Methylation changes at the <i>GNAS</i> imprinted locus in pancreatic cystic neoplasms are important for the diagnosis of malignant cysts

Faias, Sandra; Duarte, Marlene; Pereira, Luísa; Chaves, Paula; Cravo, Marília; Pereira, António Dias; Albuquerque, Cristina

doi:10.4251/wjgo.v12.i9.1056

Cited by 8 publications

(4 citation statements)

References 20 publications

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“…At a tissue level, i.e., resected specimens, cyst fluid, and pancreatic juice, methylation-based markers have previously been investigated for IPMN stratification [ 17 – 24 ]. Some of the studies utilized methylation status of tumor suppressor genes ( WWOX , SMAD4 , and CDO1 genes) [ 17 , 23 ] or markers related to mucinous lineage (such as GNAS, MUC family) [ 19 , 24 ]. Similar to our study, the investigators used a multigene approach to enhance diagnostic accuracy [ 20 , 22 ].…”

Section: Discussionmentioning

confidence: 99%

Utility of promoter hypermethylation in malignant risk stratification of intraductal papillary mucinous neoplasms

et al. 2023

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Background Intraductal papillary mucinous neoplasms (IPMNs), a type of cystic pancreatic cancer (PC) precursors, are increasingly identified on cross-sectional imaging and present a significant diagnostic challenge. While surgical resection of IPMN-related advanced neoplasia, i.e., IPMN-related high-grade dysplasia or PC, is an essential early PC detection strategy, resection is not recommended for IPMN-low-grade dysplasia (LGD) due to minimal risk of carcinogenesis, and significant procedural risks. Based on their promising results in prior validation studies targeting early detection of classical PC, DNA hypermethylation-based markers may serve as a biomarker for malignant risk stratification of IPMNs. This study investigates our DNA methylation-based PC biomarker panel (ADAMTS1, BNC1, and CACNA1G genes) in differentiating IPMN-advanced neoplasia from IPMN-LGDs. Methods Our previously described genome-wide pharmaco-epigenetic method identified multiple genes as potential targets for PC detection. The combination was further optimized and validated for early detection of classical PC in previous case–control studies. These promising genes were evaluated among micro-dissected IPMN tissue (IPMN-LGD: 35, IPMN-advanced neoplasia: 35) through Methylation-Specific PCR. The discriminant capacity of individual and combination of genes were delineated through Receiver Operating Characteristics curve analysis. Results As compared to IPMN-LGDs, IPMN-advanced neoplasia had higher hypermethylation frequency of candidate genes: ADAMTS1 (60% vs. 14%), BNC1 (66% vs. 3%), and CACGNA1G (25% vs. 0%). We observed Area Under Curve (AUC) values of 0.73 for ADAMTS1, 0.81 for BNC1, and 0.63 for CACNA1G genes. The combination of the BNC1/ CACNA1G genes resulted in an AUC of 0.84, sensitivity of 71%, and specificity of 97%. Combining the methylation status of the BNC1/CACNA1G genes, blood-based CA19-9, and IPMN lesion size enhanced the AUC to 0.92. Conclusion DNA-methylation based biomarkers have shown a high diagnostic specificity and moderate sensitivity for differentiating IPMN-advanced neoplasia from LGDs. Addition of specific methylation targets can improve the accuracy of the methylation biomarker panel and enable the development of noninvasive IPMN stratification biomarkers.

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Section: Discussionmentioning

confidence: 99%

Utility of promoter hypermethylation in malignant risk stratification of intraductal papillary mucinous neoplasms

et al. 2023

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“…As discussed above, DNA methylation patterns have been described in IPMNs [ 35 , 99 , 100 , 101 , 102 , 103 ], and methylation profiles are detectable in cyst fluid [ 100 ]. The methylation of certain genes, including BNIP3 , CDO1 , EBF3 , NXPH1 , PTCHD2 , and SOX17 , have been reported to be more prevalent in high-grade IPMNs than in low-grade ones [ 101 , 103 ].…”

Section: Advanced Diagnostic Tools For Pancreatic Cystic Lesionsmentioning

confidence: 99%

Molecular Pathology of Pancreatic Cystic Lesions with a Focus on Malignant Progression

