Genetic alterations during the neoplastic cascade towards cholangiocarcinoma in primary sclerosing cholangitis

Kamp, Eline; Dinjens, Winand N.M.; Doukas, Michail; Marion, Ronald van; Verheij, Joanne; Ponsioen, Cyriel Y.; Bruno, Marco J.; Koerkamp, B. Groot; Trivedi, Palak; Peppelenbosch, Maikel P.; Vries, Annemarie C. de

doi:10.1002/path.5994

Cited by 8 publications

(7 citation statements)

References 46 publications

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“…The mutational profile of cholangiocarcinoma in PSC is heterogeneous and affects genes similar to those in non-PSC associated cholangiocarcinoma, the most frequently mutated being TP53, KRAS, PI3KCA and GNAS. In low-grade and high-grade dysplastic lesions, loss or amplifications of several genes, as well as mutations in ERBB2 and TP53, can already occur [48,49]. Our work extend these data at the transcriptomic level and highlight that low-grade BilIN can be very closely related to adenocarcinoma.…”

Section: Discussionsupporting

confidence: 69%

Spatial transcriptomics profiling of gallbladder adenocarcinoma: a detailed two-case study of progression from precursor lesions to cancer

Pirenne,

Manzano-Núñez,

Loriot

et al. 2024

Preprint

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Background: Most studies on tumour progression from precursor lesion toward gallbladder adenocarcinoma investigate lesions sampled from distinct patients, providing an overarching view of pathogenic cascades. Whether this reflects the tumourigenic process in individual patients remains insufficiently explored. Genomic and epigenomic studies suggest that a subset of gallbladder cancers originate from biliary intraepithelial neoplasia (BilIN) precursor lesions, whereas others form independently from BilINs. Spatial transcriptomics data supporting these conclusions are missing. Moreover, multiple areas with precursor or adenocarcinoma lesions can be detected within the same pathological sample. Yet, knowledge about intra-patient variability of such lesions is lacking. Methods: To characterise the spatial transcriptomics of gallbladder cancer tumourigenesis in individual patients, we selected two patients with distinct cancer aetiology and whose samples simultaneously displayed multiple areas of normal epithelium, BilINs and adenocarcinoma. Using GeoMx digital spatial profiling, we characterised the whole transcriptome of a high number of regions of interest (ROIs) per sample in the two patients (24 and 32 ROIs respectively), with each ROI covering approximately 200 cells of normal epithelium, low-grade BilIN, high-grade BilIN or adenocarcinoma. Human gallbladder organoids and cell-ine derived tumours were used to investigate the tumour-promoting role of genes. Results: Spatial transcriptomics revealed that each type of lesion displayed limited intra-patient transcriptomic variability. Our data further suggest that adenocarcinoma derived from high-grade BilIN in one patient and from low-grade BilIN in the other patient, with co-existing high-grade BilIN evolving via a distinct process in the latter case. The two patients displayed distinct sequences of signalling pathway activation during tumour progression, but Semaphorin 4A (SEMA4A) expression was repressed in both patients. Using human gallbladder-derived organoids and cell line-derived tumours, we provide evidence that repression of SEMA4A promotes pseudostratification of the epithelium and enhances cell migration and survival. Conclusion: Gallbladder adenocarcinoma can develop according to patient-specific processes, and limited intra-patient variability of precursor and cancer lesions was noticed. Our data suggest that repression of SEMA4A can promote tumour progression. They also highlight the need to gain gene expression data in addition to histological information to avoid understimating the risk of low-grade preneoplastic lesions.

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Section: Discussionsupporting

confidence: 69%

Spatial transcriptomics profiling of gallbladder adenocarcinoma: a detailed two-case study of progression from precursor lesions to cancer

Pirenne,

Manzano-Núñez,

Loriot

et al. 2024

Preprint

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“… 7 Some mutations are already present in dysplastic bile ducts and PSC-associated CCA; however, copy number variations appear early in cholangiocarcinogenesis. 12 Importantly, identifying HGD before its progression to invasive CCA is vital for early liver transplantation (LT) or, in cases with early CCA, LT after neoadjuvant chemoradiation. 13 …”

Section: Introductionmentioning

confidence: 99%

NGS of brush cytology samples improves the detection of high-grade dysplasia and cholangiocarcinoma in patients with primary sclerosing cholangitis: A retrospective and prospective study

