Regional differences in gallbladder cancer pathogenesis: Insights from a multi‐institutional comparison of tumor mutations

Narayan, Raja R.; Creasy, John M.; Goldman, Debra A.; Gönen, Mithat; Kandoth, Cyriac; Kundra, Ritika; Solit, David B.; Askan, Gokce; Klimstra, David S.; Baştürk, Olca; Allen, Peter J.; Balachandran, Vinod P.; D’Angelica, Michael I.; DeMatteo, Ronald P.; Drebin, Jeffrey A.; Kingham, T. Peter; Simpson, Amber L.; Abou‐Alfa, Ghassan K.; Harding, James J.; O'Reilly, Eileen Mary; Butte, Jean M.; Matsuyama, Ryusei; Endo, Itaru; Jarnagin, William R.

doi:10.1002/cncr.31850

Cited by 40 publications

(67 citation statements)

References 43 publications

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“…Only one ISH study on the MET gene copy number in GBCs was found in the literature, and it revealed that no amplification was detected in 89 cases of GBCs [25]. The previous studies using NGS data reported that MET amplification was rare event in GBCs [30,31]. In our study, no MET amplification was detected by NGS method in 17 available cases.…”

Section: Discussioncontrasting

confidence: 43%

Prevalence and Clinicopathological Significance of MET Overexpression and Gene Amplification in Patients with Gallbladder Carcinoma

et al. 2020

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PurposeMesenchymal epithelial transition (MET) is a proto-oncogene that encodes a heterodimeric transmembrane receptor tyrosine kinase for the hepatocyte growth factor. Aberrant MET signaling has been described in several solid tumors—especially non-small cell lung cancer— and is associated with tumor progression and adverse prognosis. As MET is a potential therapeutic target, information regarding its prevalence and clinicopathological relevance is crucial.Materials and MethodsWe investigated MET expression and gene amplification in 113 gallbladder cancers using tissue microarray. Immunohistochemistry was used to evaluate MET overexpression, and silver/fluorescence in situ hybridization (ISH) was used to assess gene copy number.ResultsMET overexpression was found in 37 cases of gallbladder carcinoma (39.8%), and gene amplification was present in 17 cases (18.3%). MET protein expression did not correlate with MET amplification. MET amplification was significantly associated with aggressive clinicopathological features, including high histological grade, advanced pT category, lymph node metastasis, and advanced American Joint Committee on Cancer stage. There was no significant correlation between any clinicopathological factors and MET overexpression. No difference in survival was found with respect to MET overexpression and amplification status.ConclusionOur data suggested that MET might be a potential therapeutic target for targeted therapy in gallbladder cancer, because <i>MET</i> amplification was found in a subset of tumors associated with adverse prognostic factors. Detection of <i>MET</i> amplification by ISH might be a useful predictive biomarker test for anti-MET therapy.

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Section: Discussioncontrasting

confidence: 43%

Prevalence and Clinicopathological Significance of MET Overexpression and Gene Amplification in Patients with Gallbladder Carcinoma

et al. 2020

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“…We generate ortho-and heterotopic GBCs featuring the most frequent genetic alterations (p53 together with mutant KRAS, as well as p53 in conjunction with mutant ERBB2). Tumors develop with 100% penetrance and can be generated with and without loss of Pten, a gene that is inactivated in a subset of human GBCs [18,31]. Since murine Erbb2 is known to be less oncogenic than its human counterpart, we introduced the human ERBB2 gene [32].…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in the ERBB2-gene are among the most common genetic alterations in gallbladder cancer [17,18,[24][25][26]. To assess their potential as oncogenic drivers in our organoid based GBCs, we stably introduced human ERBB2 and two ERBB2 mutants (ERBB2 S310F and ERBB2 V777L ) by retroviral transduction into gallbladder organoids, in which p53 loss had been induced by Cas9-mediated genome editing ( Figure 4A).…”

Section: Overexpression Of Activating Erbb2 Mutants Give Rise To Gbcmentioning

confidence: 99%

“…Thus far, several oncogenic driver mutations have been identified in patients with gallbladder cancer, including frequent inactivating mutations in tumor suppressor genes like TP53, ARID1A, and SMAD4, as well as activating mutations in the KRAS gene. Recurrent amplifications or activating mutations in members of the ERBB2 pathway (EGFR, ERBB2, ERBB3, and ERBB4 and their downstream targets) point toward a decisive role of this pathway in gallbladder carcinogenesis [17][18][19][20]. Overall, the molecular landscape of gallbladder carcinoma is heterogeneous, and the consequences of specific genetic aberrations alone or in the context of the co-mutational spectrum remains largely elusive.…”

