Prognostic value of LINE-1 methylation level in 321 patients with primary liver cancer including hepatocellular carcinoma and intrahepatic cholangiocarcinoma

Miyata, Tatsunori; Yamashita, Yo Ichi; Baba, Yoshifumi; Harada, Kazuto; Yamao, Takanobu; Umezaki, Naoki; Tsukamoto, M; Yamamura, Kensuke; Arima, Kei; Nakagawa, Shigeki; Okabe, Hidetoshi; Imai, Katsunori; Hashimoto, Daisuke; Chikamoto, Akira; Shimokawa, Mototsugu

doi:10.18632/oncotarget.25124

Cited by 13 publications

(13 citation statements)

References 44 publications

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“…These additional markers may also help in monitoring treatment response and implement management plans appropriately. It has been an active area of research and studies have explored CpG island methylator phenotype (CIMP), osteopontin (OPN), matrix metalloproteinase 7 (MMP7), pregnancy-specific glycoprotein 9 (PSG9), methylation level of long interspersed nucleotide element-1 (LINE-1), T-cell immunoglobulin and mucin domaincontaining molecule-3, IL-6 and C-reactive protein as prognostic biomarkers in HCC patients (8,(25)(26)(27)(28).…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6 as a biomarker in patients with hepatobiliary cancers

Gosain

Anwar

Miller

et al. 2019

J. Gastrointest. Oncol

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Background: The role of inflammation has been well established in many cancers, including hepatobiliary cancers. Elevated levels of interleukin-6 (IL-6), a pro-inflammatory marker, are associated with poor overall survival (OS) in hepatocellular carcinoma (HCC) patients. Methods: We performed a study to establish the role of IL-6 as a prognostic biomarker in both HCC and biliary cancer patients and further assessed the impact of IL-6 on pain score and performance status, two parameters that affect the quality of life. We evaluated 91 patients with newly diagnosed unresectable hepatobiliary cancer and compared them with age, gender and BMI matched healthy controls. Results: We found that IL-6 levels were elevated in hepatobiliary cancer patients compared to healthy controls. Higher levels of IL-6 were associated with poor prognosis, elevated pain scores and poor performance status in patients. Interestingly, we found an association between elevated IL-6 levels and the presence of portal vein thrombosis (PVT) at the time of cancer diagnosis. Conclusions: This study suggests that IL-6 is an important prognostic biomarker in hepatobiliary cancers, where elevated levels are not only associated with a worse survival but also linked to an inferior quality of life.

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Section: Discussionmentioning

confidence: 99%

Interleukin-6 as a biomarker in patients with hepatobiliary cancers

Gosain

Anwar

Miller

et al. 2019

J. Gastrointest. Oncol

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“…Our comprehensive literature search in PubMed (search terms: L1 or LINE1 or LINE-1 AND liver AND methylation AND hepatocellular) revealed in total 11 studies addressing LINE-1 methylation in primary liver tissues [17, 23–25, 30–36] and 3 studies addressing LINE-1 methylation in the blood of HCC patients [37–39]. Various methods were used for the DNA methylation analysis including MS-PCR [36], Methyl-Light and COBRA [30], quantitative real-time PCR and bisulfite sequencing [33], pyrosequencing [17, 23–25, 34], and array-based genome-wide assessment [35]. Due to the widespread presence of DNA methylation in LINE-1 sequences under physiological conditions, detection of DNA methylation aberrations requires (semi)-quantitative methods to accurately detect changes specific for the malignant process [40].…”

Section: Discussionmentioning

confidence: 99%

“…LINE-1 hypomethylation has been reported in some gastrointestinal cancers including colorectal cancer [20], esophageal cancer [21], gastric cancer [22] and correlated with poorer clinical outcome. Although correlation of LINE-1 hypomethylation and unfavorable HCC outcome has been previously reported in patient cohorts from East Asia [23–25], there is no previous report including benign liver tumors and the comparison with adjacent healthy liver tissues.…”

Section: Introductionmentioning

confidence: 99%

LINE-1 hypomethylation in human hepatocellular carcinomas correlates with shorter overall survival and CIMP phenotype

