The Smad4/PTEN Expression Pattern Predicts Clinical Outcomes in Colorectal Adenocarcinoma

Abstract

Background Smad4 and PTEN are prognostic indicators for various tumor types. Smad4 regulates tumor suppression, whereas PTEN inhibits cell proliferation. We analyzed and compared the performance of Smad4 and PTEN for predicting the prognosis of patients with colorectal adenocarcinoma. Methods Combined expression patterns based on Smad4+/– and PTEN+/– status were evaluated by immunostaining using a tissue microarray of colorectal adenocarcinoma. The relationships between the protein expression and clinicopathological variables were analyzed. Results Smad4–/PTEN– status was most frequently observed in metastatic adenocarcinoma, followed by primary adenocarcinoma and tubular adenoma (p<.001). When Smad4–/PTEN– and Smad4+/PTEN+ groups were compared, Smad4–/PTEN– status was associated with high N stage (p=.018) and defective mismatch repair proteins (p=.006). Significant differences in diseasefree survival and overall survival were observed among the three groups (Smad4+/PTEN+, Smad4–/PTEN+ or Smad4+/PTEN–, and Smad4–/PTEN–) (all p<.05). Conclusions Concurrent loss of Smad4 and PTEN may lead to more aggressive disease and poor prognosis in patients with colorectal adenocarcinoma compared to the loss of Smad4 or PTEN alone.

Clinicopathological Characterization and Prognostic Implication of SMAD4 Expression in Colorectal Carcinoma

“…As a result, 16.4% of our cases were identified as SMAD4 loss, which falls within the range of previous reports. Consistent with the previous studies, [8][9][10][11][12][13][14][15][16][17] we observed a significant association between SMAD4 loss and higher pT and pN category, and frequent distant metastasis. Consequently, we confirmed the value of SMAD4 loss as a prognostic factor for poor CSS and PFS of CRC.…”

“…Most previous studies evaluated SMAD4 expression based on two-tier classification: loss versus no loss, or low versus high expression. 7,8,10,11,[13][14][15]17,18,20 Because of ambiguities in the definition of low expression, the reported prevalence of low-level SMAD4 expression varied significantly from 2.34% to 75.2%. On the other hand, studies that adopted a multi-tier classifica-tion reported relatively homogeneous results, with the prevalence of low-level SMAD4 expression ranging from 9.3% to 37.7%.…”

“…Meta-analyses have revealed that the loss of SMAD4 is a negative predictor of overall survival, cancer-specific survival (CSS), and relapse-free survival. 4,5 In CRC, the loss of SMAD4 is associated with poor differentiation, 6,7 higher stage, [8][9][10][11][12] frequent lymph node metastasis, [13][14][15][16][17] loss of immune infiltrates, 17 and poor response to 5-fluorouracil. [17][18][19] Accordingly, numerous studies have reported the value of determining SMAD4 loss as a negative prognostic factor.…”

“…However, only a handful of studies have explored the expression of SMAD4 and its prognostic significance in a limited number of Korean CRC patients. 15,28,33 Moreover, comprehensive clinicopathologic and molecular characterization of CRCs with respect to SMAD4 expression was rarely performed.…”

Suppressor genes as molecular markers of colorectal cancer – a review of the latest reports

“…Reports from Chung et al from 2018 show that the loss of the SMAD4 protein together with the PTEN protein has a synergistic effect leading to a more aggressive form of the disease and an unfavourable prognosis in patients with CRC compared to the loss of SMAD4 alone [37].…”