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


METHODS
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 pT(a) noninvasive and 44 pT(1) 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 pT(1) 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.
Gallagher
Emma M
EM
UCD School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland.
O'Shea
Deirdre M
DM
Fitzpatrick
Patricia
P
Harrison
Michèle
M
Gilmartin
Breege
B
Watson
Jenny A
JA
Clarke
Trevor
T
Leonard
Martin O
MO
McGoldrick
Aloysius
A
Meehan
Maria
M
Watson
Chanel
C
Furlong
Fiona
F
O'Kelly
Patrick
P
Fitzpatrick
John M
JM
Dervan
Peter A
PA
O'Grady
Anthony
A
Kay
Elaine W
EW
McCann
Amanda
A
D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism*; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D018392:Genomic Imprinting; D006801:Humans; D007150:Immunohistochemistry; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D008297:Male; D009364:Neoplasm Recurrence, Local; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000378:metabolism*
D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D007335:Insulin-Like Growth Factor II