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Zaccaria GM, Altini N, Mongelli V, Marino F, Bevilacqua V. Development and validation of a machine learning prognostic model based on an epigenomic signature in patients with pancreatic ductal adenocarcinoma. Int J Med Inform 2025; 199:105883. [PMID: 40157244 DOI: 10.1016/j.ijmedinf.2025.105883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 02/18/2025] [Accepted: 03/19/2025] [Indexed: 04/01/2025]
Abstract
BACKGROUND In Pancreatic Ductal Adenocarcinoma (PDAC), current prognostic scores are unable to fully capture the biological heterogeneity of the disease. While some approaches investigating the role of multi-omics in PDAC are emerging, the analysis of methylation data is under exploited. MATERIALS AND METHODS We analyzed CpG sites from two publicly available datasets, the TCGA-PAAD used as discovery set and the CPTAC-PDA as external test set. Single mutations and co-mutation of KRAS and TP53 genes were identified as targets, and differentially methylated CpG sites (DMC) were detected accordingly. We trained and validated Random Forest (RF) models to predict each target. Area Under the Receiver Operating Characteristic curve (AUROC) and Area Under the Precision-Recall curve (AUPRC) were used as performance metrics. Then, we performed consensus clustering from the DMCs to identify novel patients' profiles. Finally, we trained and validated a combination of eXtreme Gradient Boosting (XGB) and tree models to select an epigenomic prognostic determinant. RESULTS From 598 DMCs extracted, an RF model predicted KRAS and TP53 co-mutation on the external test set with AUROC of 0.77 and AUPRC of 0.87. The consensus clustering allowed us to identify 4 clusters (C1, C2, C3, and C4) of patients. The C4 cluster captured a subgroup of patients with favorable Overall Survival (OS) with respect to others. The XGB model perfectly predicted C4 vs other clusters on the discovery set. In both cohorts, patients were stratified into two risk groups according to methylation levels of cg16854533, individuated as the most important CpG site. CONCLUSION We analyzed methylation data to develop a classifier for the TP53 and KRAS mutational status. Four prognostic clusters were pointed out and a prognostic model using a CpG site was validated in an independent cohort. Our results evidence that the proposed use of methylation data facilitates risk stratification for PDAC.
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Affiliation(s)
- Gian Maria Zaccaria
- Department of Electrical and Information Engineering (DEI), Polytechnic University of Bari, Via Edoardo Orabona, 4, Bari 70126, Italy
| | - Nicola Altini
- Department of Electrical and Information Engineering (DEI), Polytechnic University of Bari, Via Edoardo Orabona, 4, Bari 70126, Italy.
| | - Valentina Mongelli
- Department of Electrical and Information Engineering (DEI), Polytechnic University of Bari, Via Edoardo Orabona, 4, Bari 70126, Italy
| | - Francescomaria Marino
- Department of Electrical and Information Engineering (DEI), Polytechnic University of Bari, Via Edoardo Orabona, 4, Bari 70126, Italy
| | - Vitoantonio Bevilacqua
- Department of Electrical and Information Engineering (DEI), Polytechnic University of Bari, Via Edoardo Orabona, 4, Bari 70126, Italy
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Berloco F, Zaccaria GM, Altini N, Colucci S, Bevilacqua V. A multimodal framework for assessing the link between pathomics, transcriptomics, and pancreatic cancer mutations. Comput Med Imaging Graph 2025; 123:102526. [PMID: 40107149 DOI: 10.1016/j.compmedimag.2025.102526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 02/10/2025] [Accepted: 03/05/2025] [Indexed: 03/22/2025]
Abstract
In Pancreatic Ductal Adenocarcinoma (PDAC), predicting genetic mutations directly from histopathological images using Deep Learning can provide valuable insights. The combination of several omics can provide further knowledge on mechanisms underlying tumor biology. This study aimed at developing an explainable multimodal pipeline to predict genetic mutations for the KRAS, TP53, SMAD4, and CDKN2A genes, integrating pathomic features with transcriptomics from two independent datasets, the TCGA-PAAD, assumed as training set, and the CPTAC-PDA, as external validation set. Large and small configurations of CLAM (Clustering-constrained Attention Multiple Instance Learning) models were evaluated with three different feature extractors (ResNet50, UNI, and CONCH). RNA-seq data were pre-processed both conventionally and using three autoencoder architectures. The processed transcript panels were input into machine learning (ML) models for mutation classification. Attention maps and SHAP were employed, highlighting significant features from both data modalities. A fusion layer or a voting mechanism combined the outputs from pathomic and transcriptomic models, obtaining a multimodal prediction. Performance comparisons were assessed by Area Under Receiver Operating Characteristic (AUROC) and Precision-Recall (AUPRC) curves. On the validation set, for KRAS, multimodal ML achieved 0.92 of AUROC and 0.98 of AUPRC. For TP53, the multimodal voting model achieved 0.75 of AUROC and 0.85 of AUPRC. For SMAD4 and CDKN2A, transcriptomic ML models achieved AUROC of 0.71 and 0.65, while multimodal ML showed AUPRC of 0.39 and 0.37, respectively. This approach demonstrated the potential of combining pathomics with transcriptomics, offering an interpretable framework for predicting key genetic mutations in PDAC.
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Affiliation(s)
- Francesco Berloco
- Department of Electrical and Information Engineering (DEI), Polytechnic University of Bari, Via Edoardo Orabona, 4, Bari 70126, Italy
| | - Gian Maria Zaccaria
- Department of Electrical and Information Engineering (DEI), Polytechnic University of Bari, Via Edoardo Orabona, 4, Bari 70126, Italy
| | - Nicola Altini
- Department of Electrical and Information Engineering (DEI), Polytechnic University of Bari, Via Edoardo Orabona, 4, Bari 70126, Italy.
| | - Simona Colucci
- Department of Electrical and Information Engineering (DEI), Polytechnic University of Bari, Via Edoardo Orabona, 4, Bari 70126, Italy
| | - Vitoantonio Bevilacqua
- Department of Electrical and Information Engineering (DEI), Polytechnic University of Bari, Via Edoardo Orabona, 4, Bari 70126, Italy
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Antony V, Sun T, Dolezal D, Cai G. Comprehensive Molecular Profiling of Metastatic Pancreatic Adenocarcinomas. Cancers (Basel) 2025; 17:335. [PMID: 39941707 PMCID: PMC11815932 DOI: 10.3390/cancers17030335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Revised: 01/16/2025] [Accepted: 01/19/2025] [Indexed: 02/16/2025] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed late, with an extremely poor prognosis. Treatment options like surgery, radiation, and chemotherapy are rarely curative. Tumor progression from primary to metastatic PDAC remains poorly understood at the molecular level. METHODS In the current study, we analyzed the molecular profiles of metastatic PDAC obtained via the Oncomine Comprehensive Assay in comparison to primary PDAC. RESULTS The current study cohort consisted of 115 metastatic PDAC cases, of which 71 (62%) cases succeeded in molecular testing while the remaining 44 (38%) cases contained insufficient tumor cells. Molecular profiling of 71 cases revealed a total of 239 molecular alterations, 3.4 alterations per case on average, predominantly in the form of gene mutations. The most common gene mutations included KRAS (86%) and TP53 (83%) mutations. Gene copy number alterations were also detected in 19 (27%) cases involving genes such as CCNE1 and ERBB2. Compared to the molecular profiles of primary PDAC reported in our prior study and TCGA database, there seemed to be increased rates of TP53, ARID1A, BRAF, and PIK3CA mutations in the metastatic diseases. CONCLUSIONS These findings suggest that metastatic PDAC possesses unique genetic characteristics, offering potential therapeutic targets in advanced-stage pancreatic cancer.
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Affiliation(s)
- Vijay Antony
- Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA; (V.A.); (T.S.); (D.D.)
| | - Tong Sun
- Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA; (V.A.); (T.S.); (D.D.)
| | - Darin Dolezal
- Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA; (V.A.); (T.S.); (D.D.)
| | - Guoping Cai
- Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA; (V.A.); (T.S.); (D.D.)
- Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA
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4
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Zhou C, Feng Z, Qian W, Zhu Z, Cao R, Wang Q, Zhang W, Liu R, Wu S, Hao J, Wang Z, Ma Q, Wu Z, Li X. Elevated SREBP1 accelerates the initiation and growth of pancreatic cancer by targeting SOX9. Biol Direct 2025; 20:6. [PMID: 39806513 PMCID: PMC11731174 DOI: 10.1186/s13062-025-00595-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 01/03/2025] [Indexed: 01/16/2025] Open
Abstract
Pancreatic cancer is a lethal disease with an insidious onset, and little is known about its early molecular events. Here, we found that the sterol regulatory element-binding protein 1 (SREBP1) expression is gradually upregulated during the initiation of pancreatic cancer. Through in vitro 3D culture of pancreatic acinar cells and experiments in LSL-KrasG12D/+;Pdx1-Cre (KC) mice, we found that pharmacological inhibition of SREBP1 suppressed pancreatic tumorigenesis. In vitro, either knockdown or pharmacological inhibition of SREBP1 suppressed tumor proliferation but SREBP1 overexpression promoted tumor proliferation. In LSL-KrasG12D/+;Trp53fl/+;Pdx1-Cre (KPC) mice, we confirmed the tumor-promoting role of SREBP1 in pancreatic cancer progression. Mechanistically, we revealed SOX9 as a downstream target of SREPB1. SREBP1 inhibition decreased SOX9 expression in both acinar cells and pancreatic cancer cells. Indeed, we identified SREBP1 binding sites in the SOX9 promoter region and reported that SOX9 is transcriptionally regulated by SREBP1. Taken together, our findings demonstrate that SREBP1/SOX9 inhibition suppresses pancreatic cancer initiation and growth, suggesting that SREBP1 could serve as a potential target for cancer screening and treatment.
