Loss of SATB2 expression correlates with cytokeratin 7 and PD-L1 tumor cell positivity and aggressiveness in colorectal cancer

Abstract

Colorectal carcinoma (CRC) is a disease that causes significant morbidity and mortality worldwide. To improve treatment, new biomarkers are needed to allow better patient risk stratification in terms of prognosis. This study aimed to clarify the prognostic significance of colonic-specific transcription factor special AT-rich sequence-binding protein 2 (SATB2), cytoskeletal protein cytokeratin 7 (CK7), and immune checkpoint molecule programmed death-ligand 1 (PD-L1). We analyzed a cohort of 285 patients with surgically treated CRC for quantitative associations among the three markers and five traditional prognostic indicators (i.e., tumor stage, histological grade, variant morphology, laterality, and mismatch-repair/MMR status). The results showed that loss of SATB2 expression had significant negative prognostic implications relative to overall survival (OS) and cancer-specific survival (CSS), significantly shortened 5 years OS and CSS and 10 years CSS in patients with CRC expressing CK7, and borderline insignificantly shortened OS in patients with PD-L1 + CRC. PD-L1 showed a significant negative impact in cases with strong expression (membranous staining in 50–100% of tumor cells). Loss of SATB2 was associated with CK7 expression, advanced tumor stage, mucinous or signet ring cell morphology, high grade, right-sided localization but was borderline insignificant relative to PD-L1 expression. CK7 expression was associated with high grade and SATB2 loss. Additionally, a separate analysis of 248 neoadjuvant therapy-naïve cases was performed with mostly similar results. The loss of SATB2 and CK7 expression were significant negative predictors in the multivariate analysis adjusted for associated parameters and patient age. In summary, loss of SATB2 expression and gain of CK7 and strong PD-L1 expression characterize an aggressive phenotype of CRC.

Immunohistochemical Evaluation of SATB2 Expression in Colorectal Carcinoma in Mosul City, Iraq

“…Although the current study and other studies showed no significant association with sex, future studies with a large number of cases are indicated to confirm this result. Suvaitha et al [5], Ma et al [7], krudka et al [8], Schmitt et al [19], Mezheyeusk et al [20], and Dum et al [26] found a significant association of SATB2 with tumor site; the SATB2 loss was more commonly detected in tumors located in the right colon and cecum while SATB2-high tumors were more in left colonic tumors. Although the diffuse pattern of expression in the current study was more detected in the left colon and rectum, no significant association was detected.…”

“…Therefore, new biomarkers are required to distinguish highrisk cases and classify patients according to their prognosis [8]. Although a lot of studies are being done to identify the markers that help in detecting high risk cases and aid in choosing cases for adjuvant therapy, none of them has been shown to be good markers for routine clinical use [5].…”

“…As 71-97% of primary and metastatic CRCs have been reported to stain positively for SATB2 expression [17]. It is widely used as a diagnostic immunohistochemical (IHC) marker for the diagnosis of colorectal adenocarcinomas and differentiates it from other adenocarcinomas [8,12,18].…”

“…Recent research has shown that SATB2 can guide the expression of genes required for the cell cycle (cell proliferation and division), cell differentiation, migration of the cell [5,8,12] and self-renewal of stem cells [5,8] and it can also take part in DNA replication [16]. Therefore, it may play an important role in cancer initiation, development, and spread [8]. In the CRC, data from limited literature detected that the absence of SATB2 expression is associated with poor outcomes [7,9,11,14,18].…”

Novel biomarkers used for early diagnosis and tyrosine kinase inhibitors as targeted therapies in colorectal cancer

“…Different types of glandular and ductal epithelia contain CK7. Simultaneously, CK20 is abundantly expressed in mucosal cells of the gastrointestinal and urinary tracts (Hrudka et al, 2022). Tissue expression of CK15 was significantly linked with CRC subtype and stage.…”