Single-cell genetic analysis of clonal dynamics in colorectal adenomas indicates CDX2 gain as a predictor of recurrence

• Verfasst von: Fiedler, David [VerfasserIn]
• Verfasst von: Hirsch, Daniela [VerfasserIn]
• Verfasst von: Belle, Sebastian [VerfasserIn]
• Verfasst von: Gaiser, Timo [VerfasserIn]
• Titel: Single-cell genetic analysis of clonal dynamics in colorectal adenomas indicates CDX2 gain as a predictor of recurrence
• Verf.angabe: David Fiedler, Kerstin Heselmeyer-Haddad, Daniela Hirsch, Leanora S. Hernandez, Irianna Torres, Darawalee Wangsa, Yue Hu, Luis Zapata, Josef Rueschoff, Sebastian Belle, Thomas Ried and Timo Gaiser
• Jahr: 2019
• Jahr des Originals: 2018
• Umfang: 14 S.
• Fussnoten: Online 19 Sep 2018 ; Gesehen am 07.08.2019
• Titel Quelle: Enthalten in: International journal of cancer
• Ort Quelle: Bognor Regis : Wiley-Liss, 1966
• Jahr Quelle: 2019
• Band/Heft Quelle: 144(2019), 7, Seite 1561-1573
• ISSN Quelle: 1097-0215
• DOI: doi:10.1002/ijc.31869
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: CDX2
• Sach-SW: clonal evolution
• Sach-SW: colorectal adenoma
• Sach-SW: FISH
• Sach-SW: genomic instability
• Sach-SW: intratumour heterogeneity
• Sach-SW: recurrence
• K10plus-PPN: 1670727653

Abstract

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.