High Frequency of E-Cadherin Methylation and Loss of Expression in Colorectal Signet Ring Cell Carcinoma Compared to Mucinous and Nonmucinous Adenocarcinoma
N Shafizadeh, G Deng, L Cun, YS Kim, S Kakar. University of California, San Francisco, San Francisco, CA; VA Medical Center, San Francisco, CA
Background: Signet ring cell carcinoma(SRC) is a rare subtype of colorectal cancer. Its aggressive behavior may be related to discohesive tumor cells facilitating spread of the disease. Loss of E-cadherin, an important adhesion molecule, can enable metastasis by disruption of intercellular contact.The E-cadherin status in SRC and its comparison with mucinous(MC) and nonmucinous adenocarcinoma(AC) has not been studied.
Design: E-cadherin status was determined by immunohistochemistry(IHC) and methylation in 48 colorectal carcinomas(17 SRC,17 MC,14 AC). The staining was recorded as positive (>20%) or negative (<20% tumor cells). In addition, the positive cases were divided into diffuse (>75%) and decreased expression (20-75% tumor cells) for SRC. Methylation status was determined by methylation-specific polymerase chain reaction. The relationship of E-cadherin status in SRC with clinicopathologic features as well as with previously determined molecular features like microsatellite instability (MSI), CpG island methylator phenotype (CIMP), BRAF mutations and KRAS mutations was examined.
Results: Loss of E-cadherin expression by IHC and E-cadherin methylation was seen more often in SRC compared to MC and AC(see table). SRC with E-cadherin methylation showed absent(60%) or decreased(30%) expression. Two cases of SRC without methylation also showed loss of E-cadherin. Distant metastasis was seen more often in E-cadherin negative SRC(29% vs 0%, p=0.02). There was no correlation between E-cadherin loss or methylation and age, gender, site or molecular features like MSI, CIMP, BRAF mutations and KRAS mutations.
Figures reflect percentages;p values are SRC vs MC, SRC vs AC
|E-cadherin expression||76||18||21||0.002, 0.008|
|E-cadherin methylation||79||13||47||<0.001, 0.05|
Conclusions: Methylation and loss of E-cadherin expression is observed in a vast majority of SRC compared to a minority of MC and AC. Most cases with methylation show loss or decreased E-cadherin expression. E-cadherin loss was also observed in the absence of methylation, suggesting alternative mechanisms of E-cadherin down regulation. Metastatic disease was observed exclusively in E-cadherin negative SRC. Loss of E-cadherin may breach cell to cell adhesions resulting in the discohesive appearance typical of SRC and may play a role in facilitating distant metastasis.
Monday, March 9, 2009 1:00 PM
Poster Session II # 71, Monday Afternoon