title: Evolution and heterogeneity of non-hereditary colorectal cancer revealed by single-cell exome sequencing.
abstract: Recently single-cell whole-exome sequencing (scWES) has deeply expanded and sharpened our knowledge of cancer evolution and subclonality. Herein, with scWES and matched bulk whole-exome sequencing (bulk WES) on two colorectal cancer (CRC) patients with normal or adenomatous polyps, we found that both the adenoma and cancer were of monoclonal origin, and both shared partial mutations in the same signaling pathways, but each showed a specific spectrum of heterogeneous somatic mutations. In addition, the adenoma and cancer further developed intratumor heterogeneity with the accumulation of nonrandom somatic mutations specifically in GPCR, PI3K-Akt and FGFR signaling pathways. We identified novel driver mutations that developed during adenoma and cancer evolution, particularly in OR1B1 (GPCR signaling pathway) for adenoma evolution, and LAMA1 (PI3K-Akt signaling pathway) and ADCY3 (FGFR signaling pathway) for CRC evolution. In summary, we demonstrated that both colorectal adenoma and CRC are monoclonal in origin, and the CRCs further diversified into different subclones with heterogeneous mutation profiles accumulating in GPCR, PI3K-Akt and FGFR signaling pathways. ScWES provides evidence for the importance of mutations in certain pathways that would not be as apparent from bulk sequencing of tumors, and can potentially establish whether specific mutations are mutually exclusive or occur sequentially in the same subclone of cells.
authors.affiliation: Cancer Research Institute, Hangzhou Cancer Hospital, Hangzhou, China.|Department of Life Science, Sogang University, Seoul, South Korea.
authors.forename: H
authors.initials: H
authors.lastname: Wu
authors.affiliation: Cancer Research Institute, Hangzhou Cancer Hospital, Hangzhou, China.
authors.forename: X-Y
authors.initials: XY
authors.lastname: Zhang
authors.affiliation: Cancer Research Institute, Hangzhou Cancer Hospital, Hangzhou, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Cancer Research Institute, Hangzhou Cancer Hospital, Hangzhou, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Hou
authors.affiliation: Cancer Research Institute, Hangzhou Cancer Hospital, Hangzhou, China.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Cancer Research Institute, Hangzhou Cancer Hospital, Hangzhou, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: Cancer Research Institute, Hangzhou Cancer Hospital, Hangzhou, China.
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.affiliation: Cancer Research Institute, Hangzhou Cancer Hospital, Hangzhou, China.
authors.forename: J
authors.initials: J
authors.lastname: Yue
authors.affiliation: Cancer Research Institute, Hangzhou Cancer Hospital, Hangzhou, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Weissman
authors.affiliation: Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
authors.forename: X
authors.initials: X
authors.lastname: Pan
authors.affiliation: Department of Life Science, Sogang University, Seoul, South Korea.
authors.forename: B-G
authors.initials: BG
authors.lastname: Ju
authors.affiliation: Cancer Research Institute, Hangzhou Cancer Hospital, Hangzhou, China.
authors.forename: S
authors.initials: S
authors.lastname: Wu
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D003111:Colonic Polyps / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D015179:Colorectal Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017422:Sequence Analysis, DNA; D059010:Single-Cell Analysis
chemical_list: D015415:Biomarkers; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt