Analysis of mutational and proteomic heterogeneity of gastric cancer suggests an effective pipeline to monitor post-treatment tumor burden using circulating tumor DNA
Open Access
- 7 October 2020
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 15 (10), e0239966
- https://doi.org/10.1371/journal.pone.0239966
Abstract
Circulating tumor DNA (ctDNA) is released from tumor cells into blood in advanced cancer patients. Although gene mutations in individual tumors can be diverse and heterogenous, ctDNA has the potential to provide comprehensive biomarker information. Here, we performed multi-region sampling (three sites) per resected specimen from 10 gastric cancer patients followed by targeted sequencing and proteomic profiling using reverse-phase protein arrays. A total of 126 non-synonymous mutations were identified from 30 samples from 10 tumors. Of these, 16 (12.7%) were present in all three regions and were designated as founder mutations. Variant allele frequencies (VAFs) of founder mutations were significantly higher than those of non-founder mutations. Phylogenetic analysis also demonstrated a good concordance between founder and truncal mutations, defined as mutations shared by all simulated clones at the trunk of the tumor phylogenetic tree. These findings led us to prioritize founder mutations for quantitative ctDNA monitoring by digital PCR with individually-designed primer/probe sets. In preoperative plasma, the average ctDNA VAF of founder mutations was significantly higher than that of non-founder mutations (p = 0.039). Proteomic heterogeneity was present across the tumor regions both within and between patients independent of mutational status. Our results suggest that, in practice, mutations having high VAF identified without multi-regional sequencing may be immediately useful for quantitative ctDNA monitoring but do not provide sufficient information to predict the proteomic composition of tumors.Funding Information
- Japan Society for the Promotion of Science (15KK0317)
- Japan Society for the Promotion of Science (19K09224)
- Japan Society for the Promotion of Science (19K09130)
- Japan Society for the Promotion of Science (17K10605)
- Japan Society for the Promotion of Science (JP16H01578)
This publication has 46 references indexed in Scilit:
- Phylogenetic ctDNA analysis depicts early-stage lung cancer evolutionNature, 2017
- Heterogeneity Underlies the Emergence of EGFRT790 Wild-Type Clones Following Treatment of T790M-Positive Cancers with a Third-Generation EGFR InhibitorCancer Discovery, 2015
- Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patientsNature Medicine, 2015
- Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 studyThe Lancet Oncology, 2014
- Analysis of Circulating Tumor DNA to Monitor Metastatic Breast CancerThe New England Journal of Medicine, 2013
- Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trialThe Lancet Oncology, 2012
- Plasma nucleic acid analysis by massively parallel sequencing: pathological insights and diagnostic implicationsThe Journal of Pathology, 2011
- Improved Survival with Vemurafenib in Melanoma with BRAF V600E MutationThe New England Journal of Medicine, 2011
- Cell-free nucleic acids as biomarkers in cancer patientsNature Reviews Cancer, 2011
- Genetic Heterogeneity of the Epidermal Growth Factor Receptor in Non–Small Cell Lung Cancer Cell Lines Revealed by a Rapid and Sensitive Detection System, the Peptide Nucleic Acid-Locked Nucleic Acid PCR ClampCancer Research, 2005