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Transcriptome Analysis Identifies Putative Multi-Gene Signature Distinguishing Benign and Malignant Pancreatic Head Mass

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Transcriptome Analysis Identifies Putative Multi-Gene Signature Distinguishing Benign and Malignant Pancreatic Head Mass Chhatriya et al. J Transl Med (2020) 18:420 https://doi.org/10.1186/s12967-020-02597-1 Journal of Translational Medicine RESEARCH Open Access Transcriptome analysis identifes putative multi-gene signature distinguishing benign and malignant pancreatic head mass Bishnupriya Chhatriya1, Moumita Mukherjee1, Sukanta Ray2, Barsha Saha1, Somdatta Lahiri3, Sandip Halder3, Indranil Ghosh4, Sujan Khamrui2, Kshaunish Das2, Samsiddhi Bhattacharjee1, Saroj Kant Mohapatra1 and Srikanta Goswami1* Abstract Background: Most often, the patients with pancreatic diseases are presented with a mass in pancreatic head region and existing methods of diagnosis fail to confrm whether the head mass is malignant or benign. As subsequent man- agement of the disease hugely depends on the correct diagnosis, we wanted to explore possible biomarkers which could distinguish benign and malignant pancreatic head masses. Methods: In order to address that gap, we performed a case–control study to identify genome-wide diferentially expressed coding and noncoding genes between pancreatic tissues collected from benign and malignant head masses. These genes were next shortlisted using stringent criteria followed by selection of top malignancy specifc genes. They subsequently got validated by quantitative RT-PCR and also in other patient cohorts. Survival analysis and ROC analysis were also performed. Results: We identifed 55 coding and 13 noncoding genes specifc for malignant pancreatic head masses. Further shortlisting and validation, however, resulted in 5 coding genes as part of malignancy specifc multi-gene signature, which was validated in three independent patient cohorts of 145 normal and 153 PDAC patients. We also found that overexpression of these genes resulted in survival disadvantage in the patients and ROC analysis identifed that com- bination of 5 coding genes had the AUROC of 0.94, making them potential biomarker. Conclusions: Our study identifed a multi-gene signature comprising of 5 coding genes (CDCA7, DLGAP5, FOXM1, TPX2 and OSBPL3) to distinguish malignant head masses from benign ones. Keywords: Pancreatic head mass, Transcriptome, Signature, Biomarker potential Background infammatory mass is formed in pancreatic head region Pancreatic cancer is one of the most aggressive forms of which is very much similar to malignant pancreatic head cancers, with 5-year survival as low as 7 per cent. Chronic mass which occurs in about 65–70% of PC [1]. Jaundice, pancreatitis (CP) is considered as a major risk factor for gastric outlet obstruction, weight loss, back-ache are pancreatic cancer. In about 30–75% of CP cases, a benign symptoms common to both. Diagnosis is difcult even during the surgery as features like hard mass, vascular invasion are present in both the cases. Distinguishing *Correspondence: [email protected] benign and malignant head mass based on their clinical 1 National Institute of Biomedical Genomics, P.O.: N.S.S., Kalyani 741251, and imaging features is very challenging but necessary West Bengal, India Full list of author information is available at the end of the article as they have very diferent treatment and management © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Chhatriya et al. J Transl Med (2020) 18:420 Page 2 of 15 strategies. Misdiagnosis of benign head mass as malig- condition i.e. chronic pancreatitis as well as for malig- nant head mass will result in unnecessary surgical treat- nant pancreatic disease condition i.e. pancreatic cancer. ment and misdiagnosis of malignant head mass as benign Additionally, adjacent normal pancreatic tissue samples head mass could result in unnecessary delay in required were also collected and all tissue samples were stored in treatment. In doubtful situations radical approach is used RNA-Later. All the tissues were collected while perform- and pancreaticoduodenectomy is performed. Te situ- ing the surgery after careful investigation of the head ation further worsens in regions where tropical calcifc mass. Histopathological examination by expert patholo- pancreatitis (TCP) is more common. Pancreaticoduo- gists confrmed whether