Wilson disease, ABCC2 c.3972C &gt; T polymorphism and primary liver cancers: suggestions from a familial cluster

Brandi, Giovanni; Rizzo, Alessandro; Deserti, Marzia; Relli, Valeria; Indio, Valentina; Bin, Sofia; Pariali, M.; Palloni, Andrea; Lorenzo, Stefania De; Tovoli, Francesco; Tavolari, Simona

doi:10.1186/s12881-020-01165-0

Cited by 6 publications

(4 citation statements)

References 25 publications

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“…Here, the frequency of ABCC2 variant c.3972T (rs3740066) allele T was significantly higher in CCA patients (39.2%) compared to healthy controls, suggesting that ABCC2 c.3972C > T (rs3740066) polymorphism is associated with an increased risk of CCA [ 28 ]. Brandi et al reported an interesting example of this SNP [ 68 ]. The authors conducted genotyping of five siblings from the same family and all five were identified as ABCC2 rs3740066 carriers.…”

Section: Resultsmentioning

confidence: 99%

The Role of Single-Nucleotide Polymorphisms in Cholangiocarcinoma: A Systematic Review

Wang

Heij

Liu

et al. 2022

Cancers

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Single-nucleotide polymorphisms (SNPs) play an essential role in various malignancies, but their role in cholangiocarcinoma (CCA) remains to be elucidated. Therefore, the purpose of this systematic review was to evaluate the association between SNPs and CCA, focusing on tumorigenesis and prognosis. A systematic literature search was carried out using PubMed, Embase, Web of Science and the Cochrane database for the association between SNPs and CCA, including literature published between January 2000 and April 2022. This systematic review compiles 43 SNPs in 32 genes associated with CCA risk, metastatic progression and overall prognosis based on 34 studies. Susceptibility to CCA was associated with SNPs in genes related to inflammation (PTGS2/COX2, IL6, IFNG/IFN-γ, TNF/TNF-α), DNA repair (ERCC1, MTHFR, MUTYH, XRCC1, OGG1), detoxification (NAT1, NAT2 and ABCC2), enzymes (SERPINA1, GSTO1, APOBEC3A, APOBEC3B), RNA (HOTAIR) and membrane-based proteins (EGFR, GAB1, KLRK1/NKG2D). Overall oncological prognosis was also related to SNPs in eight genes (GNB3, NFE2L2/NRF2, GALNT14, EGFR, XRCC1, EZH2, GNAS, CXCR1). Our findings indicate that multiple SNPs play different roles at various stages of CCA and might serve as biomarkers guiding treatment and allowing oncological risk assessment. Considering the differences in SNP detection methods, patient ethnicity and corresponding environmental factors, more large-scale multicentric investigations are needed to fully determine the potential of SNP analysis for CCA susceptibility prediction and prognostication.

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Section: Resultsmentioning

confidence: 99%

The Role of Single-Nucleotide Polymorphisms in Cholangiocarcinoma: A Systematic Review

Wang

Heij

Liu

et al. 2022

Cancers

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“…This research suggests that carcino-genesis may arise from liver damage, subsequently leading to chronic inflammation and cirrhosis due to chronic copper accumulation [ 10 , 11 ]. Recent research indicates that certain genetic variations, particularly the c.3972C > T variant at exon 28 of the ABCC2 gene, may play a role in enhancing susceptibility to primary liver cancer, including both HCC and IHCC [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

