Cyclin E low molecular weight isoforms occur commonly in early-onset gastric cancer and independently predict survival

Department of Pathology, University Medical Centre, Utrecht, The Netherlands.
Journal of clinical pathology (Impact Factor: 2.92). 04/2008; 61(3):311-6. DOI: 10.1136/jcp.2006.042648
Source: PubMed


Post-translational cleavage of full-length cyclin E from the N-terminus can produce low molecular weight (LMW) isoforms of cyclin E containing the C-terminus only.
To assess their presence in early-onset gastric cancer (EOGC), stump cancers and conventional gastric cancers and ascertain how they influence survival in EOGC.
The expression of full-length and LMW isoforms of cyclin E in 330 gastric cancers, including early-onset gastric cancer (EOGC), stump cancer and conventional gastric cancer (>45 years old) was compared using antibodies targeted to the N- and C-terminals.
LMW isoforms were found in 35% of EOGCs, compared to 8% of conventional gastric cancers and 4% of stump cancers; their presence was visualised in cell lines using western blot analysis. In addition, C-terminal staining was a positive predictor of survival in EOGC. In contrast, no correlation with survival was found with the N-terminal antibody which detects only full-length cyclin E.
EOGCs have a unique molecular phenotype and LMW isoforms of cyclin E may independently influence survival in EOGC.

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Available from: F.H.M. Morsink, Oct 03, 2015
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    • "It has been shown that over-expression of cyclin E is associated with tumor progression and that high levels of total or processed cyclin E strongly predicts poor prognosis of breast cancer patients [3] [4] [5]. Moreover, truncated cyclin E is also observed in other kinds of tumors and is indicative of poor survival [6] [7] [8]. Recently, it is shown that resistance to letrozole in breast cancer is due to overexpression of proteolyzed cyclin E [9]. "
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    ABSTRACT: In the current study, we investigated whether 17beta-estradiol (E2) induces cyclin E expression and triggers cyclin E processing via calpain in MCF-7 breast cancer cells. We found that E2 induced increased expression of cyclin E in a slow and persistent manner, and a rapid yet sustained processing of cyclin E. In addition, estrogenic ethanol was able to stimulate cyclin E truncation. Calpeptin or ALLN greatly suppressed the E2-triggered cyclin E processing and its expression, suggesting a calpain-mediated action for E2. Finally, the E2-induced effects could also be significantly suppressed by BAPTA or U0126, indicating involvement of calcium/ERK signaling. Taken together, these results show that estrogen may contribute to both up-regulation and proteolysis of cyclin E through calpain in MCF-7 cells.
    FEBS letters 03/2012; 586(6):892-6. DOI:10.1016/j.febslet.2012.02.018 · 3.17 Impact Factor
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    • "The present study reports frequencies in the lower range, with EOGC having an even lower percentage of amplification (2%) and overexpression (0%) than late onset GC (8% and 7% respectively). Other studies have shown that EOGC have a different molecular expression profile than late onset GC [26, 27] which is consistent with the finding that these cancers show a different (lower) HER2 overexpression and amplification frequency than late onset GC. Other studies using whole slides have reported lower frequencies of overexpression as well [3, 38, 41]. "
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    ABSTRACT: The recent ToGA trial results indicated that trastuzumab is a new, effective, and well-tolerated treatment for HER2-positive gastric cancer (GC). Although GC mainly affects older patients, fewer than 10% of GC patients are considered early-onset (EOGC) (presenting at the age of 45 years or younger). These EOGC show different clinicopathological and molecular profiles compared to late onset GC suggesting that they represent a separate entity within gastric carcinogenesis. In light of potential trastuzumab benefit, subpopulations of GC such as EOGC (versus late onset) should be evaluated for their frequency of amplification and overexpression using currently available techniques. Tissue microarray (TMA) blocks of 108 early onset GC and 91 late onset GC were stained by immunohistochemistry (IHC, Hercep test, DAKO) and chromogenic in situ hybridization (CISH, SPoT-Light, Invitrogen). Overall, we found only 5% HER2 high level amplification and 3% HER2 3+ overexpression (6/199). In addition, 8 patients (4%) showed a low level CISH amplification and 9 patients (4.5%) showed a 2+ IHC score. IHC and CISH showed 92% concordance and CISH showed less heterogeneity than IHC. In 2/199 cases (1%), IHC showed clinically relevant heterogeneity between TMA cores, but all cases with focal IHC 3+ expression were uniformly CISH high level amplified. Early onset GCs showed a significantly lower frequency of HER2 amplification (2%) and overexpression (0%) than late onset GCs (8% and 7% respectively) (p=0.085 and p=0.008 respectively). Proximal GC had more HER2 amplification (9% versus 3%) and overexpression (7% versus 2%) than distal tumours although this difference was not significant (p=0.181 and p=0.182 respectively). HER2 CISH showed more high level amplification in the intestinal type (7%, 16% if low-level included) compared to the mixed (5%, 5% if low-level included) and diffuse type (3%, 4% if low-level included) GCs (p=0.029). A similar association was seen for HER2 IHC and histologic type (p=0.008). Logistic regression indicated a significant association between HER2 expression and age, which remained significant when adjusted for both location and histological type. Even focal HER2 overexpression in GC points to uniform HER2 amplification by CISH. We show for the first time that early onset GC has a lower frequency of HER2 amplification and overexpression than late onset GC, and confirm that intestinal type GC shows the highest rate of HER2 amplification and overexpression.
    03/2011; 34(2):89-95. DOI:10.1007/s13402-011-0021-0
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    ABSTRACT: ObjectiveThe aim of the study was to investigate the expression and significance of cyclin E in gastric carcinoma. MethodsWe detected the expression of cyclin E in three different pathologic types gastric carcinoma samples by immuno-histochemical staining technique (SP method). ResultsIn 59 gastric carcinoma samples the positive rate of cyclin E expression in gastric carcinoma was 55.93% (33/59), and it was significantly higher than that of normal gastric mucosa (10.53%, 2/19). The positive rates of cyclin E expression in poor differentiation group and mucoid carcinoma group were 68.75% (11/16) and 66.67% (16/24), respectively, and these were significantly higher than that in well-middle differentiation group (31.58%, 6/19), but there was no significant difference between the fronted two groups (P > 0.05). ConclusionThe high expression of cyclin E is associated with the progression of gastric carcinoma and probably related to the behavior of cellular biology. Key wordscyclin E-gastric carcinoma-expression
    The Chinese-German Journal of Clinical Oncology 09/2010; 9(9):516-518. DOI:10.1007/s10330-010-0659-5
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