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Usefulness of Cell-Free Human Telomerase Reverse Transcriptase Mutant DNA Quantification in Blood for Predicting Hepatocellular Carcinoma Treatment Efficacy.

ABSTRACT: Although the usefulness of liquid biopsy as a biomarker in the treatment of hepatocellular carcinoma (HCC) has been suggested, its usefulness in transcatheter arterial chemoembolization (TACE) or tyrosine kinase inhibitor (TKI) therapies has not been reported in detail. In this study, we investigated the clinical value of a cell-free (cf)DNA quantification system targeting the human telomerase reverse transcriptase (hTERT) promoter mutation in advanced HCC treatment. Plasma from 67 patients with advanced HCC, treated with TACE and TKI, was used for extraction of cfDNA. We defined cfDNA with the hTERT promoter C228T mutation as circulating mutant DNA (mutant DNA) and without the mutation as circulating wild-type DNA (wild-type DNA). We analyzed the changes in mutant and wild-type DNA levels during HCC treatment and examined the relationship between changes in the cfDNA level and the clinical course. Mutant DNA was detected in 73.1% (49/67) of the patients during HCC treatment. In univariate analysis, factors associated with detection of mutant DNA before treatment were the intrahepatic maximum tumor diameter (P = 0.015) and protein induced by vitamin K absence (PIVKAII) (P = 0.006). The degree of mutant DNA change after TACE was significantly correlated with tumor volume (P < 0.001), reflecting the treated tumor volume. Responders with peak cfDNA levels within 1 week of TKI initiation had significantly better progression-free survival than nonresponders (P = 0.004). Conclusion: Changes in blood hTERT promoter mutant DNA levels during TACE or TKI treatment indirectly reflect the amount of HCCs and are useful for predicting long-term treatment responses.

SUBMITTER: Muraoka M

PROVIDER: S-EPMC8557313 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Usefulness of Cell-Free Human Telomerase Reverse Transcriptase Mutant DNA Quantification in Blood for Predicting Hepatocellular Carcinoma Treatment Efficacy.

Muraoka Masaru M Maekawa Shinya S Katoh Ryo R Komiyama Yasuyuki Y Nakakuki Natsuko N Takada Hitomi H Matsuda Shuya S Suzuki Yuichiro Y Sato Mitsuaki M Tatsumi Akihisa A Miura Mika M Amemiya Fumitake F Shindo Hiroko H Takano Shinichi S Fukasawa Mitsuharu M Yamauchi Kozue K Yamaguchi Tatsuya T Nakayama Yasuhiro Y Inoue Taisuke T Enomoto Nobuyuki N

Hepatology communications 20210728 11

Although the usefulness of liquid biopsy as a biomarker in the treatment of hepatocellular carcinoma (HCC) has been suggested, its usefulness in transcatheter arterial chemoembolization (TACE) or tyrosine kinase inhibitor (TKI) therapies has not been reported in detail. In this study, we investigated the clinical value of a cell-free (cf)DNA quantification system targeting the human telomerase reverse transcriptase (hTERT) promoter mutation in advanced HCC treatment. Plasma from 67 patients with ...[more]

PMID: 34558819

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Project description:Telomerase plays important roles in the development and progression of malignant tumors, and its activity is primarily determined by transcriptional regulation of human telomerase reverse transcriptase (hTERT). Several mRNA alternative splicing variants (ASVs) for hTERT have been identified, but it remains unclear whether telomerase activity is directly associated with hTERT splicing transcripts. In this study, we developed novel real-time PCR protocols using molecular beacons and applied to lung carcinoma cell lines and cancerous tissues for quantification of telomerase activity and three essential hTERT deletion transcripts respectively. The results showed that lung carcinoma cell lines consistently demonstrated telomerase activity (14.22-31.43 TPG units per 100 cells) and various hTERT alternative splicing transcripts. For 165 lung cancer cases, telomerase activity showed significant correlation with tumor differentiation (poorly->moderately->well-differentiated, P<0.01) and with histotypes (combined small cell and squamous cell carcinoma>squamous cell carcinoma>adenosquamous carcinoma>adenocarcinoma, P<0.05). Although the overall hTERT transcripts were detected in all the samples, they were not associated with telomerase activity (r = 0.092, P = 0.24). Telomerase activity was significantly correlated with the transcriptional constituent ratio of α-deletion (r = -0.267, P = 0.026), β-deletion (r = -0.693, P = 0.0001) and γ-deletion (r = -0.614, P = 0.001). The positive rate and average constituent ratio of β-deletion transcripts (92.12%, 0.23) were higher than those of α-deletion (41.82%, 0.12) or γ-deletion (16.36%, 0.18) transcripts. The combined small-cell and squamous cell carcinomas expressed less deletion transcripts, especially β-deletion, than other histotypes, which might explain their higher telomerase activity. In conclusion, the molecular beacon-based real-time PCR protocols are rapid, sensitive and specific methods to quantify telomerase activity and hTERT ASVs. Telomerase activity may serve as a reliable and effective molecular marker to assist the evaluation of histological subtype and differentiation of lung carcinomas. Further studies on hTERT deletion splicing transcripts, rather than the overall hTERT transcripts, may improve our understanding of telomerase regulation.

Dataset Information

Usefulness of Cell-Free Human Telomerase Reverse Transcriptase Mutant DNA Quantification in Blood for Predicting Hepatocellular Carcinoma Treatment Efficacy.

Publications

Usefulness of Cell-Free Human Telomerase Reverse Transcriptase Mutant DNA Quantification in Blood for Predicting Hepatocellular Carcinoma Treatment Efficacy.

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