Intrahepatic Cholangiocarcinoma in Wilson’s Disease: A Case Report

Jang,

Kang,

Kim

2023

Am J Case Rep

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Patient: Female, 39-year-old Final Diagnosis: Intrahepatic cholangiocarcinoma Symptoms: Non Clinical Procedure: — Specialty: Oncology • Surgery Objective: Rare disease Background: Wilson’s disease is a rare autosomal recessive disorder characterized by excessive accumulation of copper in the liver, brain, and kidneys. Although it affects only approximately 1 in 30 000 individuals, it leads to progressive liver damage and neurological issue. Wilson’s disease presents a wide spectrum of clinical manifestations related to hepatic disease, ranging from asymptomatic cases to acute liver failure. The occurrence of hepatobiliary malignancies, including intrahepatic cholangiocarcinoma, is relatively uncommon in Wilson’s disease, even among patients with cirrhosis. Only 14 cases have been published so far, including the present report, and its etiology remains unclear. Case Report: We report the successful treatment of intrahepatic cholangiocarcinoma in a 39-year-old woman with Wilson’s disease. Twenty-two years after being diagnosed with Wilson’s disease, intrahepatic cholangiocarcinoma was diagnosed. She had an intrahepatic mass that was found to be a 4.3-cm ill-defined hypodense lesion in liver segment 3/4, with features suggesting infiltrative intrahepatic cholangiocarcinoma rather than hepatocellular carcinoma. Laboratory results showed slightly elevated liver enzymes and tumor markers. There was no evidence of metastasis on chest computed tomography or positron emission tomography, and the tumor was resectable, so surgery was the first-choice treatment option. Left hepatectomy was performed successfully, and the final pathology confirmed adenocarcinoma with clear resection margins. The patient received adjuvant chemotherapy with capecitabine. To date, the patient has been doing well without evidence of recurrence or metastasis. Conclusions: Despite limited knowledge regarding hepatic malignancy in Wilson’s disease, it is crucial to prioritize careful monitoring and develop suitable treatment strategies upon diagnosis to achieve favorable outcomes, considering the potential occurrence of intrahepatic cholangiocarcinoma in Wilson’s disease.

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“…10 By performing next generation sequencing in patients affected by DJS, several naturally occurring variants were found in ABCC2 sequence, including exon skipping, nonsense, missense, small deletions or insertions, and splice site variations, causing truncated and dysfunctional MRP2. [11][12][13][14][15] Previous studies have yielded initial insight into the mechanisms Open access by which DJS-causing variants in the ABCC2 gene alter MRP2 function, resulting in the inhibition of bile acid excretion as well as ineffective transport of bilirubin out of hepatocytes. 16 These findings are related to aberrant protein synthesis, and for missense variants to alter sublocalisation or secretory activity, which may cause MRP2 to remain in the endoplasmic reticulum rather than moving to the canalicular membrane, or finally to increased protein degradation.…”

Section: What This Study Addsmentioning

confidence: 99%

ABCC2p.R393W variant contributes to Dubin-Johnson syndrome by targeting MRP2 to proteasome degradation

Sun,

Chen,

Zhu

et al. 2024

egastro

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BackgroundDubin-Johnson syndrome (DJS), a rare autosomal recessive liver condition, is caused by biallelic loss-of-function mutations of theABCC2gene. This study aimed to investigate genetic variations in the drug efflux transporterABCC2(MRP2) gene in patients with DJS and to characterise the expression and mechanism of theABCC2gene variant.MethodsTrio whole exome sequencing was performed in the family to identify the genetic causes. Bioinformatics analysis was performed to assess pathogenicity. Inin vitroexperiments, site-directed mutagenesis was used to introduceABCC2variants in constructs then expressed in HEK293T, HuH-7 and HepG2 cell lines. The expression of total and cell membrane MRP2 was quantified in cells expressing the wild-type or variant forms. Chloroquine and MG132 were used to evaluate the effects of p.R393W on lysosomal and/or proteasomal degradation.ResultsThe twin probands carry DJS-associated variants c.1177C>T (rs777902199) in theABCC2gene inherited from the father and the c.3632T>C mutation in the other allele inherited from the mother. TheABCC2variant, c.1177C>T, results in a p.R393W substitution in MRP2 that is highly conserved among vertebrates, drastically decreasing the expression of mutant protein by promoting proteasomal degradation. Another variant c.3632T>C results in a p.L1211P substitution in MRP2, decreasing the expression of membrane MRP2 but not changing the expression of total protein.ConclusionThese results strongly suggest that the p.R393W variant affects the stability of the MRP2 protein and decreases its expression by ubiquitin-mediated proteasomal degradation, and the p.L1211P decreases the expression of membrane MRP2, indicating that these two variants, respectively, cause a loss-of-function of the MRP2 protein and membrane MRP2 ultimately leading to DJS development.

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Wilson disease, ABCC2 c.3972C > T polymorphism and primary liver cancers: suggestions from a familial cluster

Cited by 6 publications

References 25 publications

The Role of Single-Nucleotide Polymorphisms in Cholangiocarcinoma: A Systematic Review

The Role of Single-Nucleotide Polymorphisms in Cholangiocarcinoma: A Systematic Review

Intrahepatic Cholangiocarcinoma in Wilson’s Disease: A Case Report

ABCC2p.R393W variant contributes to Dubin-Johnson syndrome by targeting MRP2 to proteasome degradation

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