Linc-ing Circulating Long Non-coding RNAs to the Diagnosis and Malignant Prediction of Intraductal Papillary Mucinous Neoplasms of the Pancreas

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease that lacks effective biomarkers for early detection. We hypothesized that circulating long non-coding RNAs (lncRNAs) may act as diagnostic markers of incidentally-detected cystic PDAC precursors known as intraductal papillary mucinous neoplasms (IPMNs) and predictors of their pathology/histological classification. Using NanoString nCounter® technology, we measured the abundance of 28 candidate lncRNAs in pre-operative plasma from a cohort of pathologically-confirmed IPMN cases of various grades of severity and non-diseased controls. Results showed that two lncRNAs (GAS5 and SRA) aided in differentiating IPMNs from controls. An 8-lncRNA signature (including ADARB2-AS1, ANRIL, GLIS3-AS1, LINC00472, MEG3, PANDA, PVT1, and UCA1) had greater accuracy than standard clinical and radiologic features in distinguishing ‘aggressive/malignant’ IPMNs that warrant surgical removal from ‘indolent/benign’ IPMNs that can be observed. When the 8-lncRNA signature was combined with plasma miRNA data and quantitative ‘radiomic’ imaging features, the accuracy of predicting IPMN pathological classification improved. Our findings provide novel information on the ability to detect lncRNAs in plasma from patients with IPMNs and suggest that an lncRNA-based blood test may have utility as a diagnostic adjunct for identifying IPMNs and their pathology, especially when incorporated with biomarkers such as miRNAs, quantitative imaging features, and clinical data.

<p>Novel Tumor Suppressor lncRNA Growth Arrest-Specific 5 (GAS5) In Human Cancer</p>

“…28,29,78 Lower expression of GAS5 in plasma was found in intraductal papillary mucinous neoplasms (IPMNs) compared to non-diseased controls, suggesting that a GAS5-based blood test may be used as an adjunct diagnostic tool for identifying IPMNs. 79 Thus, GAS5 may be used as a potential biomarker for diagnosis in patients with PC. Ovarian cancer (OC) is one of the most common gynecological malignancies in the world with low 5-year OS.…”

Blood-based markers for predicting malignancy in intraductal papillary mucinous neoplasms of the pancreas – what’s beyond the horizon?

“…The sensitivity was 81% with a specificity of 53%. In another study by the same research group, it was shown that 8 lncRNAs (ADARB2-AS1, ANRIL, GLIS3-AS1, LINC00472, MEG3, PANDA, PVT1 and UCA1) could predict malignant IPMN (high-grade dysplasia or invasive carcinoma) with a sensitivity of 77% and specificity of 76% [17]. When the lncRNA panel was combined with the miRNA data, radiomic data and standard clinical and radiologic features, the accuracy of predicting IPMN grade could be improved, yielding a sensitivity of 93% and specificity of 82% with an AUC of 0.92.…”

The multifaceted roles of long noncoding RNAs in pancreatic cancer: an update on what we know

“…Another mechanism of target gene regulation is achieved by binding to chromatin complexes or causing histone epigenetic modifications, which is the case for the lncRNA HOTAIR [4]. LincRNAs may act as enhancers and actively regulate the transcription of proximal genes [26].…”

“…Other reports have shown that GAS5 contributes to drug-induced apoptosis through PTEN regulation by miR-32-5p in different PC cell lines [87]. Jennifer et al successfully quantified 28 lncRNA mutants in preoperative archived plasma from a cohort of pathologically confirmed intraductal papillary mucinous neoplasm (IPMN) cases and unaffected controls [26]. Their results showed that GAS5 could differentiate IPMN samples from healthy samples.…”