from benign cysts. Integrated gene analyses highlight the Arp 2/3 complex and show its associated genes are upregulated in PC and vary across tumor cell types, implicating roles in the tumor microenvironment. Results support Arp 2/3 complex genes as potential biomarkers for malignant transformation and targets for early detection and therapy.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages13

Reading Time33 min

AccessFree to download

Background

Rationale for early diagnosis

IPMN dysplasia progression to cancer

Study approach

GWAS discovery of cyst-associated variants

Case-control comparison to highlight PC-associated variants

Gene integration and molecular mechanism discovery

Findings and implications

Arp 2/3 complex upregulation in PC

Tumor microenvironment involvement across cell types

Potential biomarkers for malignant transformation

[www. nature.com/scientificreports](www. nature.com/scientificreports) OPEN Proteogenomic analysis reveals Arp 2/3 complex as a common molecular mechanism in high risk pancreatic cysts and pancreatic cancer A. K. M. Firoj Mahmud1,4, Dina Gamaleldin Mansour Aly1,4, Yelin Zhao1, Mikael Benson1, Martin Smelik1, Oleg Sysoev2, Hui Wang1,3 & Xinxiu Li1􀀍 Pancreatic cysts, particularly intraductal papillary mucinous neoplasms (IPMNs), pose a potential risk for progressing to pancreatic cancer (PC). This study investigates the genetic architecture of benign pancreatic cysts and its potential connection to PC using genome-wide association studies (GWAS) . The discovery GWAS identified significant genetic variants associated with benign cysts, specifically the rs142409042 variant near the OPCML gene. A pairwise GWAS comparing PC to benign cysts revealed the rs7190458 variant near the BCAR1 and CTRB1 genes. Further analysis with identified GWAS genes highlighted the Actin Related Protein (Arp) 2/3 complex as a potentially important molecular mechanism connecting benign cysts and PC. The Arp2/3 complex-associated genes were significantly upregulated in PC, suggesting their role in the malignant transformation of pancreatic cysts. Differential expression of these genes was observed across various cell types in PC, indicating their involvement in the tumor microenvironment. These findings suggest that the Arp2/3 complexassociated genes can serve as potential biomarkers for predicting the malignant transformation of pancreatic cysts, opening new avenues for targeted therapies and early detection strategies. Pancreatic cysts are increasingly detected by different imaging methods. The majority of the cysts are benign, but a subset has the potential to progress to pancreatic cancer (PC)1,2. PC is associated with a highly lethal malignant transformation and a poor prognosis. Thus, early diagnosis of pancreatic cysts that do or do not increase risk of malignancy is of great clinical importance. However, only about 0.25% of pancreatic cysts identified incidentally are cancerous, and less than 0.25% of these benign cysts transform into cancer within a year of their discovery 3. The transformation of pancreatic cysts from intraductal papillary mucinous neoplasms (IPMNs) to PC is often characterized by a sequence of dysplastic stages. It begins with low-grade dysplasia (LGD), advances to high-grade dysplasia (HGD), and invasive IPMN, which may ultimately lead to PC4. LGD represents an early, less severe form of pre-cancerous alteration, characterized by minimal cellular abnormalities. As the dysplasia progresses to HGD, the abnormalities become more pronounced, indicating a higher risk of transitioning to an invasive cancer. This progression highlights the critical need to monitor and understand the molecular and genetic architecture changes occurring within IPMNs. The presence of HGD is a strong predictor of the potential for malignancy and serves as an indicator for surgical intervention4. Desipte advances in surgical thechniques, systemic treatment options for PC remain limited. Converntional chemotherapy and radiotherapy can only slightly prolong life expectancy by a few months5. Novel treatments, including targeted therapies, immunotherapy and optimized nutrution have been investigated to improve patient outcomes6–11. 1Medical Digital Twin Research Group, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden. 2Division of Statistics and Machine Learning, Department of Computer and Information Science, Linköping University, Linköping, Sweden. 3Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou 221000, Jiangsu, China. 4A. K. M. Firoj Mahmud and Dina Gamaleldin Mansour Aly contributed equally to this work. 􀀍 email: [xinxiu.li@ki.se](xinxiu.li@ki.se) [www. nature.com/scientificreports/](www. n

FAQs

What disease transition does the study focus on?

The study focuses on how benign pancreatic cysts, especially IPMNs, can progress through dysplastic stages and transform into pancreatic cancer.

Which genetic variants were identified by the GWAS analyses?

The discovery GWAS highlighted a variant rs142409042 near the OPCML gene for benign cysts, and a pairwise GWAS comparing PC to benign cysts identified rs7190458 near BCAR1 and CTRB1.

Why is the Arp 2/3 complex considered important in PC?

Integrated analyses indicate Arp 2/3 complex-associated genes are upregulated in pancreatic cancer and show differential expression across multiple PC cell types, suggesting involvement in malignant transformation and the tumor microenvironment.

Sep 23, 2026

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