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Affiliation(s)
- Cancan Zhou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China
- Pancreas Center, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Zhengyuan Feng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China
- Pancreas Center, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Weikun Qian
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China
- Pancreas Center, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Zeen Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China
- Pancreas Center, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Ruiqi Cao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China
- Pancreas Center, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Qiqi Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China
- Pancreas Center, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Wunai Zhang
- Department of General Surgery, Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, China
| | - Rujuan Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China
- Pancreas Center, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Shuai Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China
- Pancreas Center, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Jie Hao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China
- Pancreas Center, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Zheng Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China
- Pancreas Center, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Qingyong Ma
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China
- Pancreas Center, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Zheng Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China.
- Pancreas Center, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
| | - Xuqi Li
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China.
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Matykiewicz J, Adamus-Białek W, Wawszczak-Kasza M, Molasy B, Kołomańska M, Oblap R, Madej Ł, Kozieł D, Głuszek S. The known genetic variants of BRCA1, BRCA2 and NOD2 in pancreatitis and pancreatic cancer risk assessment. Sci Rep 2025; 15:1791. [PMID: 39805914 PMCID: PMC11729861 DOI: 10.1038/s41598-025-86249-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 01/09/2025] [Indexed: 01/16/2025] Open
Abstract
The single nucleotide polymorphism in NOD2 (rs2066847) is associated with conditions that may predispose to the development of gastrointestinal disorders, as well as the known BRCA1 and BRCA2 variants classified as risk factors in many cancers. In our study, we analyzed these variants in a group of patients with pancreatitis and pancreatic cancer to clarify their role in pancreatic disease development. The DNA was isolated from whole blood samples of 553 patients with pancreatitis, 83 patients with pancreatic cancer, 44 cases of other pancreatic diseases, and 116 healthy volunteers. The NOD2 (rs2066847), BRCA1 (rs80357914) and BRCA2 (rs276174813) were genotyped. The statistically significant 3-fold increased risk of pancreatic cancer was detected among the patients with rs2066847 polymorphism (OR = 2.77, p-value = 0.019). We did not find the studied polymorphisms in BRCA1 (rs80357914) and BRCA2 (rs276174813). However, the adjacent polymorphisms have been detected only in patients with pancreatic diseases. The studied variant in NOD2 occurs more frequently in pancreatic patients and significantly increases the risk of pancreatic cancer. It can be considered as a genetic risk factor that predisposes to cancer development. The analyzed regions in BRCA1 and BRCA2 may be a potential target in further search for a genetic marker of pancreatic diseases.
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Affiliation(s)
- Jarosław Matykiewicz
- Institute of Medical Sciences, Jan Kochanowski University of Kielce, Kielce, Poland
| | | | | | - Bartosz Molasy
- Institute of Medical Sciences, Jan Kochanowski University of Kielce, Kielce, Poland
| | - Magdalena Kołomańska
- Institute of Medical Sciences, Jan Kochanowski University of Kielce, Kielce, Poland
| | - Rusłan Oblap
- Institute of Medical Sciences, Jan Kochanowski University of Kielce, Kielce, Poland
| | - Łukasz Madej
- Institute of Medical Sciences, Jan Kochanowski University of Kielce, Kielce, Poland
| | - Dorota Kozieł
- Institute of Medical Sciences, Jan Kochanowski University of Kielce, Kielce, Poland
| | - Stanisław Głuszek
- Institute of Medical Sciences, Jan Kochanowski University of Kielce, Kielce, Poland
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Zaccaria GM, Berloco F, Buongiorno D, Brunetti A, Altini N, Bevilacqua V. A time-dependent explainable radiomic analysis from the multi-omic cohort of CPTAC-Pancreatic Ductal Adenocarcinoma. COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE 2024; 257:108408. [PMID: 39342876 DOI: 10.1016/j.cmpb.2024.108408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 07/05/2024] [Accepted: 09/04/2024] [Indexed: 10/01/2024]
Abstract
BACKGROUND AND OBJECTIVE In Pancreatic Ductal Adenocarcinoma (PDA), multi-omic models are emerging to answer unmet clinical needs to derive novel quantitative prognostic factors. We realized a pipeline that relies on survival machine-learning (SML) classifiers and explainability based on patients' follow-up (FU) to stratify prognosis from the public-available multi-omic datasets of the CPTAC-PDA project. MATERIALS AND METHODS Analyzed datasets included tumor-annotated radiologic images, clinical, and mutational data. A feature selection was based on univariate (UV) and multivariate (MV) survival analyses according to Overall Survival (OS) and recurrence (REC). In this study, we considered seven multi-omic datasets and compared four SML classifiers: Cox, survival random forest, generalized boosted, and support vector machines (SVM). For each classifier, we assessed the concordance (C) index on the validation set. The best classifiers for the validation set on both OS and REC underwent explainability analyses using SurvSHAP(t), which extends SHapley Additive exPlanations (SHAP). RESULTS According to OS, after UV and MV analyses we selected 18/37 and 10/37 multi-omic features, respectively. According to REC, based on UV and MV analyses we selected 10/35 and 5/35 determinants, respectively. Generally, SML classifiers including radiomics outperformed those modelled on clinical or mutational predictors. For OS, the Cox model encompassing radiomic, clinical, and mutational features reached 75 % of C index, outperforming other classifiers. On the other hand, for REC, the SVM model including only radiomics emerged as the best-performing, with 68 % of C index. For OS, SurvSHAP(t) identified the first order Median Gray Level (GL) intensities, the gender, the tumor grade, the Joint Energy GL Co-occurrence Matrix (GLCM), and the GLCM Informational Measures of Correlations of type 1 as the most important features. For REC, the first order Median GL intensities, the GL size zone matrix Small Area Low GL Emphasis, and first order variance of GL intensities emerged as the most discriminative. CONCLUSIONS In this work, radiomics showed the potential for improving patients' risk stratification in PDA. Furthermore, a deeper understanding of how radiomics can contribute to prognosis in PDA was achieved with a time-dependent explainability of the top multi-omic predictors.
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Affiliation(s)
- Gian Maria Zaccaria
- Department of Electrical and Information Engineering (DEI), Polytechnic University of Bari, Via Edoardo Orabona, 4, Bari, 70126, Italy
| | - Francesco Berloco
- Department of Electrical and Information Engineering (DEI), Polytechnic University of Bari, Via Edoardo Orabona, 4, Bari, 70126, Italy.
| | - Domenico Buongiorno
- Department of Electrical and Information Engineering (DEI), Polytechnic University of Bari, Via Edoardo Orabona, 4, Bari, 70126, Italy; Apulian Bioengineering srl, Via delle Violette, 14, Modugno, 70026, Italy
| | - Antonio Brunetti
- Department of Electrical and Information Engineering (DEI), Polytechnic University of Bari, Via Edoardo Orabona, 4, Bari, 70126, Italy; Apulian Bioengineering srl, Via delle Violette, 14, Modugno, 70026, Italy
| | - Nicola Altini
- Department of Electrical and Information Engineering (DEI), Polytechnic University of Bari, Via Edoardo Orabona, 4, Bari, 70126, Italy
| | - Vitoantonio Bevilacqua
- Department of Electrical and Information Engineering (DEI), Polytechnic University of Bari, Via Edoardo Orabona, 4, Bari, 70126, Italy; Apulian Bioengineering srl, Via delle Violette, 14, Modugno, 70026, Italy
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Kinny-Köster B, Ahmad Y, Pflüger MJ, Habib JR, Fujikura K, Hutchings D, Cameron JL, Shubert CR, Lafaro KJ, Burkhart RA, Burns WR, Javed AA, Yu J, Hruban RH, Wood LD, Thompson ED, He J. Clinical Relevance of Cancerization of Ducts in Resected Pancreatic Ductal Adenocarcinoma. Pancreas 2024; 53:e528-e536. [PMID: 38888841 DOI: 10.1097/mpa.0000000000002326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/20/2024]
Abstract
OBJECTIVES Although prevalent in 50%-90% of pancreatic ductal adenocarcinomas, the clinical relevance of "cancerization of ducts" (COD) remains unknown. METHODS Pathologists retrospectively reviewed slides classifying prevalence of COD. Histopathological parameters, location of first recurrence, recurrence-free survival (RFS), and overall survival (OS) were collected from the institutional pancreatectomy registry. RESULTS Among 311 pancreatic ductal adenocarcinomas, COD was present in 216 (69.5%) and more prevalent in the cohort that underwent upfront surgery (75.3% vs 63.1%, P = 0.019). Furthermore, COD was associated with female gender (P = 0.040), advanced T stage (P = 0.007), perineural invasion (P = 0.014), lymphovascular invasion (P = 0.025), and R1 margin (P = 0.009), but not N stage (P = 0.401) or tumor differentiation (P = 0.717). In multivariable regression, COD was associated with less liver recurrence (odds ratio, 0.44; P < 0.005). This association was driven by the cohort of patients who had received preoperative treatment (odds ratio, 0.18; P < 0.001). COD was not predictive for RFS or OS. CONCLUSIONS Cancerization of ducts was not associated with RFS or OS. Currently underrecognized, standardized implementation into histopathological reports may have merit, and further mechanistic scientific experiments need to illuminate its clinical and biologic impact.