Boyd,

Mustamäki,

Sjöblom

et al. 2024

Hepatology Communications

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Background: Biliary dysplasia, a precursor of cholangiocarcinoma (CCA), is a common complication of primary sclerosing cholangitis. Patients with high-grade dysplasia (HGD) or early CCA who have received oncological treatment are candidates for liver transplantation. The preoperative diagnosis of CCA or HGD is challenging, and the sensitivity of biliary brush cytology (BC) is limited. Methods: By using next-generation sequencing (NGS), we retrospectively analyzed archived tissue samples (n=62) obtained from explanted liver tissue and CCA samples to identify oncogenic mutations that occur during primary sclerosing cholangitis carcinogenesis. BC samples were prospectively collected from patients with primary sclerosing cholangitis (n=97) referred for endoscopic retrograde cholangiography to measure the diagnostic utility of NGS combined with BC compared with traditional cytology alone. Results: Mutations in KRAS, GNAS, FLT3, RNF43, TP53, ATRX, and SMAD4 were detected in archived CCA or HGD samples. KRAS, GNAS, TP53, CDKN2A, FBXW7, BRAF, and ATM mutations were detected in prospectively collected brush samples from patients with histologically verified CCA or HGD. One patient with low-grade dysplasia in the explanted liver had KRAS and GNAS mutations in brush sample. No mutations were observed in brush samples or archived tissues in liver transplantation cases without biliary neoplasia. While KRAS mutations are common in biliary neoplasms, they were also observed in patients without biliary neoplasia during surveillance. Conclusions: In summary, NGS of BC samples increased the sensitivity of detecting biliary neoplasia compared with traditional cytology. Performing NGS on BC samples may help diagnose HGD or early CCA, benefiting the timing of liver transplantation.

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“…Results are even more variable in wild-type mice. TAA is not mutagenic per se; instead, the initiation of chronic sclerosing inflammation and continuous regeneration drives the spontaneous accumulation of mutations in biliary cells, which then become cancerous, as is observed in patients with chronic cholangiopathies 105,106 . Therefore, combined with BDL, a classic model of obstructive cholestasis and subsequent bile duct proliferation, TAA accelerates the formation of biliary tumours in rats 106,107 .…”

Section: Chemically Induced Modelsmentioning

confidence: 99%

Criteria for preclinical models of cholangiocarcinoma: scientific and medical relevance

Calvisi

Boulter

Vaquero

et al. 2023

Nat Rev Gastroenterol Hepatol

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Cholangiocarcinoma (CCA) is a rare malignancy that develops at any point along the biliary tree. CCA has a poor prognosis, its clinical management remains challenging, and effective treatments are lacking. Therefore, preclinical research is of pivotal importance and necessary to acquire a deeper understanding of CCA and improve therapeutic outcomes. Preclinical research involves developing and managing complementary experimental models, from in vitro assays using primary cells or cell lines cultured in 2D or 3D to in vivo models with engrafted material, chemically induced CCA or genetically engineered models. All are valuable tools with well-defined advantages and limitations. The choice of a preclinical model is guided by the question(s) to be addressed; ideally, results should be recapitulated in independent approaches. In this Consensus Statement, a task force of 45 experts in CCA molecular and cellular biology and clinicians, including pathologists, from ten countries provides recommendations on the minimal criteria for preclinical models to provide a uniform approach. These recommendations are based on two rounds of questionnaires completed by 35 (first round) and 45 (second round) experts to reach a consensus with 13 statements. An agreement was defined when at least 90% of the participants voting anonymously agreed with a statement. The ultimate goal was to transfer basic laboratory research to the clinics through increased disease understanding and to develop clinical biomarkers and innovative therapies for patients with CCA. Sections Introduction Methods Clinical features to consider In vivo CCA models In vitro CCA models Addressing clinical needs Study strengths and limitations Conclusions

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Genetic alterations during the neoplastic cascade towards cholangiocarcinoma in primary sclerosing cholangitis

Cited by 8 publications

References 46 publications

Spatial transcriptomics profiling of gallbladder adenocarcinoma: a detailed two-case study of progression from precursor lesions to cancer

Spatial transcriptomics profiling of gallbladder adenocarcinoma: a detailed two-case study of progression from precursor lesions to cancer

NGS of brush cytology samples improves the detection of high-grade dysplasia and cholangiocarcinoma in patients with primary sclerosing cholangitis: A retrospective and prospective study

Criteria for preclinical models of cholangiocarcinoma: scientific and medical relevance

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