Identification and monitoring of mutations in circulating cell-free tumor DNA in hepatocellular carcinoma treated with lenvatinib
Abstract Background There has been a recent surge in interest in predicting biological effects associated with genomic alterations in order to implement personalized cancer treatment strategies. However, no reports have yet evaluated the utility of profiling blood-based circulating tumor DNA (ctDNA)...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Language: | English |
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BMC
2021-06-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-021-02016-3 |
| _version_ | 1819156176875552768 |
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| author | Yasutoshi Fujii Atsushi Ono C. Nelson Hayes Hiroshi Aikata Masami Yamauchi Shinsuke Uchikawa Kenichiro Kodama Yuji Teraoka Hatsue Fujino Takashi Nakahara Eisuke Murakami Daiki Miki Wataru Okamoto Tomokazu Kawaoka Masataka Tsuge Michio Imamura Kazuaki Chayama |
| author_facet | Yasutoshi Fujii Atsushi Ono C. Nelson Hayes Hiroshi Aikata Masami Yamauchi Shinsuke Uchikawa Kenichiro Kodama Yuji Teraoka Hatsue Fujino Takashi Nakahara Eisuke Murakami Daiki Miki Wataru Okamoto Tomokazu Kawaoka Masataka Tsuge Michio Imamura Kazuaki Chayama |
| author_sort | Yasutoshi Fujii |
| collection | DOAJ |
| description | Abstract Background There has been a recent surge in interest in predicting biological effects associated with genomic alterations in order to implement personalized cancer treatment strategies. However, no reports have yet evaluated the utility of profiling blood-based circulating tumor DNA (ctDNA) in hepatocellular carcinoma (HCC) patients treated with lenvatinib (LEN). Method We retrospectively performed ctDNA next-generation sequencing (NGS) analysis in 24 patients with advanced HCC at baseline and 4 weeks after initiation of LEN. Association of the changes in variant allele frequencies (VAFs) during treatment and clinical outcome were evaluated. Results In total, 131 single nucleotide variants, 17 indels, and 23 copy number variations were detected as somatic alterations in 28, 6, and 12 genes, respectively in 23 of 24 patients. The most frequently altered genes were TP53 (54%), CTNNB1 (42%), TERT (42%), ATM (25%), and ARID1A (13%). The reduction in the mean frequency of variants (VAFmean) following 4 weeks of LEN treatment was associated with longer progression-free survival. The specificity and sensitivity of the reduction of VAFmean for predicting partial response were 0.67 and 1.0, respectively, which were higher than those of serum α-fetoprotein level (0.10 and 0.93, respectively). No association between the mutation status at baseline and the effectiveness of LEN was observed. Conclusion Our study demonstrated that somatic alterations could be detected in the majority of advanced HCC patients by ctDNA profiling and that ctDNA-kinetics during LEN treatment was a useful marker of disease progression. These results suggest that ctDNA profiling is a promising method that provides valuable information in clinical practice. |
| first_indexed | 2024-12-22T15:48:43Z |
| format | Article |
| id | doaj.art-6a95b65a536041269b13c996e42b4676 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-22T15:48:43Z |
| publishDate | 2021-06-01 |
| publisher | BMC |
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| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-6a95b65a536041269b13c996e42b46762022-12-21T18:20:58ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662021-06-0140111810.1186/s13046-021-02016-3Identification and monitoring of mutations in circulating cell-free tumor DNA in hepatocellular carcinoma treated with lenvatinibYasutoshi Fujii0Atsushi Ono1C. Nelson Hayes2Hiroshi Aikata3Masami Yamauchi4Shinsuke Uchikawa5Kenichiro Kodama6Yuji Teraoka7Hatsue Fujino8Takashi Nakahara9Eisuke Murakami10Daiki Miki11Wataru Okamoto12Tomokazu Kawaoka13Masataka Tsuge14Michio Imamura15Kazuaki Chayama16Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima UniversityDepartment of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima UniversityDepartment of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima UniversityDepartment of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima UniversityDepartment of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima UniversityDepartment