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Affiliation(s)
- Benedict Kinny-Köster
- From the Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Yembur Ahmad
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Michael J Pflüger
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Joseph R Habib
- From the Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Kohei Fujikura
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Danielle Hutchings
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - John L Cameron
- From the Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Christopher R Shubert
- From the Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Kelly J Lafaro
- From the Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Richard A Burkhart
- From the Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - William R Burns
- From the Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Ammar A Javed
- From the Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Jun Yu
- From the Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Ralph H Hruban
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Laura D Wood
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Elizabeth D Thompson
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Jin He
- From the Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
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8
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D’Amora P, Silva IDCG, Evans SS, Nagourney AJ, Kirby KA, Herrmann B, Cavalheiro D, Francisco FR, Bernard PJ, Nagourney RA. Diagnostic and Prognostic Performance of Metabolic Signatures in Pancreatic Ductal Adenocarcinoma: The Clinical Application of Quantitative NextGen Mass Spectrometry. Metabolites 2024; 14:148. [PMID: 38535308 PMCID: PMC10972340 DOI: 10.3390/metabo14030148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 02/20/2024] [Accepted: 02/27/2024] [Indexed: 10/24/2024] Open
Abstract
With 64,050 new diagnoses and 50,550 deaths in the US in 2023, pancreatic ductal adenocarcinoma (PDAC) is among the most lethal of all human malignancies. Early detection and improved prognostication remain critical unmet needs. We applied next-generation metabolomics, using quantitative tandem mass spectrometry on plasma, to develop biochemical signatures that identify PDAC. We first compared plasma from 10 PDAC patients to 169 samples from healthy controls. Using metabolomic algorithms and machine learning, we identified ratios that incorporate amino acids, biogenic amines, lysophosphatidylcholines, phosphatidylcholines and acylcarnitines that distinguished PDAC from normal controls. A confirmatory analysis then applied the algorithms to 30 PDACs compared with 60 age- and sex-matched controls. Metabolic signatures were then analyzed to compare survival, measured in months, from date of diagnosis to date of death that identified metabolite ratios that stratified PDACs into distinct survival groups. The results suggest that metabolic signatures could provide PDAC diagnoses earlier than tumor markers or radiographic measures and offer insights into disease severity that could allow more judicious use of therapy by stratifying patients into metabolic-risk subgroups.
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Affiliation(s)
- Paulo D’Amora
- Metabolomycs, Inc., 750 E. 29th Street, Long Beach, CA 90806, USA; (P.D.); (I.D.C.G.S.); (S.S.E.); (P.J.B.)
- Nagourney Cancer Institute, 750 E. 29th Street, Long Beach, CA 90806, USA; (A.J.N.); (B.H.); (D.C.); (F.R.F.)
- Gynecology Department, School of Medicine of the Federal University of São Paulo (EPM-UNIFESP), Rua Pedro de Toledo 781—4th Floor, São Paulo 04039-032, SP, Brazil
| | - Ismael D. C. G. Silva
- Metabolomycs, Inc., 750 E. 29th Street, Long Beach, CA 90806, USA; (P.D.); (I.D.C.G.S.); (S.S.E.); (P.J.B.)
- Gynecology Department, School of Medicine of the Federal University of São Paulo (EPM-UNIFESP), Rua Pedro de Toledo 781—4th Floor, São Paulo 04039-032, SP, Brazil
| | - Steven S. Evans
- Metabolomycs, Inc., 750 E. 29th Street, Long Beach, CA 90806, USA; (P.D.); (I.D.C.G.S.); (S.S.E.); (P.J.B.)
- Nagourney Cancer Institute, 750 E. 29th Street, Long Beach, CA 90806, USA; (A.J.N.); (B.H.); (D.C.); (F.R.F.)
| | - Adam J. Nagourney
- Nagourney Cancer Institute, 750 E. 29th Street, Long Beach, CA 90806, USA; (A.J.N.); (B.H.); (D.C.); (F.R.F.)
| | - Katharine A. Kirby
- Center for Statistical Consulting, Department of Statistics, University of California Irvine, (UC Irvine), 843 Health Science Rd., Irvine, CA 92697, USA;
| | - Brett Herrmann
- Nagourney Cancer Institute, 750 E. 29th Street, Long Beach, CA 90806, USA; (A.J.N.); (B.H.); (D.C.); (F.R.F.)
| | - Daniela Cavalheiro
- Nagourney Cancer Institute, 750 E. 29th Street, Long Beach, CA 90806, USA; (A.J.N.); (B.H.); (D.C.); (F.R.F.)
| | - Federico R. Francisco
- Nagourney Cancer Institute, 750 E. 29th Street, Long Beach, CA 90806, USA; (A.J.N.); (B.H.); (D.C.); (F.R.F.)
| | - Paula J. Bernard
- Metabolomycs, Inc., 750 E. 29th Street, Long Beach, CA 90806, USA; (P.D.); (I.D.C.G.S.); (S.S.E.); (P.J.B.)
- Nagourney Cancer Institute, 750 E. 29th Street, Long Beach, CA 90806, USA; (A.J.N.); (B.H.); (D.C.); (F.R.F.)
| | - Robert A. Nagourney
- Metabolomycs, Inc., 750 E. 29th Street, Long Beach, CA 90806, USA; (P.D.); (I.D.C.G.S.); (S.S.E.); (P.J.B.)
- Nagourney Cancer Institute, 750 E. 29th Street, Long Beach, CA 90806, USA; (A.J.N.); (B.H.); (D.C.); (F.R.F.)
- Department of Obstetrics and Gynecology, University of California Irvine (UC Irvine), 101 The City Dr S, Orange, CA 92868, USA
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9
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Lih TM, Cao L, Minoo P, Omenn GS, Hruban RH, Chan DW, Bathe OF, Zhang H. Detection of Pancreatic Ductal Adenocarcinoma-Associated Proteins in Serum. Mol Cell Proteomics 2024; 23:100687. [PMID: 38029961 PMCID: PMC10792492 DOI: 10.1016/j.mcpro.2023.100687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Revised: 11/14/2023] [Accepted: 11/24/2023] [Indexed: 12/01/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancer types, partly because it is frequently identified at an advanced stage, when surgery is no longer feasible. Therefore, early detection using minimally invasive methods such as blood tests may improve outcomes. However, studies to discover molecular signatures for the early detection of PDAC using blood tests have only been marginally successful. In the current study, a quantitative glycoproteomic approach via data-independent acquisition mass spectrometry was utilized to detect glycoproteins in 29 patient-matched PDAC tissues and sera. A total of 892 N-linked glycopeptides originating from 141 glycoproteins had PDAC-associated changes beyond normal variation. We further evaluated the specificity of these serum-detectable glycoproteins by comparing their abundance in 53 independent PDAC patient sera and 65 cancer-free controls. The PDAC tissue-associated glycoproteins we have identified represent an inventory of serum-detectable PDAC-associated glycoproteins as candidate biomarkers that can be potentially used for the detection of PDAC using blood tests.
