Frequent post-operative monitoring of colorectal cancer using individualised ctDNA validated by multiregional molecular profiling

Mizunori Yaegashi, Takeshi Iwaya, Noriyuki Sasaki, Masashi Fujita, Zhenlin Ju, Doris Siwak, Tsuyoshi Hachiya, Kei Sato, Fumitaka Endo, Toshimoto Kimura, Koki Otsuka, Ryo Sugimoto, Tamotsu Sugai, Lance Liotta, Yiling Lu, Gordon B. Mills, Hidewaki Nakagawa, Satoshi S. Nishizuka

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Background: Circulating tumour DNA (ctDNA) is known as a tumour-specific personalised biomarker, but the mutation-selection criteria from heterogeneous tumours remain a challenge. Methods: We conducted multiregional sequencing of 42 specimens from 14 colorectal tumours of 12 patients, including two double-cancer cases, to identify mutational heterogeneity to develop personalised ctDNA assays using 175 plasma samples. Results: “Founder” mutations, defined as a mutation that is present in all regions of the tumour in a binary manner (i.e., present or absent), were identified in 12/14 tumours. In contrast, “truncal” mutations, which are the first mutation that occurs prior to the divergence of branches in the phylogenetic tree using variant allele frequency (VAF) as continuous variables, were identified in 12/14 tumours. Two tumours without founder and truncal mutations were hypermutators. Most founder and truncal mutations exhibited higher VAFs than “non-founder” and “branch” mutations, resulting in a high chance to be detected in ctDNA. In post-operative long-term observation for 10/12 patients, early relapse prediction, treatment efficacy and non-relapse corroboration were achievable from frequent ctDNA monitoring. Conclusions: A single biopsy is sufficient to develop custom dPCR probes for monitoring tumour burden in most CRC patients. However, it may not be effective for those with hypermutated tumours.

    Original languageEnglish (US)
    JournalBritish Journal of Cancer
    DOIs
    StateAccepted/In press - 2021

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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