Section: Introductionmentioning

confidence: 99%

“…Considering that EpCAM is uniformly expressed by the epithelial cells lining the luminal site of the gallbladder, it appears likely that the cell of origin of gallbladder organoids resides within this compartment ( Figure 1B). TP53 and KRAS are among the most frequently mutated genes in GBC [7,18]. To investigate whether alteration of these genes in gallbladder organoids leads to GBC, we first generated organoids from Kras lslG12D mice.…”

Section: Introduction Of Cancer Drivers Into Gb Organoids Leads To Tumentioning

confidence: 99%

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Potent Antitumor Activity of Liposomal Irinotecan in an Organoid- and CRISPR-Cas9-Based Murine Model of Gallbladder Cancer

Erlangga

Wolff

Poth

et al. 2019

Cancers

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Gallbladder cancer is associated with a dismal prognosis, and accurate in vivo models will be elemental to improve our understanding of this deadly disease and develop better treatment options. We have generated a transplantation-based murine model for gallbladder cancer that histologically mimics the human disease, including the development of distant metastasis. Murine gallbladder–derived organoids are genetically modified by either retroviral transduction or transfection with CRISPR/Cas9 encoding plasmids, thereby allowing the rapid generation of complex cancer genotypes. We characterize the model in the presence of two of the most frequent oncogenic drivers—Kras and ERBB2—and provide evidence that the tumor histology is highly dependent on the driver oncogene. Further, we demonstrate the utility of the model for the preclinical assessment of novel therapeutic approaches by showing that liposomal Irinotecan (Nal-IRI) is retained in tumor cells and significantly prolongs the survival of gallbladder cancer–bearing mice compared to conventional irinotecan.

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Comparison of genomic profiling of circulating tumor DNA in pancreaticobiliary malignancies in plasma and bile

Ohyama

Hirotsu

Amemiya

et al. 2023

Cancer

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Background: Obtaining sufficient pancreaticobiliary tumor tissue for genomic profiling has limitations. Liquid biopsies using plasma do not provide sufficient sensitivity. Thus, this study aimed to determine the effectiveness of liquid biopsy between bile and plasma for identifying oncogenic and drug-matched mutations.Methods: This study created a panel of 60 significantly mutated genes specific to pancreaticobiliary cancer (PBCA) and used it for genomic analysis of 212 deoxyribonucleic acid (DNA) samples (87 bile supernatant, 87 bile precipitate, and 38 plasma) from 87 patients with PBCA. The quantity of extracted DNA from bile and plasma was compared, as were genomic profiles of 38 pairs of bile and plasma from 38 patients with PBCA. Finally, we investigated 87 bile and 38 plasma for the ability to detect druggable mutations. Results:The amount of DNA was significantly lower in plasma than in bile (p < .001).Oncogenic mutations were identified in 21 of 38 (55%) patients in bile and nine (24%) in plasma samples (p = .005). Bile was significantly more sensitive than plasma in identifying druggable mutations (p = .032). The authors detected 23 drugmatched mutations in combined bile and plasma, including five ERBB2, four ATM, three BRAF, three BRCA2, three NF1, two PIK3CA, one BRCA1, one IDH1, and one PALB2.Conclusions: Liquid biopsy using bile may be useful in searching for therapeutic agents, and using the obtained genomic information may improve the prognoses of patients with PBCA.

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Regional differences in gallbladder cancer pathogenesis: Insights from a multi‐institutional comparison of tumor mutations

Cited by 40 publications

References 43 publications

Prevalence and Clinicopathological Significance of MET Overexpression and Gene Amplification in Patients with Gallbladder Carcinoma

Prevalence and Clinicopathological Significance of MET Overexpression and Gene Amplification in Patients with Gallbladder Carcinoma

Potent Antitumor Activity of Liposomal Irinotecan in an Organoid- and CRISPR-Cas9-Based Murine Model of Gallbladder Cancer

Comparison of genomic profiling of circulating tumor DNA in pancreaticobiliary malignancies in plasma and bile

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