Single-cell genetic analysis of clonal dynamics in colorectal adenomas indicates CDX2 gain as a predictor of recurrence.
Adenoma
/ genetics
Aged
Biomarkers, Tumor
/ genetics
CDX2 Transcription Factor
/ genetics
Chromosome Aberrations
Clonal Evolution
Colorectal Neoplasms
/ genetics
Comparative Genomic Hybridization
DNA Copy Number Variations
Female
Humans
In Situ Hybridization, Fluorescence
Male
Middle Aged
Neoplasm Recurrence, Local
/ genetics
Single-Cell Analysis
/ methods
CDX2
FISH
clonal evolution
colorectal adenoma
genomic instability
intratumour heterogeneity
recurrence
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
01 04 2019
01 04 2019
Historique:
received:
17
05
2018
revised:
11
07
2018
accepted:
13
08
2018
pubmed:
20
9
2018
medline:
22
5
2019
entrez:
20
9
2018
Statut:
ppublish
Résumé
Colorectal adenomas are common precancerous lesions with the potential for malignant transformation to colorectal adenocarcinoma. Endoscopic polypectomy provides an opportunity for cancer prevention; however, recurrence rates are high. We collected formalin-fixed paraffin-embedded tissue of 15 primary adenomas with recurrence, 15 adenomas without recurrence, and 14 matched pair samples (primary adenoma and the corresponding recurrent adenoma). The samples were analysed by array-comparative genomic hybridisation (aCGH) and single-cell multiplex interphase fluorescence in situ hybridisation (miFISH) to understand clonal evolution, to examine the dynamics of copy number alterations (CNAs) and to identify molecular markers for recurrence prediction. The miFISH probe panel consisted of 14 colorectal carcinogenesis-relevant genes (COX2, PIK3CA, APC, CLIC1, EGFR, MYC, CCND1, CDX2, CDH1, TP53, HER2, SMAD7, SMAD4 and ZNF217), and a centromere probe (CEP10). The aCGH analysis confirmed the genetic landscape typical for colorectal tumorigenesis, that is, CNAs of chromosomes 7, 13q, 18 and 20q. Focal aberrations (≤10 Mbp) were mapped to chromosome bands 6p22.1-p21.33 (33.3%), 7q22.1 (31.4%) and 16q21 (29.4%). MiFISH detected gains of EGFR (23.6%), CDX2 (21.8%) and ZNF217 (18.2%). Most adenomas exhibited a major clone population which was accompanied by multiple smaller clone populations. Gains of CDX2 were exclusively seen in primary adenomas with recurrence (25%) compared to primary adenomas without recurrence (0%). Generation of phylogenetic trees for matched pair samples revealed four distinct patterns of clonal dynamics. In conclusion, adenoma development and recurrence are complex genetic processes driven by multiple CNAs whose evaluations by miFISH, with emphasis on CDX2, might serve as a predictor of recurrence.
Identifiants
pubmed: 30229897
doi: 10.1002/ijc.31869
pmc: PMC6361680
mid: NIHMS993080
doi:
Substances chimiques
Biomarkers, Tumor
0
CDX2 Transcription Factor
0
CDX2 protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1561-1573Subventions
Organisme : Intramural NIH HHS
ID : Z01 BC010833-01
Pays : United States
Informations de copyright
© 2018 UICC.
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