P62 and ubiquitin are small regulatory proteins demonstrated to have implications in the prognosis and survival of various malignancies including: hepatocellular, breast, ovarian, and some gastrointestinal carcinomas. Several trials studied the link of their activity to the extrinsic apoptosis pathway and showed that their autophagy modification has a critical stand point in tumorigenesis. These findings explain their vital role in controlling the process of cell death and survival. It has been shown recently that p62 and ubiquitin overexpression in different types of cancers, such as triple negative breast and ovarian cancers, have directly correlated with incidence of distant metastases. We aim to evaluate p62/ubiquitin expression in gastrointestinal carcinomas of gastric, colonic, and pancreatic origin, and correlate with annotated clinicopathologic data. In gastric carcinoma (61), positive p62 nuclear expression was noted in 57% and cytoplasmic in 61%, while positive ubiquitin was nuclear expressed in 68.8%, and cytoplasmic in 29.5%. In colon carcinoma (45), positive p62 nuclear expression was noted in 29% and cytoplasmic in 71%, while positive ubiquitin was nuclear in 58% and cytoplasmic in 44%. In pancreatic cancer (18), positive p62 nuclear expression was noted in 78% and cytoplasmic in 56%, while positive ubiquitin was nuclear in 83% and cytoplasmic in 72%. Normal gastric (6), colon (4), and pancreatic (4) tissues were negative for both P62 and ubiquitin (nuclear and cytoplasmic staining <20%). Ubiquitin high expression was associated with more lymph node metastases in colon (4.14 vs 1.70, P = 0.04), and pancreatic adenocarcinomas (3.07 vs 0.33, P = 0.03). Also, ubiquitin high expression was associated with worse pancreatic adenocarcinoma overall survival (1.37 vs 2.26 mos, P = 0.04). In addition, gastric cancer patients with high p62 expression tend to have more poorly differentiated grade when compared to those with low expression (21 vs 17, P = 0.04) but less lymph node metastases (2.77 vs 5.73, P = 0.01). P62 and ubiquitin expression did not correlate with other clinicopathologic parameters in gastric, colon or pancreatic denocarcinomas. The results suggest that p62 and ubiquitin are highly expressed in gastric, colonic, and pancreatic carcinomas. High ubiquitin expression was noted to have an impact on number of lymph node metastases in patients with colon and pancreatic adenocarcinomas, but on overall survival only in patients with pancreatic adenocarcinoma. Also, P62 high expression is correlated with poor differentiation, but less lymph node metastases, in gastric carcinoma.

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Background:P62 and ubiquitin are small regulatory proteins demonstrated to have implications in the prognosis and survival of various malignancies including: hepatocellular, breast, ovarian, and some gastrointestinal carcinomas. They play a vital role in controlling the process of cell death and survival. In order to understand the roles p62/ubiquitin play in gastrointestinal carcinomas, we carried out immunohistochemical analyses of p62/ubiquitin expression in a cohort of patients with annotated clinicopathologic data. Methods:Tissue microarrays (TMAs) of two 1mm cores each of 130 gastrointestinal carcinomas were immunostained for p62 and ubiquitin expression. Normal gastric, colon and pancreatic tissues were included as negative controls. Subjects were categorized into positive and negative groups based on the 20% cutoff of staining area. The staging of these three types of cancer were classified into early (Stage 0-3A) and advanced stage (equal or more than stage 3B).Chi-square or Fisher's exact test was used for assessing the comparability of cancer staging (pathologic stage, tumor size, lymph node metastases, and distant metastases) between positive and negative groups. A two-sample t-test was used to evaluate the association between log-transformed survival time and the positivity of tumor cells. All the statistical analyses were conducted using SAS statistical software version 9.3 (SAS Institute, Inc.,Cary, NC), and P&lt;0.05 was considered statistically significant. Results:Of 130 carcinoma, there were 45 gastric, 70 colorectal and 15 pancreatic carcinoma. In gastric carcinoma (45), positive p62 nuclear expression was noted in 25 (53%) and cytoplasmic in 26 (57%), while positive ubiquitin was nuclear expressed in 36 (80%), and cytoplasmic in 11 (24%). In colon carcinoma (70), positive p62 nuclear expression was noted in 29 (41%) and cytoplasmic in 48 (68.5%), while positive ubiquitin was nuclear in 40 (57%) and cytoplasmic in 30 (42%). In pancreatic cancer (15), positive p62 nuclear expression was noted in 13 (86%) and cytoplasmic in 9 (60%), while positive ubiquitin was nuclear in 15 (100%) and cytoplasmic in 12 (80%). Normal gastric (6), colon (4) and pancreatic (4) tissues were negative for both p62 and ubiquitin (nuclear and cytoplasmic staining &lt;20%). Ubiquitin high expression was associated with worse pancreatic adenocarcinoma overall survival (1.37 vs 2.26 mos, P = 0.04). P62 and ubiquitin expression did not correlate with clinicopathologic parameters in gastric and colon adenocarcinomas. Conclusion:This study revealed that both p62 and ubiquitin are highly expressed in nuclei and cytoplasm of gastrointestinal carcinomas (gastric, colonic and pancreatic carcinomas). High ubiquitin expression was noted to have an impact on overall survival in patients with pancreatic adenocarcinoma. Citation Format: Amr Mohamed, Ayman AlKhoder, Wang Tengteng, Charles Kovach, Ahmed Kaseb, Momin T. Siddiqui, Cynthia Cohen. Correlation of p62/ubiquitin IHC expression with clinicopathologic outcome in gastrointestinal carcinomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2728. doi:10.1158/1538-7445.AM2015-2728