Pathways of Progression From Intraductal Papillary Mucinous Neoplasm to Pancreatic Ductal Adenocarcinoma Based on Molecular Features

Omori, Yuko; Ono, Yoshio; Tanino, Mishie; Karasaki, Hidenori; Yamaguchi, Hiroshi; Furukawa, Toru; Enomoto, Katsuro; Ueda, Junji; Sumi, Atsuko; Katayama, Jin; Muraki, Mineo; Taniue, Kenzui; Takahashi, Kuniyuki; Ambo, Yoshiyasu; Shinohara, Toshiya; Nishihara, Hiroshi; Sasajima, Junpei; Maguchi, Hiroyuki; Mizukami, Yusuke; Okumura, Toshikatsu; Tanaka, Shinya

doi:10.1053/j.gastro.2018.10.029

Cited by 132 publications

(109 citation statements)

References 48 publications

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“…Of note, the mutation profile obtained via EUS-FNB revealed equal levels of mutated alleles in KRAS and SMAD4, suggesting that the sampled tissue represented a tumor region harboring both mutations, whereas the pancreatic duct biopsy obtained during extended radical resection contained a mutation in KRAS but not SMAD4. Endoscopic biopsies may be less informative when assessing the mutational burdens and heterogeneities because they provide only locoregional information (unless multiple extractions from different areas of the tumor are performed) [9]. In our patient, the mutation-enriched tumor cells collected by EUS-FNB consistently exhibited high mutational burdens of both KRAS and SMAD4, which were observed in the recurrent gastric wall tumor.…”

Section: Discussionmentioning

confidence: 67%

“…When KRAS G12 D and G12V are found in multiple lesions, it is not easy to determine if they are clonally related or developed independently [7,8]. We therefore performed targeted sequencing to search for genes that are commonly mutated in human PDA [9], wherein we revealed a pathogenic mutation in SMAD4 across the specimens. However, genetic tracing does not confirm that EUS-FNB was indeed responsible for tumor dissemination because metastasis to the gastric wall could also have occurred via direct invasion.…”

Section: Discussionmentioning

confidence: 99%

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Genetic analysis of postoperative recurrence of pancreatic cancer potentially owing to needle tract seeding during EUS-FNB

Kawabata

Miyazawa²,

Sato³

et al. 2019

Endosc Int Open

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Background and study aims Needle tract seeding during endoscopic ultrasound fine-needle biopsy (EUS-FNB) remains a concern. We investigated whether such seeding occurred in a patient with pancreatic ductal adenocarcinoma (PDA). Patient and methods Surgically resected and EUS-FNB-derived specimens were genotyped to determine if a gastric wall tumor that emerged 3 years after curative resection of an early-stage PDA was clonally related to the original tumor. Results The gastric tumor histologically resembled the primary PDA; the lesions also shared KRAS, SMAD4, and RNF43 mutations. Genotyping of the preoperative EUS-FNB specimen, in which cancer was not detected, nevertheless revealed mutations that were identical to those in the resected primary and recurrent tumors. While the primary PDA had a low frequency of mutant SMAD4, such mutations were highly prevalent in both the EUS-FNB and recurrent tumor specimens. Conclusions The genetic lineages of sampled tissues from our patient revealed that needle tract seeding may have incidentally occurred when a subset of neoplastic cells within a heterogeneous tumor (i. e., an aggressive clone) was targeted during EUS-FNB.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Genetic analysis of postoperative recurrence of pancreatic cancer potentially owing to needle tract seeding during EUS-FNB

Kawabata

Miyazawa²,

Sato³

et al. 2019

Endosc Int Open

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“…For the three patients with metachronous tumors, pancreatic cut margin statuses at the initial surgery were negative. NGS analysis of tumors from the nine patients found no GNAS mutation, a major driver of IPMN tumorigenesis . None of the nine patients had a family history of pancreatic cancer in first‐degree relatives.…”

Section: Methodsmentioning

confidence: 92%

Pathogenesis of multiple pancreatic cancers involves multicentric carcinogenesis and intrapancreatic metastasis

et al. 2020

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There are increased opportunities in oncology clinics to identify multiple pancreatic ductal adenocarcinomas (PDAC) that co‐occur simultaneously or arise metachronously in the pancreatic parenchyma, yet their pathogenesis remains elusive. We hypothesized that two potential pathways, multicentric carcinogenesis and intrapancreatic metastasis, might contribute to forming multiple PDAC. Among 241 resected cases, we identified 20 cancer nodules from nine patients with multiple PDAC (six with synchronous PDAC, one with metachronous PDAC, and two with both synchronous and metachronous PDAC). Integrated clinical, pathological, and mutational analyses, using TP53 and SMAD4 immunostaining and targeted next‐generation sequencing of 50 cancer‐related genes, were conducted to examine the intertumor relationships. Four of the nine patients were assessed as having undergone multicentric carcinogenesis because of heterogeneity of immunohistochemical and/or mutation characteristics. In contrast, tumors in the other five patients showed intertumor molecular relatedness. Two of these five patients, available for matched sequencing data, showed two or more shared mutations. Moreover, all the smaller nodules in these five patients showed identical TP53 and SMAD4 expression patterns to the corresponding main tumors. Consequently, these five patients were considered to have undergone intrapancreatic metastasis. None of the five smaller nodules arising from intrapancreatic metastasis was accompanied by pancreatic intraepithelial neoplasia, and three of them were tiny (≤1mm). Patients whose tumors resulted from intrapancreatic metastasis appeared to have higher disease stages and worse outcome than those with tumors from multicentric carcinogenesis. Our results provide insight into pancreatic carcinogenesis, showing that the development of multiple PDAC involves distinct evolutionary paths that potentially affect patient prognosis.

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“…Detailed histologic and genetic analyses of PDAC and concurrent IPMNs have reportedly revealed three different genetic pathways in which alterations cause progression of IPMN-related PDAC of the molecular subtypes classified into sequential, branch-off and de novo subtypes. Information on the unique genetically altered pathways for progression to PDAC might reveal effective methods for evaluating the risk of PDAC in high-risk individuals [15]. Because of the low incidence and rapid progression of PDAC, CTCs might be superior to ctDNA as a screening method to improve prognosis.…”

Section: Blood-based Biomarkers For Early Detection Of Pdacmentioning

confidence: 99%

Trends in biomarker discoveries for the early detection and risk stratification of pancreatic cancer using omics studies

Kobayashi

Honda²

2019

Expert Review of Molecular Diagnostics

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Pathways of Progression From Intraductal Papillary Mucinous Neoplasm to Pancreatic Ductal Adenocarcinoma Based on Molecular Features

Cited by 132 publications

References 48 publications

Genetic analysis of postoperative recurrence of pancreatic cancer potentially owing to needle tract seeding during EUS-FNB

Genetic analysis of postoperative recurrence of pancreatic cancer potentially owing to needle tract seeding during EUS-FNB

Pathogenesis of multiple pancreatic cancers involves multicentric carcinogenesis and intrapancreatic metastasis

Trends in biomarker discoveries for the early detection and risk stratification of pancreatic cancer using omics studies

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