Recurrence of urothelial carcinoma of the bladder: A role for insulin-like growth factor-II loss of imprinting and cytoplasmic E-cadherin immunolocalization

Emma M. Gallagher, Deirdre M. O'Shea, Patricia Fitzpatrick, Michèle Harrison, Breege Gilmartin, Jenny A. Watson, Trevor Clarke, Martin O. Leonard, Aloysius McGoldrick, Maria Meehan, Chanel Watson, Fiona Furlong, Patrick O'Kelly, John M. Fitzpatrick, Peter A. Dervan, Anthony O'Grady, Elaine W. Kay, Amanda McCann*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)


Purpose: This study documents the frequency of insulin-like growth factor-II (IGF-II) loss of imprinting (LOI) in a series of 87 bladder tissues. E-cadherin (CDH1) immunolocalization was also investigated due to the known redistribution of this adherence protein to the cytoplasm following exogenous exposure to IGF-II. Experimental Design: Informative IGF-II cases were identified following DNA-PCR amplification and subsequent sequencing of the transcribable ApaI RFLP in exon 9 of IGF-II. Similar approaches using primer-specific cDNA templates identified the imprinting status of IGF-II in these informative cases. CDH1 cellular localization was assessed on a tissue microarray platform of 114 urothelial carcinoma of the bladder (UCB) cases (70 pTa noninvasive and 44 pT1 lamina propria invasive) using the commercially available Novocastra antibody. Results: IGF-II LOI was evident in 7 of 17 (41%) UCB tumors and 4 of 11 (36%) tumor-associated normal urothelial samples. Two of four pT1 grade 3 tumors, the subject of much debate concerning their suitability for radical cystectomy, showed LOI at the IGF-II locus. In those tumors showing IGF-II LOI, 4 of 7 (57%) displayed concomitant CDH1 cytoplasmic staining. In contrast, only 3 of 10 (30%) IGF-II maintenance of imprinting tumors had concomitant CDH1 cytoplasmic localization. UCB cell lines displaying cytoplasmic CDH1 immunolocalization expressed significantly higher levels of IGF-II (CAL29, HT1376, and RT112) compared with RT4, a cell line displaying crisp membranous CDH1 staining. Finally, cytoplasmic CDH1 staining was an independent predictor of a shorter time to recurrence independent of tumor grade and stage. Conclusions: We suggest that CDH1 cytoplasmic immunolocalization as a result of increased IGF-II levels identifies those nonmuscle invasive presentations most likely to recur and therefore might benefit from more radical nonconserving bladder surgery.

Original languageEnglish
Pages (from-to)6829-6838
Number of pages10
JournalClinical Cancer Research
Issue number21
Publication statusPublished - 1 Nov 2008
Externally publishedYes


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