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Affiliation(s)
- T Mamie Lih
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
| | - Liwei Cao
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Parham Minoo
- Department of Pathology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Gilbert S Omenn
- Departments of Computational Medicine & Bioinformatics, Internal Medicine, Human Genetics, and School of Public Health, University of Michigan, Ann Arbor, Michigan, USA
| | - Ralph H Hruban
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA; The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, Maryland, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Daniel W Chan
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Oliver F Bathe
- Departments of Surgery and Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Hui Zhang
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
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10
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Oketch DJA, Giulietti M, Piva F. Copy Number Variations in Pancreatic Cancer: From Biological Significance to Clinical Utility. Int J Mol Sci 2023; 25:391. [PMID: 38203561 PMCID: PMC10779192 DOI: 10.3390/ijms25010391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 12/20/2023] [Accepted: 12/24/2023] [Indexed: 01/12/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, characterized by high tumor heterogeneity and a poor prognosis. Inter- and intra-tumoral heterogeneity in PDAC is a major obstacle to effective PDAC treatment; therefore, it is highly desirable to explore the tumor heterogeneity and underlying mechanisms for the improvement of PDAC prognosis. Gene copy number variations (CNVs) are increasingly recognized as a common and heritable source of inter-individual variation in genomic sequence. In this review, we outline the origin, main characteristics, and pathological aspects of CNVs. We then describe the occurrence of CNVs in PDAC, including those that have been clearly shown to have a pathogenic role, and further highlight some key examples of their involvement in tumor development and progression. The ability to efficiently identify and analyze CNVs in tumor samples is important to support translational research and foster precision oncology, as copy number variants can be utilized to guide clinical decisions. We provide insights into understanding the CNV landscapes and the role of both somatic and germline CNVs in PDAC, which could lead to significant advances in diagnosis, prognosis, and treatment. Although there has been significant progress in this field, understanding the full contribution of CNVs to the genetic basis of PDAC will require further research, with more accurate CNV assays such as single-cell techniques and larger cohorts than have been performed to date.
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Affiliation(s)
| | - Matteo Giulietti
- Department of Specialistic Clinical and Odontostomatological Sciences, Polytechnic University of Marche, 60131 Ancona, Italy
| | - Francesco Piva
- Department of Specialistic Clinical and Odontostomatological Sciences, Polytechnic University of Marche, 60131 Ancona, Italy
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11
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Ziogas DC, Papadopoulou E, Gogas H, Sakellariou S, Felekouras E, Theocharopoulos C, Stefanou DT, Theochari M, Boukovinas I, Matthaios D, Koumarianou A, Zairi E, Liontos M, Koutsoukos K, Metaxa-Mariatou V, Kapetsis G, Meintani A, Tsaousis GN, Nasioulas G. Digging into the NGS Information from a Large-Scale South European Population with Metastatic/Unresectable Pancreatic Ductal Adenocarcinoma: A Real-World Genomic Depiction. Cancers (Basel) 2023; 16:2. [PMID: 38201431 PMCID: PMC10778112 DOI: 10.3390/cancers16010002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 12/06/2023] [Accepted: 12/11/2023] [Indexed: 01/12/2024] Open
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.
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Affiliation(s)
- Dimitrios C. Ziogas
- First Department of Internal Medicine, Laikon General Hospital, School of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece; (H.G.); (C.T.); (D.T.S.); (M.T.)
| | - Eirini Papadopoulou
- GeneKor Medical S.A., 15344 Gerakas, Greece; (E.P.); (V.M.-M.); (G.K.); (A.M.); (G.N.T.); (G.N.)
| | - Helen Gogas
- First Department of Internal Medicine, Laikon General Hospital, School of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece; (H.G.); (C.T.); (D.T.S.); (M.T.)
| | - Stratigoula Sakellariou
- First Department of Pathology, School of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Evangellos Felekouras
- First Department of Surgery, Laikon General Hospital, School of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Charalampos Theocharopoulos
- First Department of Internal Medicine, Laikon General Hospital, School of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece; (H.G.); (C.T.); (D.T.S.); (M.T.)
| | - Dimitra T. Stefanou
- First Department of Internal Medicine, Laikon General Hospital, School of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece; (H.G.); (C.T.); (D.T.S.); (M.T.)
| | - Maria Theochari
- First Department of Internal Medicine, Laikon General Hospital, School of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece; (H.G.); (C.T.); (D.T.S.); (M.T.)
| | - Ioannis Boukovinas
- Department of Medical Oncology, Bioclinic Hospital, 54622 Thessaloniki, Greece;
| | | | - Anna Koumarianou
- Hematology Oncology Unit, Fourth Department of Internal Medicine, School of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Eleni Zairi
- Oncology Department, St. Lukes Hospital, 55236 Thessaloniki, Greece;
| | - Michalis Liontos
- Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece; (M.L.); (K.K.)
| | - Konstantinos Koutsoukos
- Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece; (M.L.); (K.K.)
| | - Vasiliki Metaxa-Mariatou
- GeneKor Medical S.A., 15344 Gerakas, Greece; (E.P.); (V.M.-M.); (G.K.); (A.M.); (G.N.T.); (G.N.)
| | - George Kapetsis
- GeneKor Medical S.A., 15344 Gerakas, Greece; (E.P.); (V.M.-M.); (G.K.); (A.M.); (G.N.T.); (G.N.)
| | - Angeliki Meintani
- GeneKor Medical S.A., 15344 Gerakas, Greece; (E.P.); (V.M.-M.); (G.K.); (A.M.); (G.N.T.); (G.N.)
| | - Georgios N. Tsaousis
- GeneKor Medical S.A., 15344 Gerakas, Greece; (E.P.); (V.M.-M.); (G.K.); (A.M.); (G.N.T.); (G.N.)
| | - George Nasioulas
- GeneKor Medical S.A., 15344 Gerakas, Greece; (E.P.); (V.M.-M.); (G.K.); (A.M.); (G.N.T.); (G.N.)
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12
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Bararia A, Das A, Mitra S, Banerjee S, Chatterjee A, Sikdar N. Deoxyribonucleic acid methylation driven aberrations in pancreatic cancer-related pathways. World J Gastrointest Oncol 2023; 15:1505-1519. [PMID: 37746645 PMCID: PMC10514732 DOI: 10.4251/wjgo.v15.i9.1505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 05/29/2023] [Accepted: 08/01/2023] [Indexed: 09/13/2023] Open
Abstract
Pancreatic cancer (PanCa) presents a catastrophic disease with poor overall survival at advanced stages, with immediate requirement of new and effective treatment options. Besides genetic mutations, epigenetic dysregulation of signaling pathway-associated enriched genes are considered as novel therapeutic target. Mechanisms beneath the deoxyribonucleic acid methylation and its utility in developing of epi-drugs in PanCa are under trails. Combinations of epigenetic medicines with conventional cytotoxic treatments or targeted therapy are promising options to improving the dismal response and survival rate of PanCa patients. Recent studies have identified potentially valid pathways that support the prediction that future PanCa clinical trials will include vigorous testing of epigenomic therapies. Epigenetics thus promises to generate a significant amount of new knowledge of biological and medical importance. Our review could identify various components of epigenetic mechanisms known to be involved in the initiation and development of pancreatic ductal adenocarcinoma and related precancerous lesions, and novel pharmacological strategies that target these components could potentially lead to breakthroughs. We aim to highlight the possibilities that exist and the potential therapeutic interventions.
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Affiliation(s)
- Akash Bararia
- Human Genetics Unit, Indian Statistical Institute, Kolkata 700108, India
| | - Amlan Das
- Department of Biochemistry, Royal Global University, Assam 781035, India
| | - Sangeeta Mitra
- Department of Biochemistry and Biophysics, University of Kalyani, West Bengal 741235, India
| | - Sudeep Banerjee
- Department of Gastrointestinal Surgery, Tata Medical Center, Kolkata 700160, India
| | - Aniruddha Chatterjee
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand
- School of Health Sciences and Technology, University of Petroleum and Energy Studies, Dehradun 248007, India
| | - Nilabja Sikdar
- Human Genetics Unit, Indian Statistical Institute, Kolkata 700108, India
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13
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Zhu YH, Zheng JH, Jia QY, Duan ZH, Yao HF, Yang J, Sun YW, Jiang SH, Liu DJ, Huo YM. Immunosuppression, immune escape, and immunotherapy in pancreatic cancer: focused on the tumor microenvironment. Cell Oncol (Dordr) 2023; 46:17-48. [PMID: 36367669 DOI: 10.1007/s13402-022-00741-1] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/26/2022] [Indexed: 11/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is characterized by poor treatment response and low survival time. The current clinical treatment for advanced PDAC is still not effective. In recent years, the research and application of immunotherapy have developed rapidly and achieved substantial results in many malignant tumors. However, the translational application in PDAC is still far from satisfactory and needs to be developed urgently. To carry out the study of immunotherapy, it is necessary to fully decipher the immune characteristics of PDAC. This review summarizes the recent progress of the tumor microenvironment (TME) of PDAC and highlights its link with immunotherapy. We describe the molecular cues and corresponding intervention methods, collate several promising targets and progress worthy of further study, and put forward the importance of integrated immunotherapy to provide ideas for future research of TME and immunotherapy of PDAC.
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Affiliation(s)
- Yu-Heng Zhu
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Jia-Hao Zheng
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Qin-Yuan Jia
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Zong-Hao Duan
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Hong-Fei Yao
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Jian Yang
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Yong-Wei Sun
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China.
| | - Shu-Heng Jiang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 800 Dongchuan Road, 200240, People's Republic of China.
| | - De-Jun Liu
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China.
| | - Yan-Miao Huo
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China.
