Genomic instability and oncogene amplifications in colorectal adenomas predict recurrence and synchronous carcinoma

Habermann, J.; Brucker, CA; Freitag‐Wolf, Sandra; Heselmeyer‐Haddad, Kerstin; Krüger, Stefan; Barenboim, Linda; Downing, Tricia E.; Hp, Bruch; Auer, Gert; Roblick, UJ; Ried, Thomas

doi:10.1055/s-0031-1285737

Cited by 6 publications

(12 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The frequency of EGFR CNAs in 42.9% (6/14) of adenomas without recurrence underlines the early occurrence of this CNA which is not related to recurrence. The overexpression of this transmembrane protein with intrinsic tyrosine‐kinase activity promotes tumour expansion by resistance to apoptosis and increased proliferation . However, CNAs detected by miFISH might, in fact, resemble disruptions of chromosomal regions exceeding single genes as confirmed by aCGH.…”

Section: Discussionsupporting

confidence: 88%

“…The gain of EGFR was the most frequent CNA observed by miFISH affecting 23.6% (13/55) of colorectal adenomas consistent with the results from Habermann et al . The frequency of EGFR CNAs in 42.9% (6/14) of adenomas without recurrence underlines the early occurrence of this CNA which is not related to recurrence.…”

Section: Discussionmentioning

confidence: 99%

“…However, underlying genetic changes and markers predicting local recurrence of colorectal adenomas remain largely elusive. By analysing colorectal adenomas, Habermann and colleagues reported the gain of 20q as an indicator of adenoma recurrence and/or synchronous carcinoma . To identify specific patterns of chromosomal aberrations that indicate local recurrence, we collected colorectal adenomas with and without recurrence and mapped genomic imbalances using array‐comparative genomic hybridisation (aCGH).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Fiedler

Heselmeyer‐Haddad

Hirsch

et al. 2018

Intl Journal of Cancer

View full text Add to dashboard Cite

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 fifteen primary adenomas with recurrence, fifteen adenomas without recurrence, and fourteen 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 fourteen colorectal carcinogenesis-relevant genes (COX2, PIK3CA, APC, CLIC1, EGFR, MYC, CCND1, CDX2, CDH1, TP53, HER2, SMAD7, SMAD4 and ZNF217), and a centromere probe (CEP10). ACGH analysis confirmed the genetic landscape typical for colorectal tumorigenesis, i.e., 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 evaluation by miFISH, with emphasis on CDX2, might serve as predictor of recurrence. This article is protected by copyright. All rights reserved.

show abstract

Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Fiedler

Heselmeyer‐Haddad

Hirsch

et al. 2018

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…Our study does not directly address this, and there is no clinical correlation in this regard concerning APC in the literature. However, genomic amplification of other oncogenes has been associated with adenoma recurrence and the presence of synchronous carcinomas [ 19 ], lymph node metastases [ 2 ], and prognosis [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

Copy number of the Adenomatous Polyposis Coli gene is not always neutral in sporadic colorectal cancers with loss of heterozygosity for the gene

2016

View full text Add to dashboard Cite

Background: Changes in the number of alleles of a chromosome may have an impact upon gene expression. Loss of heterozygosity (LOH) indicates that one allele of a gene has been lost, and knowing the exact copy number of the gene would indicate whether duplication of the remaining allele has occurred. We were interested to determine the copy number of the Adenomatous Polyposis Coli (APC) gene in sporadic colorectal cancers with LOH. Methods: We selected 38 carcinomas with LOH for the APC gene region of chromosome 5, as determined by amplification of the CA repeat region within the D5S346 loci. The copy number status of APC was ascertained using the SALSA® MLPA® P043-B1 APC Kit. LOH for the DCC gene, KRAS gene mutation, and microsatellite instability were also evaluated for each tumor, utilizing standard polymerase chain reaction methods. Results: No tumor demonstrated microsatellite instability. LOH of the DCC gene was also present in 33 of 36 (91.7 %) informative tumors. A KRAS gene mutation was present in 16 of the 38 (42.1 %) tumors. Twenty-four (63.2 %) of the tumors were copy number neutral, 10 (26.3 %) tumors demonstrated major loss, while two (5.3 %) showed partial loss. Two tumors (5.3 %) had copy number gain. Conclusions: Results of APC and DCC LOH, KRAS and microsatellite instability indicate our colorectal cancer cases were typical of sporadic cancers following the 'chromosomal instability' pathway. The majority of our colorectal carcinomas with LOH for APC gene are copy number neutral. However, one-third of our cases showed copy number loss, suggesting that duplication of the remaining allele is not required for the development of a colorectal carcinoma.

show abstract

“…Th is leads to pathophysiological considerations: a dysfunction of the TP53 pathway contributes to an increase of chromosomal instability and could therefore facilitate the emergence of a complex or a monosomal karyotype. It is indeed known to facilitate aneuploidies by apoptotic default [8] and cooperation with oncogenic pathways such as MYC [9], amplifi cation of which has been associated with the presence of aneuploid cells in colorectal adenomas [10]. Moreover, it has been demonstrated that a TP53 loss is strongly associated with the presence of a mutated form on the other allele [11].…”

Section: Letter To the Editor 337mentioning

confidence: 99%

Monosomal karyotype routinely defines a poor prognosis subgroup in acute myeloid leukemia and is frequently associated withTP53deletion

Gaillard

Chiésa

Reboul

et al. 2011

Leukemia & Lymphoma

View full text Add to dashboard Cite

Genomic instability and oncogene amplifications in colorectal adenomas predict recurrence and synchronous carcinoma

Cited by 6 publications

References 0 publications

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

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

Copy number of the Adenomatous Polyposis Coli gene is not always neutral in sporadic colorectal cancers with loss of heterozygosity for the gene

Monosomal karyotype routinely defines a poor prognosis subgroup in acute myeloid leukemia and is frequently associated withTP53deletion

Contact Info

Product

Resources

About