title: Exome capture sequencing of adenoma reveals genetic alterations in multiple cellular pathways at the early stage of colorectal tumorigenesis.
abstract: Most of colorectal adenocarcinomas are believed to arise from adenomas, which are premalignant lesions. Sequencing the whole exome of the adenoma will help identifying molecular biomarkers that can predict the occurrence of adenocarcinoma more precisely and help understanding the molecular pathways underlying the initial stage of colorectal tumorigenesis. We performed the exome capture sequencing of the normal mucosa, adenoma and adenocarcinoma tissues from the same patient and sequenced the identified mutations in additional 73 adenomas and 288 adenocarcinomas. Somatic single nucleotide variations (SNVs) were identified in both the adenoma and adenocarcinoma by comparing with the normal control from the same patient. We identified 12 nonsynonymous somatic SNVs in the adenoma and 42 nonsynonymous somatic SNVs in the adenocarcinoma. Most of these mutations including OR6X1, SLC15A3, KRTHB4, RBFOX1, LAMA3, CDH20, BIRC6, NMBR, GLCCI1, EFR3A, and FTHL17 were newly reported in colorectal adenomas. Functional annotation of these mutated genes showed that multiple cellular pathways including Wnt, cell adhesion and ubiquitin mediated proteolysis pathways were altered genetically in the adenoma and that the genetic alterations in the same pathways persist in the adenocarcinoma. CDH20 and LAMA3 were mutated in the adenoma while NRXN3 and COL4A6 were mutated in the adenocarcinoma from the same patient, suggesting for the first time that genetic alterations in the cell adhesion pathway occur as early as in the adenoma. Thus, the comparison of genomic mutations between adenoma and adenocarcinoma provides us a new insight into the molecular events governing the early step of colorectal tumorigenesis.
authors.affiliation: The Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, the Key Laboratory of Molecular Biology in Medical Sciences of Zhejiang Province, Cancer Institute, Hangzhou, Zhejiang, China.
authors.forename: Donger
authors.initials: D
authors.lastname: Zhou
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.forename: Liangtao
authors.initials: L
authors.lastname: Zheng
authors.forename: Weiting
authors.initials: W
authors.lastname: Ge
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xueda
authors.initials: X
authors.lastname: Hu
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Gao
authors.forename: Jinghong
authors.initials: J
authors.lastname: Xu
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Huang
authors.forename: Hanguang
authors.initials: H
authors.lastname: Hu
authors.forename: Hang
authors.initials: H
authors.lastname: Zhang
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.forename: Mingming
authors.initials: M
authors.lastname: Liu
authors.forename: Huanming
authors.initials: H
authors.lastname: Yang
authors.forename: Lei
authors.initials: L
authors.lastname: Zheng
authors.forename: Shu
authors.initials: S
authors.lastname: Zheng
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics; D000236:Adenoma / Q000235:genetics*; D000368:Aged; D002448:Cell Adhesion; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002874:Chromosome Mapping; D015179:Colorectal Neoplasms / Q000235:genetics*; D059472:Exome; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA / Q000379:methods*