Intraductal Papillary Mucinous Neoplasms Arise From Multiple Independent Clones, Each With Distinct Mutations

Fischer, Catherine G.; Guthrie, Violeta Beleva; Braxton, Alicia M.; Zheng, Lily; Wang, Pei; Song, Qianqian; Griffin, James F.; Chianchiano, Peter; Hosoda, Waki; Niknafs, Noushin; Springer, Simeon; Molin, Marco Dal; Masica, David L.; Scharpf, Robert B.; Thompson, Elizabeth D.; He, Jin; Wolfgang, Christopher L.; Hruban, Ralph H.; Roberts, Nicholas J.; Lennon, Anne Marie; Jiao, Yuchen; Karchin, Rachel; Wood, Laura D.

doi:10.1053/j.gastro.2019.06.001

Cited by 92 publications

(83 citation statements)

References 42 publications

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“…We showed that the organoid culture model can recapitulate the morphological and mutational profiles of resected IPMNs, consistent with existing data on primary PDAC tumors [18][19][20][21] and a recently published manuscript on IPMNs 23 . Discordance of somatic mutations was reported in several parental tumor-PDO pairs, suggesting a different subclone of parental tissue may have been sequenced compared to the subclone(s) that grew into organoid culture, consistent with prior studies which reveal driver gene heterogeneity in IPMNs 23,40 .…”

Section: Discussionsupporting

confidence: 85%

“…DNA fingerprinting. To assess sample quality and integrity and establish sample identity, [34][35][36][37][38][39][40][41][42] ng (15 ng/µL) of isolated DNA from each sample was aliquoted and used to generate a DNA fingerprint with the 96-SNP Advanta™ SampleID Genotyping Panel (Fluidigm, Inc). Briefly, the DNA samples were pre-amplified using the Advanta specific target amplification (STA) primers according to the manufacturer's protocol and the amplified DNA along with the Advanta SampleID allele-specific (ASP) and locus-specific (LSP) primers were transferred to a Fluidigm 96.96 Dynamic Array Integrated Fluidics Circuit (IFC) for Genotyping.…”

Section: Imaging and Digital Quantification Of Patient-derived Organoidmentioning

confidence: 99%

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Establishing a Living Biobank of Patient-Derived Organoids of Intraductal Papillary Mucinous Neoplasms of the Pancreas

Beato

Reverón

Dezsi

et al. 2020

Preprint

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Pancreatic cancer (PaCa) is the third leading cause of cancer-related deaths in the United States. There is an unmet need to develop strategies to detect PaCa at an early, operable stage and prevent its progression. Intraductal papillary mucinous neoplasms (IPMNs) are cystic PaCa precursors that comprise nearly 50% of pancreatic cysts detected incidentally via cross-sectional imaging. Since IPMNs can progress from low- and moderate-grade dysplasia to high-grade dysplasia and invasion, the study of these lesions offers a prime opportunity to develop early detection and prevention strategies. Organoids are an ideal preclinical platform to study IPMNs, and the objective of the current investigation was to establish a living biobank of patient-derived organoids (PDO) from IPMNs. IPMN tumors and adjacent normal pancreatic tissues were successfully harvested from 15 patients with IPMNs undergoing pancreatic surgical resection at Moffitt Cancer Center & Research Institute (Tampa, FL) between May of 2017 and March of 2019. Organoid cultures were also generated from cryopreserved tissues. Organoid count and size were determined over time by both Image-Pro Premier 3D Version 9.1 digital platform and Matlab application of a Circular Hough Transform algorithm, and histologic and genomic characterization of a subset of the organoids was performed using immunohistochemistry and targeted sequencing, respectively. The success rates for organoid generation from IPMN tumor and adjacent normal pancreatic tissues were 81% and 87%, respectively. IPMN organoids derived from different epithelial subtypes showed different morphologies in vitro, and organoids recapitulated histologic and genomic characteristics of the parental IPMN tumor. In summary, this pre-clinical model has the potential to provide new opportunities to unveil mechanisms of IPMN progression to invasion and to shed insight into novel biomarkers for early detection and targets for chemoprevention.