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14
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Li QK, Hu Y, Chen L, Schnaubelt M, Cui Zhou D, Li Y, Lu RJH, Thiagarajan M, Hostetter G, Newton CJ, Jewell SD, Omenn G, Robles AI, Mesri M, Bathe OF, Zhang B, Ding L, Hruban RH, Chan DW, Zhang H. Neoplastic cell enrichment of tumor tissues using coring and laser microdissection for proteomic and genomic analyses of pancreatic ductal adenocarcinoma. Clin Proteomics 2022; 19:36. [PMID: 36266629 DOI: 10.1186/s12014-022-09373-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 09/26/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The identification of differentially expressed tumor-associated proteins and genomic alterations driving neoplasia is critical in the development of clinical assays to detect cancers and forms the foundation for understanding cancer biology. One of the challenges in the analysis of pancreatic ductal adenocarcinoma (PDAC) is the low neoplastic cellularity and heterogeneous composition of bulk tumors. To enrich neoplastic cells from bulk tumor tissue, coring, and laser microdissection (LMD) sampling techniques have been employed. In this study, we assessed the protein and KRAS mutation changes associated with samples obtained by these enrichment techniques and evaluated the fraction of neoplastic cells in PDAC for proteomic and genomic analyses. METHODS Three fresh frozen PDAC tumors and their tumor-matched normal adjacent tissues (NATs) were obtained from three sampling techniques using bulk, coring, and LMD; and analyzed by TMT-based quantitative proteomics. The protein profiles and characterizations of differentially expressed proteins in three sampling groups were determined. These three PDACs and samples of five additional PDACs obtained by the same three sampling techniques were also subjected to genomic analysis to characterize KRAS mutations. RESULTS The neoplastic cellularity of eight PDACs ranged from less than 10% to over 80% based on morphological review. Distinctive proteomic patterns and abundances of certain tumor-associated proteins were revealed when comparing the tumors and NATs by different sampling techniques. Coring and bulk tissues had comparable proteome profiles, while LMD samples had the most distinct proteome composition compared to bulk tissues. Further genomic analysis of bulk, cored, or LMD samples demonstrated that KRAS mutations were significantly enriched in LMD samples while coring was less effective in enriching for KRAS mutations when bulk tissues contained a relatively low neoplastic cellularity. CONCLUSIONS In addition to bulk tissues, samples from LMD and coring techniques can be used for proteogenomic studies. The greatest enrichment of neoplastic cellularity is obtained with the LMD technique.
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Affiliation(s)
- Qing Kay Li
- Department of Pathology, the Johns Hopkins University, 400 N Broadway, Smith Bldg Rm 4011, Baltimore, MD, 21231, USA. .,Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins Medical Institutions, 600 N. Wolfe Street, Baltimore, MD, USA.
| | - Yingwei Hu
- Department of Pathology, the Johns Hopkins University, 400 N Broadway, Smith Bldg Rm 4011, Baltimore, MD, 21231, USA
| | - Lijun Chen
- Department of Pathology, the Johns Hopkins University, 400 N Broadway, Smith Bldg Rm 4011, Baltimore, MD, 21231, USA
| | - Michael Schnaubelt
- Department of Pathology, the Johns Hopkins University, 400 N Broadway, Smith Bldg Rm 4011, Baltimore, MD, 21231, USA
| | - Daniel Cui Zhou
- Department of Oncology, Washington University at Saint Louis, St Louis, MO, USA
| | - Yize Li
- Department of Oncology, Washington University at Saint Louis, St Louis, MO, USA
| | - Rita Jui-Hsien Lu
- Department of Oncology, Washington University at Saint Louis, St Louis, MO, USA
| | - Mathangi Thiagarajan
- Leidos Biomedical Research Inc, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | | | | | | | - Gil Omenn
- Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, USA
| | - Ana I Robles
- Office of Cancer Clinical Proteomics Research, National Cancer Institute, Rockville, MD, USA
| | - Mehdi Mesri
- Office of Cancer Clinical Proteomics Research, National Cancer Institute, Rockville, MD, USA
| | - Oliver F Bathe
- Department of Surgery and Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Bing Zhang
- Lester and Sue Smith Breast Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Li Ding
- Department of Oncology, Washington University at Saint Louis, St Louis, MO, USA
| | - Ralph H Hruban
- Department of Pathology, the Johns Hopkins University, 400 N Broadway, Smith Bldg Rm 4011, Baltimore, MD, 21231, USA.,Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins Medical Institutions, 600 N. Wolfe Street, Baltimore, MD, USA
| | - Daniel W Chan
- Department of Pathology, the Johns Hopkins University, 400 N Broadway, Smith Bldg Rm 4011, Baltimore, MD, 21231, USA.,Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins Medical Institutions, 600 N. Wolfe Street, Baltimore, MD, USA
| | - Hui Zhang
- Department of Pathology, the Johns Hopkins University, 400 N Broadway, Smith Bldg Rm 4011, Baltimore, MD, 21231, USA. .,Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins Medical Institutions, 600 N. Wolfe Street, Baltimore, MD, USA.
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15
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Razzano D, Bouza SJ, Hernandez PV, Wang M, Robert ME, Walther Z, Cai G. Comprehensive molecular profiling of pancreatic ductal adenocarcinoma in FNA, biopsy, and resection specimens. Cancer Cytopathol 2022; 130:726-734. [PMID: 35511415 DOI: 10.1002/cncy.22589] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 04/08/2022] [Accepted: 04/15/2022] [Indexed: 11/08/2022]
Abstract
BACKGROUND Molecular testing to identify molecular alterations in pancreatic ductal adenocarcinoma (PDAC) has been increasingly requested because of potential therapeutic implications. In this study, we compared the performance of PDAC fine-needle aspiration (FNA), fine-needle biopsy (FNB), and resection specimens for comprehensive molecular analysis. METHODS A next-generation sequencing-based Oncomine Comprehensive Assay (OCA) was used to analyze molecular alterations in FNA, FNB, or resection specimens. We examined adequacy and success rates for completion of molecular testing and catalogued molecular alterations in these specimen types. RESULTS The cohort included 23 FNA, 20 FNB, and 27 resection cases. Gene mutation or amplification analysis was successful in 18 (78%) FNA and 16 (80%) FNB specimens, whereas gene fusion assessment succeeded in 12 (52%) FNA and 12 (60%) FNB samples. All 27 (100%) resection specimens were adequate for complete OCA. There were significant differences in success rates for mutation and amplification analysis between resection and FNA or FNB specimens (P < .01) but not between FNA and FNB samples (P > .05). Manual microdissection was less likely to be performed for FNA specimens than FNB or resection specimens (P < .01). KRAS mutation was the most common mutation identified (90%), followed by mutations in TP53 (64%), CDKN2A (25%), and SMAD4 (15%) genes. CONCLUSIONS Our study demonstrated similar success rates for comprehensive molecular analysis using FNA and FNB specimens of PDAC, suggesting that FNA material could serve as an alternative source for comprehensive molecular testing. The molecular alterations identified in these specimens may have potential diagnostic and therapeutic implications.
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Affiliation(s)
- Dana Razzano
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
| | - Soumar J Bouza
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
| | - Patricia V Hernandez
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
| | - Minhua Wang
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
| | - Marie E Robert
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
| | - Zenta Walther
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
| | - Guoping Cai
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
- Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut
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16
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Masugi Y. The Desmoplastic Stroma of Pancreatic Cancer: Multilayered Levels of Heterogeneity, Clinical Significance, and Therapeutic Opportunities. Cancers (Basel) 2022; 14:cancers14133293. [PMID: 35805064 PMCID: PMC9265767 DOI: 10.3390/cancers14133293] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 06/27/2022] [Accepted: 07/04/2022] [Indexed: 02/01/2023] Open
Abstract
Simple Summary Pancreatic cancer is a highly malignant disease with treatment resistance to standardized chemotherapies. In addition, only a small fraction of patients with pancreatic cancer has, to date, actionable genetic aberrations, leading to a narrow therapeutic window for molecularly targeted therapies or immunotherapies. A lot of preclinical and translational studies are ongoing to discover potential vulnerabilities to treat pancreatic cancer. Histologically, human pancreatic cancer is characterized by abundant cancer-associated fibrotic stroma, called “desmoplastic stroma”. Recent technological advances have revealed that desmoplastic stroma in pancreatic cancer is much more complicated than previously thought, playing pleiotropic roles in manipulating tumor cell fate and anti-tumor immunity. Moreover, real-world specimen-based analyses of pancreatic cancer stroma have also uncovered spatial heterogeneity and an intertumoral variety associated with molecular alterations, clinicopathological factors, and patient outcomes. This review describes an overview of the current efforts in the field of pancreatic cancer stromal biology and discusses treatment opportunities of stroma-modifying therapies against this hard-to-treat cancer. Abstract Pancreatic cancer remains one of the most lethal malignancies and is becoming a dramatically increasing cause of cancer-related mortality worldwide. Abundant desmoplastic stroma is a histological hallmark of pancreatic ductal adenocarcinoma. Emerging evidence suggests a promising therapeutic effect of several stroma-modifying therapies that target desmoplastic stromal elements in the pancreatic cancer microenvironment. The evidence also unveils multifaceted roles of cancer-associated fibroblasts (CAFs) in manipulating pancreatic cancer progression, immunity, and chemotherapeutic response. Current state-of-the-art technologies, including single-cell transcriptomics and multiplexed tissue imaging techniques, have provided a more profound knowledge of CAF heterogeneity in real-world specimens from pancreatic cancer patients, as well as in genetically engineered mouse models. In this review, we describe recent advances in the understanding of the molecular pathology bases of pancreatic cancer desmoplastic stroma at multilayered levels of heterogeneity, namely, (1) variations in cellular and non-cellular members, including CAF subtypes and extracellular matrix (ECM) proteins; (2) geographical heterogeneity in relation to cell–cell interactions and signaling pathways at niche levels and spatial heterogeneity at locoregional levels or organ levels; and (3) intertumoral stromal heterogeneity at individual levels. This review further discusses the clinicopathological significance of desmoplastic stroma and the potential opportunities for stroma-targeted therapies against this lethal malignancy.
