Abstract
Intraductal papillary mucinous neoplasm (IPMN) of pancreas has a high risk to develop into invasive cancer or co‐occur with malignant lesion. Therefore, it is important to assess its malignant risk by less‐invasive approach. Pancreatic juice cell‐free DNA (PJD) would be an ideal material in this purpose, but genetic biomarkers for predicting malignant risk from PJD are not yet established. We here performed deep exome sequencing analysis of PJD from 39 IPMN patients with or without malignant lesion. Somatic alterations and copy number alterations (CNAs) detected in PJD were compared with the histologic grade of IPMN to evaluate their potential as a malignancy marker. Somatic mutations of KRAS, GNAS, TP53, and RNF43 were commonly detected in PJD of IPMNs, but no association with the histologic grades of IPMN was found. Instead, mutation burden was positively correlated with the histologic grade (r = 0.427, P = 0.015). We also observed frequent copy number deletions in 17p13 (TP53) and amplifications in 7q21 and 8q24 (MYC) in PJDs. The amplifications in 7q21 and 8q24 were positively correlated with the histologic grade and most prevalent in the cases of invasive carcinoma (P = 0.002 and 7/11; P = 0.011 and 6/11, respectively). We concluded that mutation burden and CNAs detected in PJD may have potential to assess the malignant progression risk of IPMNs.
Highlights
Intraductal papillary mucinous neoplasms (IPMNs), described for the first time in 1982 by Ohashi et al.[1,2] and posteriorly defined by the World Health Organization, are pancreatic tumors with unique characteristics including hyper‐production of mucin in tall columnar epitheliums, and dilatation and papillary growth inside the pancreatic ducts.[3-6]
After the establishment of its diagnosis, the incidence of IPMN has been rapidly increasing, and it is understood that IPMN can be classified along the spectrum of adenoma to carcinoma, and it can be a precursor of pancreatic cancer.[7]
We detected critical mutations such as KRAS and GNAS, known markers in IPMN that prove to a certain extent the reliability of this sample source, and found out that the mutation burden is significantly correlated with IPMN histologic grade which has been previously reported in late stages of gynecologic cancers.[46-48]
Summary
Intraductal papillary mucinous neoplasms (IPMNs), described for the first time in 1982 by Ohashi et al.[1,2] and posteriorly defined by the World Health Organization, are pancreatic tumors with unique characteristics including hyper‐production of mucin in tall columnar epitheliums, and dilatation and papillary growth inside the pancreatic ducts.[3-6]. GNAS, another oncogene, has been reported as mutated in codon 201 in more than half (61%) of their patients with IPMN 21 and has been previously detected by droplet digital polymerase chain reaction in cfDNA obtained from blood samples.[22]. Oncogenes such as BRAF, PI3KCA, and TERT, tumor suppressor genes such as CDKN2A or TP53, as well as pathways such as the Sonic Hedgehog signaling pathway have been reported as altered in some studies.[12,23-25]. More comprehensive genomic analysis of pancreatic juice cfDNA (PJD) may help to discover better markers of malignancy and to overcome the intratumoral heterogeneity of IPMN. We performed deep exome sequencing of PJDs from 40 IPMN patients and found that mutational burden and copy number alterations (CNAs) detected in PJDs could evaluate the malignancy of IPMN
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