et al. 2019

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Reactivation of interspersed repetitive sequences due to loss of methylation is associated with genomic instability, one of the hallmarks of cancer cells. LINE-1 hypomethylation is a surrogate marker for global methylation loss and is potentially a new diagnostic and prognostic biomarker in tumors. However, the correlation of LINE-1 hypomethylation with clinicopathological parameters and the CpG island methylator phenotype (CIMP) in patients with liver tumors is not yet well defined, particularly in Caucasians who show quite low rates of HCV/HBV infection and a higher incidence of liver steatosis. Therefore, quantitative DNA methylation analysis of LINE-1 , RASSF1A , and CCND2 using pyrosequencing was performed in human hepatocellular carcinomas (HCC, n = 40), hepatocellular adenoma (HCA, n = 10), focal nodular hyperplasia (FNH, n = 5), and corresponding peritumoral liver tissues as well as healthy liver tissues (n = 5) from Caucasian patients. Methylation results were correlated with histopathological findings and clinical data. We found loss of LINE-1 DNA methylation only in HCC. It correlated significantly with poor survival (log rank test, p = 0.007). An inverse correlation was found for LINE-1 and RASSF1A DNA methylation levels (r 2 = -0.47, p = 0.002). LINE-1 hypomethylation correlated with concurrent RASSF1 / CCND2 hypermethylation (Fisher’s exact test, p = 0.02). Both LINE-1 hypomethylation and RASSF1A / CCND2 hypermethylation were not found in benign hepatocellular tumors (HCA and FNH). Our results show that LINE-1 hypomethylation and RASSF1A / CCND2 hypermethylation are epigenetic aberrations specific for the process of malignant liver transformation. In addition, LINE-1 hypomethylation might serve as a future predictive biomarker to identify HCC patients with unfavorable overall survival.

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“…There were no findings of chronic bile duct injury, proliferative changes, and lesion of biliary intraepithelial neoplasm (BilIN) by pathological assessment. To assess the genetic characteristics in each tumor, the intratumoral methylation levels of long interspersed nucleotide factor-1(LINE-1), which is regarded as a surrogate marker of global DNA methylation [7], were measured by laser micro-dissection and bisulfite genomic sequencing in each tumor (intra-and extra-hepatic cholangiocarcinomas) as previously described [8,9]. The methylation levels of intrahepatic and extrahepatic cholangiocarcinomas (segment III, segment VI, and extrahepatic hepatic duct) were 75.23 ± 4.42, 85.88 ± 1.9, and 82.34 ± 3.11, respectively.…”

Section: Case Presentationmentioning

confidence: 99%

Multiple cholangiocarcinomas in the intrahepatic and extrahepatic biliary tree due to dichloromethane exposure: a case report

et al. 2020

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Background: An outbreak of cholangiocarcinoma in Japan has led to widespread concern among workers in printing plants. In March 2013, the Japanese Ministry of Health, Labour and Welfare, confirmed a causal relationship between cholangiocarcinoma and long-term exposure to dichloromethane (DCM) and 1,2-dichloropropane (DCP), which were widely used in printing plants. We herein report a rare case of successful radical resection of multiple cholangiocarcinomas in the intrahepatic and extrahepatic bile ducts caused by past exposure to DCM. Case presentation: A 54-year-old man developed brown urine 22 years after his last exposure to DCP and DCM. He had an 11-year history of working at a printing plant from the age of 21 to 31 years and dealt with organic solvents during his employment. Enhanced computed tomography revealed a thickened distal bile duct wall with upstream biliary dilatation and multiple intrahepatic cholangiocarcinomas located in liver segments III, VI, and VIII. Biopsy of the distal bile duct wall revealed adenocarcinoma, and a diagnosis of distal cholangiocarcinoma was made. Tumor marker levels were within the reference range (carcinoembryonic antigen, 3.3 ng/mL; carbohydrate antigen 19-9, 25.4 U/mL; SPAN-1, 13 U/mL; and DUPAN-2, 33 U/mL). The multiple intrahepatic and extrahepatic bile duct cancers were treated by subtotal stomach-preserving pancreatoduodenectomy and partial hepatectomy of segments III, VI, and VIII. Pathological examination of the surgical specimens revealed multiple cholangiocarcinomas with well-differentiated adenocarcinoma in the biliary tree. The patient was still alive without recurrence 17 months after the operation. Conclusions: We experienced a rare case of multiple cholangiocarcinomas in the intrahepatic and extrahepatic bile ducts that developed 22 years after the patient's last exposure to DCP and DCM. Long-term and careful follow-up is required for workers with an occupational history of exposure to organic solvents because of the risk of development of cholangiocarcinoma.

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Prognostic value of LINE-1 methylation level in 321 patients with primary liver cancer including hepatocellular carcinoma and intrahepatic cholangiocarcinoma

Cited by 13 publications

References 44 publications

Interleukin-6 as a biomarker in patients with hepatobiliary cancers

Interleukin-6 as a biomarker in patients with hepatobiliary cancers

LINE-1 hypomethylation in human hepatocellular carcinomas correlates with shorter overall survival and CIMP phenotype

Multiple cholangiocarcinomas in the intrahepatic and extrahepatic biliary tree due to dichloromethane exposure: a case report

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