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Affiliation(s)
- Yohei Masugi
- Division of Diagnostic Pathology, Keio University School of Medicine, Tokyo 1608582, Japan; ; Tel.: +81-3-5363-3764; Fax: +81-3-3353-3290
- Department of Pathology, Keio University School of Medicine, Tokyo 1608582, Japan
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17
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Pancreatic cancer cells spectral library by DIA-MS and the phenotype analysis of gemcitabine sensitivity. Sci Data 2022; 9:283. [PMID: 35680938 PMCID: PMC9184632 DOI: 10.1038/s41597-022-01407-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 05/18/2022] [Indexed: 12/05/2022] Open
Abstract
Data-independent acquisition (DIA)-mass spectrometry (MS)-based proteome strategies are increasingly used for detecting and validating protein biomarkers and therapeutic targets. Here, based on an in-depth proteome analysis of seven pancreatic cancer cell lines, we built a pancreas-specific mass spectrum library containing 10633 protein groups and 184551 peptides. The proteome difference among the seven pancreatic cancer cells was significant, especially for the divergent expression of proteins related to epithelial-mesenchymal transition (EMT). The spectra library was applied to explore the proteome difference of PANC-1 and BxPC-3 cells upon gemcitabine (GEM) treatment, and potential GEM targets were identified. The cytotoxicity test and GEM target analysis found that HPAC, CFPAC-1, and BxPC-3 were sensitive to GEM treatment, whereas PANC-1 and AsPC-1 were resistant. Finally, we found EMT was significant for CFPAC-1, AsPC-1, and PANC-1 cells, whereas BxPC-3 and HPAC cells showed more typical epithelial features. This library provides a valuable resource for in-depth proteomic analysis on pancreatic cancer cell lines, meeting the urgent demands for cell line-dependent protein differences and targeted drug analysis.
| Measurement(s) | protein expression profiling | | Technology Type(s) | Mass Spectrometry |
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18
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Kamal MA, Siddiqui I, Belgiovine C, Barbagallo M, Paleari V, Pistillo D, Chiabrando C, Schiarea S, Bottazzi B, Leone R, Avigni R, Migliore R, Spaggiari P, Gavazzi F, Capretti G, Marchesi F, Mantovani A, Zerbi A, Allavena P. Oncogenic KRAS-Induced Protein Signature in the Tumor Secretome Identifies Laminin-C2 and Pentraxin-3 as Useful Biomarkers for the Early Diagnosis of Pancreatic Cancer. Cancers (Basel) 2022; 14:2653. [PMID: 35681634 PMCID: PMC9179463 DOI: 10.3390/cancers14112653] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/23/2022] [Accepted: 05/24/2022] [Indexed: 02/04/2023] Open
Abstract
KRAS mutations characterize pancreatic cell transformation from the earliest stages of carcinogenesis, and are present in >95% of pancreatic ductal adenocarcinoma (PDAC) cases. In search of novel biomarkers for the early diagnosis of PDAC, we identified the proteins secreted by the normal human pancreatic cell line (HPDE) recently transformed by inducing the overexpression of the KRASG12V oncogene. We report a proteomic signature of KRAS-induced secreted proteins, which was confirmed in surgical tumor samples from resected PDAC patients. The putative diagnostic performance of three candidates, Laminin-C2 (LAMC2), Tenascin-C (TNC) and Pentraxin-3 (PTX3), was investigated by ELISA quantification in two cohorts of PDAC patients (n = 200) eligible for surgery. Circulating levels of LAMC2, TNC and PTX3 were significantly higher in PDAC patients compared to the healthy individuals (p < 0.0001). The Receiver Operating Characteristics (ROC) curve showed good sensitivity (1) and specificity (0.63 and 0.85) for LAMC2 and PTX3, respectively, but not for TNC, and patients with high levels of LAMC2 had significantly shorter overall survival (p = 0.0007). High levels of LAMC2 and PTX3 were detected at early stages (I−IIB) and in CA19-9-low PDAC patients. In conclusion, pancreatic tumors release LAMC2 and PTX3, which can be quantified in the systemic circulation, and may be useful in selecting patients for further diagnostic imaging.
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Affiliation(s)
- Mohammad Azhar Kamal
- Department of Immunology, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy; (M.A.K.); (I.S.); (C.B.); (M.B.); (B.B.); (R.L.); (R.A.); (R.M.); (F.M.); (A.M.)
| | - Imran Siddiqui
- Department of Immunology, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy; (M.A.K.); (I.S.); (C.B.); (M.B.); (B.B.); (R.L.); (R.A.); (R.M.); (F.M.); (A.M.)
| | - Cristina Belgiovine
- Department of Immunology, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy; (M.A.K.); (I.S.); (C.B.); (M.B.); (B.B.); (R.L.); (R.A.); (R.M.); (F.M.); (A.M.)
| | - Marialuisa Barbagallo
- Department of Immunology, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy; (M.A.K.); (I.S.); (C.B.); (M.B.); (B.B.); (R.L.); (R.A.); (R.M.); (F.M.); (A.M.)
| | - Valentina Paleari
- Biobank, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy; (V.P.); (D.P.)
| | - Daniela Pistillo
- Biobank, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy; (V.P.); (D.P.)
| | - Chiara Chiabrando
- Department of Environmental Health Sciences, Istituto di Ricerche Farmacologiche Mario Negri-IRCCS, 20156 Milan, Italy; (C.C.); (S.S.)
| | - Silvia Schiarea
- Department of Environmental Health Sciences, Istituto di Ricerche Farmacologiche Mario Negri-IRCCS, 20156 Milan, Italy; (C.C.); (S.S.)
| | - Barbara Bottazzi
- Department of Immunology, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy; (M.A.K.); (I.S.); (C.B.); (M.B.); (B.B.); (R.L.); (R.A.); (R.M.); (F.M.); (A.M.)
| | - Roberto Leone
- Department of Immunology, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy; (M.A.K.); (I.S.); (C.B.); (M.B.); (B.B.); (R.L.); (R.A.); (R.M.); (F.M.); (A.M.)
| | - Roberta Avigni
- Department of Immunology, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy; (M.A.K.); (I.S.); (C.B.); (M.B.); (B.B.); (R.L.); (R.A.); (R.M.); (F.M.); (A.M.)
| | - Roberta Migliore
- Department of Immunology, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy; (M.A.K.); (I.S.); (C.B.); (M.B.); (B.B.); (R.L.); (R.A.); (R.M.); (F.M.); (A.M.)
| | - Paola Spaggiari
- Department of Pathology, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy;
| | - Francesca Gavazzi
- Pancreatic Surgery Unit, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy; (F.G.); (G.C.); (A.Z.)
| | - Giovanni Capretti
- Pancreatic Surgery Unit, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy; (F.G.); (G.C.); (A.Z.)
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Italy
| | - Federica Marchesi
- Department of Immunology, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy; (M.A.K.); (I.S.); (C.B.); (M.B.); (B.B.); (R.L.); (R.A.); (R.M.); (F.M.); (A.M.)
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20129 Milan, Italy
| | - Alberto Mantovani
- Department of Immunology, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy; (M.A.K.); (I.S.); (C.B.); (M.B.); (B.B.); (R.L.); (R.A.); (R.M.); (F.M.); (A.M.)
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Italy
- The William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, UK
| | - Alessandro Zerbi
- Pancreatic Surgery Unit, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy; (F.G.); (G.C.); (A.Z.)
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Italy
| | - Paola Allavena
- Department of Immunology, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy; (M.A.K.); (I.S.); (C.B.); (M.B.); (B.B.); (R.L.); (R.A.); (R.M.); (F.M.); (A.M.)
