TY - JOUR
T1 - Frequent post-operative monitoring of colorectal cancer using individualised ctDNA validated by multiregional molecular profiling
AU - Yaegashi, Mizunori
AU - Iwaya, Takeshi
AU - Sasaki, Noriyuki
AU - Fujita, Masashi
AU - Ju, Zhenlin
AU - Siwak, Doris
AU - Hachiya, Tsuyoshi
AU - Sato, Kei
AU - Endo, Fumitaka
AU - Kimura, Toshimoto
AU - Otsuka, Koki
AU - Sugimoto, Ryo
AU - Sugai, Tamotsu
AU - Liotta, Lance
AU - Lu, Yiling
AU - Mills, Gordon B.
AU - Nakagawa, Hidewaki
AU - Nishizuka, Satoshi S.
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/4/27
Y1 - 2021/4/27
N2 - 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.
AB - 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.
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U2 - 10.1038/s41416-021-01266-4
DO - 10.1038/s41416-021-01266-4
M3 - Article
C2 - 33658639
AN - SCOPUS:85102031471
SN - 0007-0920
VL - 124
SP - 1556
EP - 1565
JO - British Journal of Cancer
JF - British Journal of Cancer
IS - 9
ER -