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Genomic characterization of malignant progression in neoplastic pancreatic cysts.

ABSTRACT: Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are non-invasive neoplasms that are often observed in association with invasive pancreatic cancers, but their origins and evolutionary relationships are poorly understood. In this study, we analyze 148 samples from IPMNs, MCNs, and small associated invasive carcinomas from 18 patients using whole exome or targeted sequencing. Using evolutionary analyses, we establish that both IPMNs and MCNs are direct precursors to pancreatic cancer. Mutations in SMAD4 and TGFBR2 are frequently restricted to invasive carcinoma, while RNF43 alterations are largely in non-invasive lesions. Genomic analyses suggest an average window of over three years between the development of high-grade dysplasia and pancreatic cancer. Taken together, these data establish non-invasive IPMNs and MCNs as origins of invasive pancreatic cancer, identifying potential drivers of invasion, highlighting the complex clonal dynamics prior to malignant transformation, and providing opportunities for early detection and intervention.

SUBMITTER: Noe M

PROVIDER: S-EPMC7428044 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Genomic characterization of malignant progression in neoplastic pancreatic cysts.

Noë Michaël M Niknafs Noushin N Fischer Catherine G CG Hackeng Wenzel M WM Beleva Guthrie Violeta V Hosoda Waki W Debeljak Marija M Papp Eniko E Adleff Vilmos V White James R JR Luchini Claudio C Pea Antonio A Scarpa Aldo A Butturini Giovanni G Zamboni Giuseppe G Castelli Paola P Hong Seung-Mo SM Yachida Shinichi S Hiraoka Nobuyoshi N Gill Anthony J AJ Samra Jaswinder S JS Offerhaus G Johan A GJA Hoorens Anne A Verheij Joanne J Jansen Casper C Adsay N Volkan NV Jiang Wei W Winter Jordan J Albores-Saavedra Jorge J Terris Benoit B Thompson Elizabeth D ED Roberts Nicholas J NJ Hruban Ralph H RH Karchin Rachel R Scharpf Robert B RB Brosens Lodewijk A A LAA Velculescu Victor E VE Wood Laura D LD

Nature communications 20200814 1

Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are non-invasive neoplasms that are often observed in association with invasive pancreatic cancers, but their origins and evolutionary relationships are poorly understood. In this study, we analyze 148 samples from IPMNs, MCNs, and small associated invasive carcinomas from 18 patients using whole exome or targeted sequencing. Using evolutionary analyses, we establish that both IPMNs and MCNs are direct precurso ...[more]

PMID: 32796935

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Project description:BACKGROUND:DNA mutational analysis of pancreatic cystic fluid (CF) is a useful adjunct to the evaluation of pancreatic cysts. KRAS/GNAS or RAF/PTPRD/CTNNB1/RNF43 mutations are highly specific to precancerous or advanced neoplasia. Several studies recently demonstrated the ability of next-generation sequencing (NGS) analysis to detect DNA mutations in pancreatic CF, but few studies have performed a systematic comparative analysis between pancreatic CF and neoplastic surgical tissue (NT). The value of CF-NGS analysis indicators for determining surgical resection necessitates evaluation. AIM:To confirm whether CF genomic profiles are a reliable malignancy predictor by comparing NGS mutational analyses of CF and NT. METHODS:Patients requiring surgery for high-risk pancreatic cysts were included in a multicenter prospective pilot study. DNA from CF (collected by endoscopic ultrasound-guided fine needle aspiration (known as EUS-FNA)) and NT (collected by surgery) were analyzed by NGS. The primary objective was to compare the mutation profiles of paired DNA samples. The secondary objective was to correlate the presence of specific mutations (KRAS/GNAS, RAF/ PTPRD/CTNNB1/RNF43/POLD1/TP53) with a final cancer diagnosis. Sensitivity and specificity were also evaluated. RESULTS:Between December 2016 and October 2017, 20 patients were included in this pilot study. Surgery was delayed for 3 patients. Concordant CF-NT genotypes were found in 15/17 paired DNA, with a higher proportion of mutated alleles in CF than in NT. NGS was possible for all pancreatic CF collected by EUS-FNA. In 2 cases, the presence of a KRAS/GNAS mutation was discordant between CF and NT. No mutations were found in 3 patients with NT or pancreatic cysts with high-grade dysplasia. The sensitivity and specificity of KRAS/GNAS mutations in CF to predict an appropriate indication for surgical resection were 0.78 and 0.62, respectively. The sensitivity and specificity of RAF/PTPRD/CTNNB1 /RNF43/POLD1/TP53 mutations in CF were 0.55 and 1.0, respectively. CONCLUSION:Mutational analyses of CF and NT were highly concordant, confirming the value of NGS analysis of CF in the preoperative malignancy assessment. However, these results need to be confirmed on a larger scale.

Dataset Information

Genomic characterization of malignant progression in neoplastic pancreatic cysts.

Publications

Genomic characterization of malignant progression in neoplastic pancreatic cysts.

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