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A Potential Prognostic Marker PRDM1 in Pancreatic Adenocarcinoma. JOURNAL OF ONCOLOGY 2022; 2022:1934381. [PMID: 35607327 PMCID: PMC9123419 DOI: 10.1155/2022/1934381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 04/24/2022] [Indexed: 11/18/2022]
Abstract
Pancreatic adenocarcinoma (PAAD) is a major threat to people's health. PRDM1 is a transcription factor with multiple functions, and its functions have been validated in a variety of tumors; however, there are few studies reported on PRDM1 in PAAD. Using the GEPIA2 database, this research found that PRDM1 expression in PAAD was significantly higher than that in normal pancreatic tissue. The Kaplan-Meier Plotter database showed that high expression of PRDM1 in PAAD has a poor prognosis, suggesting that PRDM1 may be a potential prognostic marker in PAAD. The cBioPortal database shows that the expression of PRDM1 in PAAD is significantly correlated with its methylation degree. Further analysis on the coexpressed genes of PRDM1 in PAAD was performed by using LinkedOmics database to explore potential mechanisms. Based on gene enrichment analysis, PRDM1 was implicated in many pathways involved in tumor progression. In the construction of a PPI network of PRDM1 and its coexpressed gene protein via the STRING database, we found that PRDM1 may be involved in the pathogenesis and development of PAAD. TIMER database suggested that a high level of PRDM1 has a significant positive correlation with macrophages, neutrophils, and DCs. Potential methylation sites of PRDM1 were found through DNMIVD database, and MethSurv database explored eight sites which were significantly related with the prognosis of PAAD. In conclusion, PRDM1 may work as a prognostic marker or even provide a potential therapeutic strategy in PAAD.
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20
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Ward A. Pancreatic Cancer Risk and Screening Recommendations: Practice Impact. J Nurse Pract 2022. [DOI: 10.1016/j.nurpra.2022.02.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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21
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Sekine K. Human Organoid and Supporting Technologies for Cancer and Toxicological Research. Front Genet 2021; 12:759366. [PMID: 34745227 PMCID: PMC8569236 DOI: 10.3389/fgene.2021.759366] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 10/06/2021] [Indexed: 11/16/2022] Open
Abstract
Recent progress in the field of organoid-based cell culture systems has enabled the use of patient-derived cells in conditions that resemble those in cancer tissue, which are better than two-dimensional (2D) cultured cell lines. In particular, organoids allow human cancer cells to be handled in conditions that resemble those in cancer tissue, resulting in more efficient establishment of cells compared with 2D cultured cell lines, thus enabling the use of multiple patient-derived cells with cells from different genetic background, in keeping with the heterogeneity of the cells. One of the most valuable points of using organoids is that human cells from either healthy or cancerous tissue can be used. Using genome editing technology such as clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein, organoid genomes can be modified to, for example, cancer-prone genomes. The normal, cancer, or genome-modified organoids can be used to evaluate whether chemicals have genotoxic or non-genotoxic carcinogenic activity by evaluating the cancer incidence, cancer progression, and cancer metastasis. In this review, the organoid technology and the accompanying technologies were summarized and the advantages of organoid-based toxicology and its application to pancreatic cancer study were discussed.
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Affiliation(s)
- Keisuke Sekine
- Laboratory of Cancer Cell Systems, National Cancer Center Research Institute, Tokyo, Japan
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22
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Tonini V, Zanni M. Pancreatic cancer in 2021: What you need to know to win. World J Gastroenterol 2021; 27:5851-5889. [PMID: 34629806 PMCID: PMC8475010 DOI: 10.3748/wjg.v27.i35.5851] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 07/14/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the solid tumors with the worst prognosis. Five-year survival rate is less than 10%. Surgical resection is the only potentially curative treatment, but the tumor is often diagnosed at an advanced stage of the disease and surgery could be performed in a very limited number of patients. Moreover, surgery is still associated with high post-operative morbidity, while other therapies still offer very disappointing results. This article reviews every aspect of pancreatic cancer, focusing on the elements that can improve prognosis. It was written with the aim of describing everything you need to know in 2021 in order to face this difficult challenge.
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Affiliation(s)
- Valeria Tonini
- Department of Medical Sciences and Surgery, University of Bologna- Emergency Surgery Unit, IRCCS Sant’Orsola Hospital, Bologna 40121, Italy
| | - Manuel Zanni
- University of Bologna, Emergency Surgery Unit, IRCCS Sant'Orsola Hospital, Bologna 40121, Italy
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23
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Hsu FC, Roberts NJ, Childs E, Porter N, Rabe KG, Borgida A, Ukaegbu C, Goggins MG, Hruban RH, Zogopoulos G, Syngal S, Gallinger S, Petersen GM, Klein AP. Risk of Pancreatic Cancer Among Individuals With Pathogenic Variants in the ATM Gene. JAMA Oncol 2021; 7:1664-1668. [PMID: 34529012 DOI: 10.1001/jamaoncol.2021.3701] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Importance Pathogenic germline variants in the ATM gene have been associated with pancreatic cancer risk. Although genetic testing identifies these variants in approximately 1% to 3% of unselected patients with pancreatic cancer, the lifetime risk of pancreatic cancer among individuals with pathogenic ATM variants has not been well estimated. Objective To estimate age-specific penetrance of pancreatic cancer in individuals with a pathogenic variant in the ATM gene. Design, Setting, and Participants This was a multicenter cohort study of pancreatic cancer family registries in the US and Canada using pedigree data from 130 pancreatic cancer kindreds with a pathogenic germline ATM variant. Data analyses were performed from January 2020 to February 2021. Main Outcomes and Measures Observational age-specific risk of pancreatic cancer. Penetrance was estimated using modified segregation analysis. Results The study population of 130 families (123 [95%] White families) comprised 2227 family members (mean age [SD], 58 [22] years; 1096 [49%] women) with complete records (ie, including familial relationships, pancreatic cancer diagnosis, ATM status, proband status, and age), of which 155 individuals had positive results for an ATM pathogenic variant, 16 had a negative result, and the remainder did not have a test result. In these 130 families, 217 individuals had pancreatic cancer: 78 families had 1 such member; 34 families had 2 such members; and 18 families had 3 or more members with pancreatic cancer. The average (range) age at diagnosis was 64 (31-98) years. The cumulative risk of pancreatic cancer among individuals with a germline pathogenic ATM variant was estimated to be 1.1% (95% CI, 0.8%-1.3%) by age 50 years; 6.3% (95% CI, 3.9%-8.7%) by age 70 years; and 9.5% (95% CI, 5.0%-14.0%) by age 80 years. Overall, the relative risk of pancreatic cancer was 6.5 (95% CI, 4.5-9.5) in ATM variant carriers compared with noncarriers. Conclusions and Relevance This multicenter cohort study found that individuals with a germline pathogenic ATM variant were at an increased lifetime risk of pancreatic cancer. These risk estimates can help guide decision-making when evaluating the risks and benefits of enhanced early detection surveillance.
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Affiliation(s)
- Fang-Chi Hsu
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland
| | - Nicholas J Roberts
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.,Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, Maryland
| | - Erica Childs
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland
| | - Nancy Porter
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland
| | - Kari G Rabe
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota
| | - Ayelet Borgida
- Divison of General Surgery, University of Toronto, Toronto, Ontario, Canada
| | - Chinedu Ukaegbu
- Division of Gastroenterology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Michael G Goggins
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.,Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, Maryland.,Division of Gastroenterology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Ralph H Hruban
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.,Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, Maryland
| | - George Zogopoulos
- The Research Institute of the McGill University Health Centre and the Rosalind and Morris Goodman Cancer Research Centre of McGill University, Montreal, Quebec, Canada
| | - Sapna Syngal
- Population Sciences Division, Dana-Farber Cancer Institute, Boston, Massachusetts.,Gastroenterology Division, Brigham and Women's Hospital, Boston, Massachusetts
| | - Steven Gallinger
- Divison of General Surgery, University of Toronto, Toronto, Ontario, Canada
| | - Gloria M Petersen
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, Maryland
| | - Alison P Klein
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.,Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, Maryland.,Division of Gastroenterology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland.,Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
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24
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Cao L, Huang C, Cui Zhou D, Hu Y, Lih TM, Savage SR, Krug K, Clark DJ, Schnaubelt M, Chen L, da Veiga Leprevost F, Eguez RV, Yang W, Pan J, Wen B, Dou Y, Jiang W, Liao Y, Shi Z, Terekhanova NV, Cao S, Lu RJH, Li Y, Liu R, Zhu H, Ronning P, Wu Y, Wyczalkowski MA, Easwaran H, Danilova L, Mer AS, Yoo S, Wang JM, Liu W, Haibe-Kains B, Thiagarajan M, Jewell SD, Hostetter G, Newton CJ, Li QK, Roehrl MH, Fenyö D, Wang P, Nesvizhskii AI, Mani DR, Omenn GS, Boja ES, Mesri M, Robles AI, Rodriguez H, Bathe OF, Chan DW, Hruban RH, Ding L, Zhang B, Zhang H. Proteogenomic characterization of pancreatic ductal adenocarcinoma. Cell 2021; 184:5031-5052.e26. [PMID: 34534465 PMCID: PMC8654574 DOI: 10.1016/j.cell.2021.08.023] [Citation(s) in RCA: 312] [Impact Index Per Article: 78.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 03/19/2021] [Accepted: 08/18/2021] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor patient survival. Toward understanding the underlying molecular alterations that drive PDAC oncogenesis, we conducted comprehensive proteogenomic analysis of 140 pancreatic cancers, 67 normal adjacent tissues, and 9 normal pancreatic ductal tissues. Proteomic, phosphoproteomic, and glycoproteomic analyses were used to characterize proteins and their modifications. In addition, whole-genome sequencing, whole-exome sequencing, methylation, RNA sequencing (RNA-seq), and microRNA sequencing (miRNA-seq) were performed on the same tissues to facilitate an integrated proteogenomic analysis and determine the impact of genomic alterations on protein expression, signaling pathways, and post-translational modifications. To ensure robust downstream analyses, tumor neoplastic cellularity was assessed via multiple orthogonal strategies using molecular features and verified via pathological estimation of tumor cellularity based on histological review. This integrated proteogenomic characterization of PDAC will serve as a valuable resource for the community, paving the way for early detection and identification of novel therapeutic targets.
