P21 in Endometrial Carcinoma, Correlation with MSI, Pathologic and Clinical Data
MJ Carlson, KE Resnick, DE Cohn, I Ivanov, JA Stephens, AA Suarez. Ohio State University, Columbus, OH
Background: Senescence precludes cells with DNA damage from proliferating. p21 is a CDK inhibitor that mediates p53 dependent senescence. Although p21 polymorphisms may impact the risk of endometrial carcinoma (EC) and p21 expression may correlate with pathological findings such as myometrial invasion, the role of this protein in EC is not clear. There is some evidence that p21 may be downstream of PMS2 in mice, potentially linking cell cycle regulation and senescence with DNA mismatch repair (MMR). We investigated the expression of p21 in human EC and its relationship with clinical outcome, histologic grade, myometrial invasion, p53, CCND1 and microsatellite instability (MSI).
Design: Immunohistochemistry (IHC) using p21, p53 and CCND1 monoclonal antibodies was performed on tissue microarrays including 368 EC. Only nuclear positivity was recorded for this IHC. MSI had been determined by a genotyping method as part of previous studies. Log-Rank tests were used to compare for overall and progression free survival . Chi-square tests were used to compare proportions.
Results: 133(36.1%) tumors had no detectable p21 immunoreactivity and only isolated (1-5%) p21 positive nuclei was seen in 185(50.3%). 41 (11.1%) tumors had 6-30% positive nuclei and 9 (2.4%) had >30%positive nuclei. Nuclear reactivity for p21 was strong in 44 (88%) of tumors with >6% positivity. Although p21 expression was associated with a higher proportion of high grade histology (p=0.014) and presence of myometrial invasion (p=0.026), no statistically significant difference between early and late stage cases and overall and progression free survival was detected. There was a significant association between p21 and CCND1 immunoreactivity (p<0.01) but p53 (p=0.109) and MSI (p=0.255) did not show statistical significance.
Conclusions: While p21 nuclear expression is detectable by IHC in a majority of EC (63.9%) it is more often present only as isolated, scattered nuclei. However, a significant minority (13.5%) of EC have >6% positive nuclei with strong p21 immunoreactivity. Expression of p21 in EC is associated with high grade histology and myometrial invasion but not with clinical outcome. p21 and CCND1 are coexpressed in a significant number of EC probably reflecting their roles in cell cycle regulation. We present evidence against a link between DNA MMR, as determined by MSI, and p21 related senescence in EC.
Wednesday, March 11, 2009 1:00 PM
Poster Session VI # 150, Wednesday Afternoon