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Section: Discussionsupporting

confidence: 85%

Section: Imaging and Digital Quantification Of Patient-derived Organoidmentioning

confidence: 99%

Establishing a Living Biobank of Patient-Derived Organoids of Intraductal Papillary Mucinous Neoplasms of the Pancreas

Beato

Reverón

Dezsi

et al. 2020

Preprint

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show abstract

“…Finally, while second primary carcinomas of the pancreas have been reported, our finding of a metachronous primary PDA in one of 10 otherwise unselected patients with an intrapancreatic mass post resection suggest that this phenomenon may be more common than previously appreciated (44,45). Detailed and formal prospective studies of intrapancreatic masses in patients who have undergone prior resection for PDA will be required to more firmly understand the frequency of second primary tumors and the risk factors associated with their development as has been shown for invasive carcinomas arising in intraductal papillary mucinous neoplasms of the pancreas (46).…”

Section: Discussionmentioning

confidence: 75%

Evolutionary Origins of Recurrent Pancreatic Cancer

Sakamoto

Attiyeh

Gerold

et al. 2019

Preprint

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Surgery is the only curative option for Stage I/II pancreatic cancer, nonetheless most patients will recur after surgery and die of their disease. To identify novel opportunities for management of recurrent pancreatic cancer we performed whole exome or targeted sequencing of 10 resected primary cancers and matched intrapancreatic recurrences or distant metastases. We identified that adjuvant or first-line platinum therapy corresponds to an increased mutational burden of recurrent disease. Recurrent disease is enriched for mutations that activate Mapk/Erk and PI3K/AKT signaling and develops from a monophyletic or polyphyletic origin. Treatment induced genetic bottlenecks lead to a modified genetic landscape and subclonal heterogeneity for driver gene alterations in part due to intermetastatic seeding. In one patient what was believed to be recurrent disease was an independent (second) primary tumor. These findings advocate for combination therapies with immunotherapy and routine post-treatment sampling as a component of management of recurrent pancreatic cancer.

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“…Progress towards identifying those MCLs that harbor high-grade dysplasia or early invasive PDAC has been made. There is increasing knowledge about the progression of IPMNs from a genetic perspective which suggests that early lesions are heterogeneous, while those with high-grade dysplasia have a smaller number of homogeneous driver genes 42 . Preliminary studies evaluating the presence of mutations in PIK3CA, SMAD4 and TP53 in cyst fluid are promising, identifying almost 80% of IPMNs with high-grade dysplasia or cancer 43 .…”

Section: Cystic Lesionsmentioning

confidence: 99%

Early detection of pancreatic cancer

Pereira

Oldfield

Ney

et al. 2020

The Lancet Gastroenterology & Hepatology

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289

283

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Pancreatic ductal adenocarcinoma (PDAC) is most frequently detected at an advanced stage. This limits treatment options and contributes to a dismal 5-year survival rate of 3 to 15%. PDAC is relatively uncommon and with current modalities, screening of the asymptomatic adult population is not feasible or recommended. However, screening of individuals in highrisk groups is undertaken. Here we review high-risk groups for PDAC, including individuals with inherited predisposition and patients with pancreatic cystic lesions. We discuss new studies aimed at finding ways of identifying PDAC in high-risk groups, such as individuals with new-onset diabetes mellitus and those attending primary and secondary care practices with suggestive symptoms. We review early detection biomarkers, explore the potential of exploiting social media for PDAC detection, appraise prediction models developed using electronic health records and research data, and examine the application of artificial intelligence to imaging for the purposes of early PDAC detection.

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Intraductal Papillary Mucinous Neoplasms Arise From Multiple Independent Clones, Each With Distinct Mutations

Cited by 92 publications

References 42 publications

Establishing a Living Biobank of Patient-Derived Organoids of Intraductal Papillary Mucinous Neoplasms of the Pancreas

Establishing a Living Biobank of Patient-Derived Organoids of Intraductal Papillary Mucinous Neoplasms of the Pancreas

Evolutionary Origins of Recurrent Pancreatic Cancer

Early detection of pancreatic cancer

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