Open AccessAnalysis of mutational and proteomic heterogeneity of gastric cancer suggests an effective pipeline to monitor post-treatment tumor burden using circulating tumor DNA
Author(s) -
Noriyuki Sasaki,
Takeshi Iwaya,
Tadatoshi Chiba,
Masashi Fujita,
Ju Zhang,
Fumitaka Endo,
Mizunori Yaegashi,
Tsuyoshi Hachiya,
Ryo Sugimoto,
Tamotsu Sugai,
Doris R. Siwak,
Lance A. Liotta,
Yiling Lu,
Gordon B. Mills,
Hidewaki Nakagawa,
Satoshi Nishizuka
Publication year - 2020
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0239966
Subject(s) - biology , cancer , founder effect , concordance , genetics , deep sequencing , digital polymerase chain reaction , cold pcr , dna sequencing , gene , mutation , somatic evolution in cancer , allele , polymerase chain reaction , point mutation , genome , haplotype
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.