Hu,

Jones,

Esnakula

et al. 2024

Cancers

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The malignant progression of pancreatic cystic lesions (PCLs) remains understudied with a knowledge gap, yet its exploration is pivotal for effectively stratifying patient risk and detecting cancer at its earliest stages. Within this review, we delve into the latest discoveries on the molecular level, revealing insights into the IPMN molecular landscape and revised progression model, associated histologic subtypes, and the role of inflammation in the pathogenesis and malignant progression of IPMN. Low-grade PCLs, particularly IPMNs, can develop into high-grade lesions or invasive carcinoma, underscoring the need for long-term surveillance of these lesions if they are not resected. Although KRAS and GNAS remain the primary oncogenic drivers of neoplastic development in IPMNs, additional genes that are important in tumorigenesis have been recently identified by whole exome sequencing. A more complete understanding of the genes involved in the molecular progression of IPMN is critical for effective monitoring to minimize the risk of malignant progression. Complicating these strategies, IPMNs are also frequently multifocal and multiclonal, as demonstrated by comparative molecular analysis. Algorithms for preoperative cyst sampling and improved radiomic techniques are emerging to model this spatial and temporal genetic heterogeneity better. Here, we review the molecular pathology of PCLs, focusing on changes associated with malignant progression. Developing models of molecular risk stratification in PCLs which can complement radiologic and clinical features, facilitate the early detection of pancreatic cancer, and enable the development of more personalized surveillance and management strategies are summarized.

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“…They have been found as somatic changes in somatotropinomas (4.4-59.5%), non-functioning PitNETs (7-10%), corticotropinomas (6%), autonomous thyroid adenomas (5%) and thyroid cancer (13% of PTC and up to 4% of follicular tumors), and occasionally, in ovarian and testicular Leydig cell tumors, prolactinomas, adrenocortical adenomas, pheochromocytomas, paragangliomas, parathyroid adenomas, and in patients with multiple endocrine tumors [10,. These variants have also been found in non-endocrine malignant neoplasms, such as pancreatic, colorectal, and lung adenocarcinomas, as well as in hepatocellular carcinomas [99][100][101][102].…”

Section: Gnasmentioning

confidence: 99%

Hotspots of Somatic Genetic Variation in Pituitary Neuroendocrine Tumors

Torres-Morán,

Franco-Álvarez,

Rebollar-Vega

et al. 2023

Cancers

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The most common genetic drivers of pituitary neuroendocrine tumors (PitNETs) lie within mutational hotspots, which are genomic regions where variants tend to cluster. Some of these hotspot defects are unique to PitNETs, while others are associated with additional neoplasms. Hotspot variants in GNAS and USP8 are the most common genetic causes of acromegaly and Cushing’s disease, respectively. Although it has been proposed that these genetic defects could define specific clinical phenotypes, results are highly variable among studies. In contrast, DICER1 hotspot variants are associated with a familial syndrome of cancer predisposition, and only exceptionally occur as somatic changes. A small number of non-USP8-driven corticotropinomas are due to somatic hotspot variants in USP48 or BRAF; the latter is a well-known mutational hotspot in cancer. Finally, somatic variants affecting a hotspot in SF3B1 have been associated with multiple cancers and, more recently, with prolactinomas. Since the associations of BRAF, USP48, and SF3B1 hotspot variants with PitNETs are very recent, their effects on clinical phenotypes are still unknown. Further research is required to fully define the role of these genetic defects as disease biomarkers and therapeutic targets.

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Methylation changes at the GNAS imprinted locus in pancreatic cystic neoplasms are important for the diagnosis of malignant cysts

Cited by 8 publications

References 20 publications

Utility of promoter hypermethylation in malignant risk stratification of intraductal papillary mucinous neoplasms

Utility of promoter hypermethylation in malignant risk stratification of intraductal papillary mucinous neoplasms

Molecular Pathology of Pancreatic Cystic Lesions with a Focus on Malignant Progression

Hotspots of Somatic Genetic Variation in Pituitary Neuroendocrine Tumors

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