of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima UniversityDepartment of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima UniversityDepartment of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima UniversityDepartment of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima UniversityDepartment of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima UniversityDepartment of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima UniversityDepartment of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima UniversityCancer Treatment Center, Hiroshima University HospitalDepartment of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima UniversityNatural Science Center for Basic Research and Development, Hiroshima UniversityDepartment of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima UniversityCollaborative Research Laboratory of Medical Innovation, Graduate School of Biomedical and Health Sciences, Hiroshima UniversityAbstract Background There has been a recent surge in interest in predicting biological effects associated with genomic alterations in order to implement personalized cancer treatment strategies. However, no reports have yet evaluated the utility of profiling blood-based circulating tumor DNA (ctDNA) in hepatocellular carcinoma (HCC) patients treated with lenvatinib (LEN). Method We retrospectively performed ctDNA next-generation sequencing (NGS) analysis in 24 patients with advanced HCC at baseline and 4 weeks after initiation of LEN. Association of the changes in variant allele frequencies (VAFs) during treatment and clinical outcome were evaluated. Results In total, 131 single nucleotide variants, 17 indels, and 23 copy number variations were detected as somatic alterations in 28, 6, and 12 genes, respectively in 23 of 24 patients. The most frequently altered genes were TP53 (54%), CTNNB1 (42%), TERT (42%), ATM (25%), and ARID1A (13%). The reduction in the mean frequency of variants (VAFmean) following 4 weeks of LEN treatment was associated with longer progression-free survival. The specificity and sensitivity of the reduction of VAFmean for predicting partial response were 0.67 and 1.0, respectively, which were higher than those of serum α-fetoprotein level (0.10 and 0.93, respectively). No association between the mutation status at baseline and the effectiveness of LEN was observed. Conclusion Our study demonstrated that somatic alterations could be detected in the majority of advanced HCC patients by ctDNA profiling and that ctDNA-kinetics during LEN treatment was a useful marker of disease progression. These results suggest that ctDNA profiling is a promising method that provides valuable information in clinical practice.https://doi.org/10.1186/s13046-021-02016-3Hepatocellular carcinomaCirculating tumor DNALenvatinib |
| spellingShingle | Yasutoshi Fujii Atsushi Ono C. Nelson Hayes Hiroshi Aikata Masami Yamauchi Shinsuke Uchikawa Kenichiro Kodama Yuji Teraoka Hatsue Fujino Takashi Nakahara Eisuke Murakami Daiki Miki Wataru Okamoto Tomokazu Kawaoka Masataka Tsuge Michio Imamura Kazuaki Chayama Identification and monitoring of mutations in circulating cell-free tumor DNA in hepatocellular carcinoma treated with lenvatinib Journal of Experimental & Clinical Cancer Research Hepatocellular carcinoma Circulating tumor DNA Lenvatinib |
| title | Identification and monitoring of mutations in circulating cell-free tumor DNA in hepatocellular carcinoma treated with lenvatinib |
| title_full | Identification and monitoring of mutations in circulating cell-free tumor DNA in hepatocellular carcinoma treated with lenvatinib |
| title_fullStr | Identification and monitoring of mutations in circulating cell-free tumor DNA in hepatocellular carcinoma treated with lenvatinib |
| title_full_unstemmed | Identification and monitoring of mutations in circulating cell-free tumor DNA in hepatocellular carcinoma treated with lenvatinib |
| title_short | Identification and monitoring of mutations in circulating cell-free tumor DNA in hepatocellular carcinoma treated with lenvatinib |
| title_sort | identification and monitoring of mutations in circulating cell free tumor dna in hepatocellular carcinoma treated with lenvatinib |
| topic | Hepatocellular carcinoma Circulating tumor DNA Lenvatinib |
| url | https://doi.org/10.1186/s13046-021-02016-3 |
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