they were malignant or benign denectomy in those patients is associated with very high in nature. For the present discovery set investigation, 9 post-operative morbidity as the patients are nutrition- normal, 6 CP and 11 PC samples were selected and 9 CP ally defcient due to exocrine and endocrine insufciency and 9 PC samples were selected for validation. Relevant [2, 3]. So, the need of distinction between benign and patient information has been given in Additional fle 1: malignant is even more pronounced in tropical country Table S1. like India. It has been shown that integration of dynamic contrast-enhanced CT scan, MRI and 18F-FDG-PET/CT RNA extraction imaging methods could be used for diferential diagno- About 20 mg of tissue sections were taken for each sis of benign and malignant head mass, but evidences samples and total RNA was extracted according to the are still not strong enough [4]. Platelet-Lymphocyte ratio instructions mentioned in the manual of All-Prep DNA/ (PLR) along with CA19-9 has been shown to address the RNA/ miRNA isolation kit from Qiagen (catalog number: issue to some extent but they have their own limitations 80224). Quantifcation was done using multi-channel [5–7]. spectrophotometer (Model number: ND 8000, Termo Hence, there is an urgent need for the identifcation Fisher Scientifc). Quality of RNA was checked by dena- of some other parameter or method which could distin- turing agarose gel electrophoresis for characteristic RNA guish between the two types of head masses confrma- bands. tively. Tere are also studies looking into the proteome profle of pancreatic cancer and pancreatitis but with not Microarray much success [8, 9]. Analysis of transcriptome has also Gene expression profling was done by microarray using been used to distinguish benign and malignant lesions in Afymetrix human transcriptome array 2.0 (HTA 2.0) other cancers [10, 11], but such studies directly address- platform, which consists of probes for both coding and ing issues with benign and malignant pancreatic head non-coding genes. cDNA was prepared from ~ 10 µg masses are lacking. Te importance of transcriptome of RNA, biotinylated according to standard Afymetrix analysis is that the investigation of identifed DEGs not protocol and then hybridized onto Afymetrix HTA 2.0 only helps us to derive and validate potential signatures Arrays for overnight in the hybridization oven and then specifc for diagnosis of a disease condition but also help the array chips were washed and stained in the Afym- to understand the biology as well. etrix Fluidics Station 450. GeneChips were scanned using In this study, we performed gene expression analysis the Afymetrix GeneChip® Scanner 3000 7G and raw between benign and malignant pancreatic head masses fles were obtained as CEL fles. and identifed diferentially expressed mRNAs and non- coding RNAs. In the next step, a small set of markers was Data acquisition and pre‑processing carefully shortlisted and validated by qRT-PCR. Addi- Raw data were obtained as CEL fles which were further tionally, their expression was checked in TCGA pancre- pre-processed before calculating diferential expression. atic cancer datasets and other publicly available datasets Te raw data were frst read into R as an afybatch object and our fndings were consistently replicated. Finally we and an expression set is created as an expression set performed ROC analysis and were able to propose a 5 object. An expression set object is created from afybatch gene signature that can efectively distinguish malignant object and then pre-processed for background correc- pancreatic head masses from benign. tion, normalization, probe summarization. Background correction and probe summarization was done by using Methods “Oligo” package of R Bioconductor [12]. Normalization Sample collection was done by ‘Invariant Set Method’ using “afyPLM” Tissue samples were collected from patients undergo- package of R [13]. In this method of normalization, a set ing surgery at IPGME&R, Kolkata, RG Kar Medical Col- of genes whose expression is consistent in all the samples lege and Hospital, Kolkata and Chittaranjan National were identifed and based on those expression values, the Cancer Institute, Kolkata for benign pancreatic disease expression values of other genes were adjusted in each Chhatriya et al. J Transl Med (2020) 18:420 Page 3 of 15 sample. Te raw and processed data have
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