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Affiliation(s)
- Liwei Cao
- Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA
| | - Chen Huang
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Daniel Cui Zhou
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 631110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA
| | - Yingwei Hu
- Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA
| | - T Mamie Lih
- Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA
| | - Sara R Savage
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Karsten Krug
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - David J Clark
- Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA
| | - Michael Schnaubelt
- Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA
| | - Lijun Chen
- Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA
| | | | | | - Weiming Yang
- Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA
| | - Jianbo Pan
- Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA
| | - Bo Wen
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Yongchao Dou
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Wen Jiang
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Yuxing Liao
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Zhiao Shi
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Nadezhda V Terekhanova
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 631110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA
| | - Song Cao
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 631110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA
| | - Rita Jui-Hsien Lu
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 631110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA
| | - Yize Li
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 631110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA
| | - Ruiyang Liu
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 631110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA
| | - Houxiang Zhu
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 631110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA
| | - Peter Ronning
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 631110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA
| | - Yige Wu
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 631110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA
| | - Matthew A Wyczalkowski
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 631110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA
| | - Hariharan Easwaran
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Ludmila Danilova
- Department of Oncology, Johns Hopkins University, Baltimore, MD 21205, USA
| | - Arvind Singh Mer
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
| | - Seungyeul Yoo
- Sema4, a Mount Sinai venture, Stamford, CT 06902, USA
| | - Joshua M Wang
- Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY 10016, USA; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Wenke Liu
- Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY 10016, USA; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Benjamin Haibe-Kains
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
| | - Mathangi Thiagarajan
- Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
| | - Scott D Jewell
- Van Andel Research Institute, Grand Rapids, MI 49503, USA
| | | | | | - Qing Kay Li
- Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA
| | - Michael H Roehrl
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - David Fenyö
- Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY 10016, USA; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Pei Wang
- Sema4, a Mount Sinai venture, Stamford, CT 06902, USA
| | | | - D R Mani
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - Gilbert S Omenn
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA
| | - Emily S Boja
- Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Mehdi Mesri
- Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Ana I Robles
- Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Henry Rodriguez
- Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Oliver F Bathe
- Departments of Surgery and Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Daniel W Chan
- Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA; The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Ralph H Hruban
- Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA; The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA; The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21231, USA
| | - Li Ding
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 631110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA.
| | - Bing Zhang
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
| | - Hui Zhang
- Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA; The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA.
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Zhou C, Porter N, Borges M, Gauthier C, Ferguson L, Huang B, Nanda N, He J, Laheru D, Hruban RH, Goggins M, Klein AP, Roberts NJ. Examination of ATM, BRCA1, and BRCA2 promoter methylation in patients with pancreatic cancer. Pancreatology 2021; 21:938-941. [PMID: 33839031 PMCID: PMC8355034 DOI: 10.1016/j.pan.2021.03.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 03/09/2021] [Accepted: 03/22/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Pancreatic cancer is a lethal disease with a poor 5-year survival rate. Pathogenic germline variants in the coding regions of ATM, BRCA1, and BRCA2 are found in up to 4.8% of pancreatic cancer patients. Germline promoter methylation and gene silencing arising from a germline variant or through other mechanisms have been described as a cause of tumor suppressor gene inactivation. METHODS We measured the level of promoter methylation of the ATM, BRCA1, and BRCA2 genes in peripheral blood lymphocytes from 655 patients with pancreatic cancer using real-time PCR. RESULTS No evidence of germline promoter methylation of any of these genes was found. Promoter methylation levels were minimal with no patient having promoter methylation greater than 3.4%, 3.3%, and 7.6% for ATM, BRCA1 and BRCA2, respectively, well below levels found in patients who have inherited promoter methylation (∼50%). CONCLUSIONS We found no evidence of germline promoter methylation for the pancreatic susceptibility genes ATM, BRCA1 and BRCA2 in patients with pancreatic cancer. This study reveals that constitutive germline methylation of promoter CpG islands is rare in pancreatic cancer.
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Affiliation(s)
- Cancan Zhou
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Nancy Porter
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Michael Borges
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Christian Gauthier
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Lindsey Ferguson
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Carlson College of Veterinary Medicine, Oregon State University, Corvallis, OR, USA
| | - Bo Huang
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Neha Nanda
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jin He
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Daniel Laheru
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ralph H Hruban
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Michael Goggins
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Alison P Klein
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
| | - Nicholas J Roberts
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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26
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Renshaw AA. Updating the Papanicolaou Society cytologic criteria for invasive adenocarcinoma in cystic pancreaticobiliary specimens. Cancer Cytopathol 2021; 129:579-580. [PMID: 34161643 DOI: 10.1002/cncy.22487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 06/01/2021] [Indexed: 11/07/2022]
Affiliation(s)
- Andrew A Renshaw
- Department of Pathology, Baptist Hospital and Miami Cancer Institute, Miami, Florida
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27
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[The microarchitecture of pancreatic cancer from the point of view of the pathologist and the radiologist]. DER PATHOLOGE 2021; 42:524-529. [PMID: 33956172 PMCID: PMC8390414 DOI: 10.1007/s00292-021-00949-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 03/26/2021] [Indexed: 11/06/2022]
Abstract
Die diagnostische Radiologie ist gemeinsam mit der diagnostischen Pathologie eines der klinisch-morphologischen Fächer, welche in unterschiedlicher makroskopischer bzw. mikroskopischer Auflösung zur Detektion, Charakterisierung sowie zum Ausbreitungsmuster eines Tumors führen. Die klinischen Disziplinen sind oft voneinander getrennt, wenngleich es vor allem in klinischen Tumorboards immer stärkere Verzahnungen gibt. Am Beispiel des Pankreaskarzinoms sind die Korrelationen radiologischer und pathologischer Diagnostik dargestellt.
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28
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Noë M, Hong SM, Wood LD, Thompson ED, Roberts NJ, Goggins MG, Klein AP, Eshleman JR, Kern SE, Hruban RH. Pancreatic cancer pathology viewed in the light of evolution. Cancer Metastasis Rev 2021; 40:661-674. [PMID: 33555482 PMCID: PMC8556193 DOI: 10.1007/s10555-020-09953-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 12/30/2020] [Indexed: 12/14/2022]
Abstract
One way to understand ductal adenocarcinoma of the pancreas (pancreatic cancer) is to view it as unimaginably large numbers of evolving living organisms interacting with their environment. This “evolutionary view” creates both expected and surprising perspectives in all stages of neoplastic progression. Advances in the field will require greater attention to this critical evolutionary prospective.
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Affiliation(s)
- Michaël Noë
- Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Carnegie 415, 600 North Wolfe Street, Baltimore, MD, 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Seung-Mo Hong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Laura D Wood
- Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Carnegie 415, 600 North Wolfe Street, Baltimore, MD, 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Elizabeth D Thompson
- Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Carnegie 415, 600 North Wolfe Street, Baltimore, MD, 21287, USA
| | - Nicholas J Roberts
- Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Carnegie 415, 600 North Wolfe Street, Baltimore, MD, 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Michael G Goggins
- Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Carnegie 415, 600 North Wolfe Street, Baltimore, MD, 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Alison P Klein
- Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Carnegie 415, 600 North Wolfe Street, Baltimore, MD, 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
- Department of Epidemiology, Bloomberg School of Public Health, The Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - James R Eshleman
- Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Carnegie 415, 600 North Wolfe Street, Baltimore, MD, 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Scott E Kern
- Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Carnegie 415, 600 North Wolfe Street, Baltimore, MD, 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Ralph H Hruban
- Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Carnegie 415, 600 North Wolfe Street, Baltimore, MD, 21287, USA.
- Sol Goldman Pancreatic Cancer Research Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
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