Loss of SMAD4 protein expression in gastrointestinal and extra‐gastrointestinal carcinomas

Abstract

Aims SMAD4 (DPC4) is a tumour suppressor gene that is dysregulated in various tumour types, particularly pancreaticobiliary and gastrointestinal carcinomas. Corresponding loss of protein expression has been reported in approximately 50% of pancreatic and 25% of colonic adenocarcinomas. In the evaluation of carcinoma of unknown primary site, immunohistochemical loss of SMAD4 expression is often used to suggest pancreaticobiliary origin, but there are limited data on the spectrum of SMAD4 expression in carcinomas of other sites. This study evaluates the frequency of SMAD4 loss in a large cohort of carcinomas from diverse anatomical sites. Methods and results Immunohistochemistry for SMAD4 was performed on tissue microarrays or whole tissue sections of 1210 carcinomas from various organs: gastrointestinal tract, liver, pancreas/biliary tract, lung, breast, thyroid, kidney, ovary and uterus. Expression was considered lost when there was complete absence of staining in tumour cell nuclei, in the presence of intact staining in non‐neoplastic cells. SMAD4 loss was seen in 58% of pancreatic adenocarcinomas, 27% of appendiceal adenocarcinomas, 19% of colorectal adenocarcinomas, 16% of cholangiocarcinomas, 10% of lung adenocarcinomas and <5% of oesophageal, breast, gastric and mucinous ovarian adenocarcinomas. All papillary thyroid, hepatocellular, non‐mucinous ovarian, endometrial and renal cell carcinomas showed intact SMAD4 nuclear expression. Conclusion In addition to pancreaticobiliary, appendiceal and colonic tumours, SMAD4 loss is also seen in a small subset of other carcinomas, specifically breast, lung, oesophageal and gastric adenocarcinomas, all of which are typically CK7‐positive, similar to pancreaticobiliary carcinoma. Awareness of SMAD4 loss in these other carcinoma types is helpful in the evaluation of carcinomas of unknown or uncertain primary site.

Identification of Novel Metabolism-Associated Subtypes for Pancreatic Cancer to Establish an Eighteen-Gene Risk Prediction Model

“…As a hallmark oncogene, KRAS upregulates glycolysis-related enzymes and promotes energy supply in cancer cells, indicating a worse survival ( Buscail et al, 2020 ). Furthermore, TP53 , SMAD4 , and CDKN2A are frequently mutated genes in malignancies ( Alhejaily et al, 2014 ; Bykov et al, 2018 ; Ritterhouse et al, 2019 ). The KRAS mutation frequency was significantly higher in the C1 group than in the C2 group, and KRAS mutations were associated with increased expression.…”

Primary mucinous ovarian tumors vs. ovarian metastases from gastrointestinal tract, pancreas and biliary tree: a review of current problematics

“…However, the sensitivity of this marker is low. A loss of DPC4 (SMAD4) expression occurs in 53% of pancreatic and only about 5-10% of primary ovarian mucinous tumors [28,36,37,95]. According to the literature, cytokeratin 17 seems to be negative in ovarian mucinous tumors and positive in 27-83% of metastatic pancreatic carcinomas, but the data is very limited [94,96].…”

Malignant epithelial/exocrine tumors of the pancreas

“…P53 aberrant staining patterns, which are strictly correlated with TP53 mutations, are represented by a complete loss of immunostaining or by a diffuse nuclear staining in at least 60-70% of tumor cells 49 , 68 . DPC4 aberrant staining pattern, which is strictly associated with SMAD4 mutations, is represented by loss of DPC4 nuclear expression 69 .…”