Analysis of mutations in DNA damage repair pathway gene in Chinese patients with hepatocellular carcinoma

Li, Jiarong; Li, Nianfeng; Azhar, Muhammad Salman; Liu, Ling; Wang, Liheng; Zhang, Qi; Sheng, Langqing; Wang, Jianhua; Feng, Sijia; Qiu, Qixuan; Xiao, Yao

doi:10.1038/s41598-022-16604-6

Cited by 6 publications

(4 citation statements)

References 25 publications

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“…8c) . Mutations detected in muc4 and blm are consistent with previous reports in human HCC 23,25,26 . To our knowledge, the other six hepatic genes mutated (Extended Data Fig.…”

Section: Resultssupporting

confidence: 91%

Loss of cis-PTase function in the liver promotes a highly penetrant form of fatty liver disease that rapidly transitions to hepatocellular carcinoma

Singh,

Chaube,

Citrin

et al. 2023

Preprint

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Obesity-linked fatty liver is a significant risk factor for hepatocellular carcinoma (HCC)1,2; however, the molecular mechanisms underlying the transition from non-alcoholic fatty liver disease (NAFLD) to HCC remains unclear. The present study explores the role of the endoplasmic reticulum (ER)-associated protein NgBR, an essential component of the cis-prenyltransferases (cis-PTase) enzyme3, in chronic liver disease. Here we show that genetic depletion of NgBR in hepatocytes of mice (N-LKO) intensifies triacylglycerol (TAG) accumulation, inflammatory responses, ER/oxidative stress, and liver fibrosis, ultimately resulting in HCC development with 100% penetrance after four months on a high-fat diet. Comprehensive genomic and single cell transcriptomic atlas from affected livers provides a detailed molecular analysis of the transition from liver pathophysiology to HCC development. Importantly, pharmacological inhibition of diacylglycerol acyltransferase-2 (DGAT2), a key enzyme in hepatic TAG synthesis, abrogates diet-induced liver damage and HCC burden in N-LKO mice. Overall, our findings establish NgBR/cis-PTase as a critical suppressor of NAFLD-HCC conversion and suggests that DGAT2 inhibition may serve as a promising therapeutic approach to delay HCC formation in patients with advanced non-alcoholic steatohepatitis (NASH).

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“…8c) . Mutations detected in muc4 and blm are consistent with previous reports in human HCC 23,25,26 . To our knowledge, the other six hepatic genes mutated (Extended Data Fig.…”

Section: Resultssupporting

confidence: 91%

Loss of cis-PTase function in the liver promotes a highly penetrant form of fatty liver disease that rapidly transitions to hepatocellular carcinoma

Singh,

Chaube,

Citrin

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…In our immunohistochemical stains for DNA mismatch, MMR proteins demonstrated the loss of MLH1 and PMS expression, compatible with MLH1 truncating mutation. In HCC and intrahepatic cholangiocarcinoma, the frequency of MLH1 mutation was less than 1% and 2.06%, respectively (55,56). Also, a previous report documented that no DNA MMR protein deficiency was observed in 24 cHCC-CCA (56), indicating that DNA MMR protein deficiency is quite rare in primary liver cancers, especially cHCC-CCA.…”

Section: Discussionmentioning

confidence: 91%

Genetic Analyses of Primary Liver Cancer Cell Lines: Correspondence With Morphological Features of Original Tumors

AKIBA,

OGASAWARA,

YANO

2024

Cancer Genomics Proteomics

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Background/Aim: Advancements in genetic analysis technologies have led to establishment of molecular classifications systems for primary liver cancers. The correlation between pathological morphology and genetic mutations in hepatocellular carcinoma (HCC) is becoming increasingly evident. To construct appropriate experimental models, it is crucial to select cell lines based on their morphology and genetic mutations. In this study, we conducted comprehensive genetic analyses of primary liver cancer cell lines and examined their correlations with morphology. Materials and Methods: Thirteen primary liver cancer cell lines established in our Department were investigated. Eleven cell lines were HCC cell lines, whereas 2 were combined hepatocellular-cholangiocarcinoma (CHC) cell line characteristics. Whole exome sequencing and fusion gene analyses were conducted using a next generation sequencing platform. We also examined correlations between cell mutations and morphological findings and conducted experiments to clarify the association between morphological findings and genetic alterations. Results: Mutations in TP53, HMCN1, PCLO, HYDIN, APOB, and EYS were found in 11,5,4,4,3,and 3 cell lines, respectively. CTNNB1 mutation was not identified in any cell line. The original tumor of four cell lines (KYN-1, KYN-2, showed morphologically macrotrabecular massive patterns and these cell lines harbor TP53 mutations. Two cell lines (KYN-2 and KMCH-2) showed an extremely high tumor mutation burden. These two cell lines possess ultra-mutations associated with DNA repair and/or DNA polymerase. Conclusion: The study identified correlations between morphological findings and genetic mutations in several HCC cell lines. Cell lines with unique genetic mutations were found. This information will be a valuable tool for the selection of suitable experimental models in HCC research.

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“… 102 P/LP germline variants were discovered in 4.2% of the patients overall, with P/LP variants in moderate to high penetrance genes ATM , BLM, BRCA1, NBN, PMS2, and RAD50 detected in HCC. Another study from China 103 examined 381 cancer-associated genes in the germline of 1427 patients with HCC and discovered 3.5% of these patients carried germline variants in ATR, BLM, BRCA1/2, CHEK2, FANCA, FANCC, FANCD2, MSH6, MLH11, MUTYH, PALB2, PMS2, RAD50, and SMARCA4 . The method for calling gene mutations was not described, and the specific variant allele sequences were not reported in this study.…”

Section: Rare Variants In Cancer-associated Genes In Hepatocellular C...mentioning

confidence: 99%

Germline Genetic Associations for Hepatobiliary Cancers

Chotiprasidhi,

Sato-Espinoza,

Wangensteen

2024

Cellular and Molecular Gastroenterology and Hepatology

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Analysis of mutations in DNA damage repair pathway gene in Chinese patients with hepatocellular carcinoma

Cited by 6 publications

References 25 publications

Loss of cis-PTase function in the liver promotes a highly penetrant form of fatty liver disease that rapidly transitions to hepatocellular carcinoma

Loss of cis-PTase function in the liver promotes a highly penetrant form of fatty liver disease that rapidly transitions to hepatocellular carcinoma

Genetic Analyses of Primary Liver Cancer Cell Lines: Correspondence With Morphological Features of Original Tumors

Germline Genetic Associations for Hepatobiliary Cancers

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