Single-cell genetic analysis of clonal dynamics in colorectal adenomas indicates CDX2 gain as a predictor of recurrence.
Date
2019-04-01ICR Author
Author
Fiedler, D
Heselmeyer-Haddad, K
Hirsch, D
Hernandez, LS
Torres, I
Wangsa, D
Hu, Y
Zapata, L
Rueschoff, J
Belle, S
Ried, T
Gaiser, T
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
CDX2
FISH
clonal evolution
colorectal adenoma
genomic instability
intratumour heterogeneity
recurrence
Adenoma
Aged
Biomarkers, Tumor
CDX2 Transcription Factor
Chromosome Aberrations
Clonal Evolution
Colorectal Neoplasms
Comparative Genomic Hybridization
DNA Copy Number Variations
Female
Humans
In Situ Hybridization, Fluorescence
Male
Middle Aged
Neoplasm Recurrence, Local
Single-Cell Analysis
Research team
Directorate for CEC
Language
eng
Date accepted
2018-08-13
License start date
2019-04-01
Citation
International Journal of Cancer, 2019, 144 (7), pp. 1561 - 1573
Publisher
WILEY