A genetic roadmap of pancreatic cancer: still evolving

Notta, Faiyaz; Hahn, Stephan A.; Real, Francisco X.

doi:10.1136/gutjnl-2016-313317

Cited by 40 publications

(35 citation statements)

References 100 publications

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“…Pancreatic ductal adenocarcinoma develops through sequential genetic and epigenetic alterations in a number of driver genes, including KRAS , TP53 , SMAD4 , and CDKN2A . Accumulating evidence from engineered mouse models attests to the importance of PanIN as a precursor of PDAC .…”

Section: Introductionmentioning

confidence: 99%

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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Section: Introductionmentioning

confidence: 99%

Pathogenesis of multiple pancreatic cancers involves multicentric carcinogenesis and intrapancreatic metastasis

et al. 2020

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“…In addition to confirming SNPs in TERT, we found strong evidence for the 484 participation of novel susceptibility genes in telomere biology (PARN) and in the post-485 transcriptional regulation of gene expression (PRKCA and EIF2B5). Our study also 486 expands the landscape of variants and genes involved in exocrine biology, including 487 SEC63, NOC2/RPH3AL and SCRT whose function is likely to participate in acinar 488 function and in acinar-ductal metaplasia, a PC pre-neoplastic lesion 45 . 489…”

Section: D-approach: Genomic Interaction Analysis 399mentioning

confidence: 82%

“…Health, New Haven, CT, US. 118 (45) Escuela Andaluza de Salud Pública (EASP), Granada, Spain; Instituto de 119 Investigación Biosanitaria Granada, Spain; Centro de Investigación Biomédica en 120…”

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A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer

Maturana¹,

Rodríguez²,

Alonso³

et al. 2020

Preprint

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150 Word count -Abstract: 148 151 Word count -Text: 4,119 152 Word count Methods: 1,963 153 Number of References: 75 154 Number of Figures: 6 155 Number of supplementary tables: 8 156 ABSTRACT 158 Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors 159 interplay. To-date, 40 GWAS hits have been associated with PC risk in individuals of 160 European descent, explaining 4.1% of the phenotypic variance. Here, we complemented 161 PanC4, have been described elsewhere 6-9 . Genotyping for PanScan studies was performed

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“…It is known that KRAS, TP53, CDKN2A, and SMAD4 mutation are the classic genetic mutations found in pancreatic cancer, but also some rare genetic mutations, such as MLL3, BCLAF1, IRF6, FLG, AXIN1, GLI3, PIK3CA, RBM TGFBR2, ARID1A, EPC1, ARID2, SF3B1, ATM, and RNF43, occur, causing increased genomic heterogeneity between pancreatic cancers. 48 The stage of pancreatic cancer is associated with different mutations, with KRAS, p16/CDKN2A, GNAS, and BRAF being mutated in early phases of pancreatic cancer, while SMAD4/DPC4 and TP53 are mutated in later stages. [49][50][51][52] The cell lines used in this study, PANC-1, BxPC-3, MIA PaCa-2, and CAPAN-2, were derived from different pancreatic cancer patients and showed different biological and genetic characteristics.…”

Section: Discussionmentioning

confidence: 99%

Verteporfin- and sodium porfimer-mediated photodynamic therapy enhances pancreatic cancer cell death without activating stromal cells in the microenvironment

Roy

Anderson

et al. 2019

J. Biomed. Opt.

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The goal of our study was to determine the susceptibility of different pancreatic cell lines to clinically applicable photodynamic therapy (PDT). The efficacy of PDT of two different commercially available photosensitizers, verteporfin and sodium porfimer, was compared using a panel of four different pancreatic cancer cell lines, PANC-1, BxPC-3, CAPAN-2, and MIA PaCa-2, and an immortalized non-neoplastic pancreatic ductal epithelium cell line, HPNE. The minimum effective concentrations and dose-dependent curves of verteporfin and sodium porfimer on PANC-1 were determined. Since pancreatic cancer is known to have significant stromal components, the effect of PDT on stromal cells was also assessed. To mimic tumor-stroma interaction, a coculture of primary human fibroblasts or human pancreatic stellate cell (HPSCs) line with PANC-1 was used to test verteporfin-PDT-mediated cell death of PANC-1. Two cytokines (TNF-α and IL-1β) were used for stimulation of primary fibroblasts (derived from human esophageal biopsies) or HPSCs. The increased expression of smooth muscle actin (α-SMA) confirmed the activation of fibroblasts or HPSC upon treatment with TNF-α and IL-1β. Cell death assays showed that both sodium porfimer-and verteporfin-mediated PDT-induced cell death in a dose-dependent manner. However, verteporfin-PDT treatment had a greater efficiency with 60× lower concentration than sodium porfimer-PDT in the PANC-1 incubated with stimulated fibroblasts or HPSC. Moreover, activation of stromal cells did not affect the treatment of the pancreatic cancer cell lines, suggesting that the effects of PDT are independent of the inflammatory microenvironment found in this two-dimensional culture model of cancers.

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A genetic roadmap of pancreatic cancer: still evolving

Cited by 40 publications

References 100 publications

Pathogenesis of multiple pancreatic cancers involves multicentric carcinogenesis and intrapancreatic metastasis

Pathogenesis of multiple pancreatic cancers involves multicentric carcinogenesis and intrapancreatic metastasis

A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer

Verteporfin- and sodium porfimer-mediated photodynamic therapy enhances pancreatic cancer cell death without activating stromal cells in the microenvironment

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