Role of HER2 and Claudins in Subtypes of Urothelial Carcinoma Identified Bygata3 and Cytokeratin5\6 Immunohistochemical Study

Abstract

Background: Bladder cancer is globally the ninth, most common malignancy, and the thirteenth most common cause, of cancer death, associated with high morbidity and mortality, if not treated optimally. Bladder cancers can be divided into molecular subtypes, referred to luminal and basal with distinct clinical behaviors. HER2 is one of the established therapeutic targets in many cancers. Claudins are tight junction proteins, known to modulate therapy resistance in cancer cells. Aim: This study aimed to assess Claudins and HER2 status in the context of tumor molecular subtypes, identified by GATA3 and CK5/6 expression, that may help to select urothelial carcinoma patients, most likely to respond to immunotherapy. Materials and Methods: This retrospective study was done upon 50 cases of conventional urothelial carcinoma. GATA3, CK5/6, HER2, Claudins1&4 and P53immunostaining were done and correlated with clinicoimmuno-pathological parameters. Results: Bladder cancers could be assigned to main intrinsic molecular subtypes, referred to luminal, basal and double negative. Basal & double negative bladder cancers were more aggressive, when compared to luminal cancers. Positive significant statistical correlation was found between HER2, claudin1 and P53 and clinicimmuno-pathological parameters as tumor size, grade, TNM stage, LVI, tumor budding and aggressive molecular subtypes (P-value< 0.05). Negative significant statistical correlation was found between claudin4 and fore mentioned clinico-immuno-pathological parameters (P-value< 0.05). Conclusions: The molecular subtypes of bladder cancers, HER2,

Immunohistochemical Expression of Claudin-1 and Claudin-4 in Urothelial Carcinoma of the Urinary Bladder

“…In the current study, we detected high Claudin-1 expression in forty-two cases (67.7%), and low expression was noticed in the remaining twenty cases (32.3%). That is near to the percentages in the study done by Saad et al [ 19 ] whichreported high Claudin-1 expression in 60% and low Claudin-1 expression in 40% of their studied cases. Moreover, Abd El-Fattah et al [ 14 ] reported high Claudin-1 expression in 50% of carcinoma cases included in their study.…”

“…As regards Claudin-4 expression, fifty-one cases (82.3%) demonstrated high Claudin-4 expression, and eleven cases (17.7%) demonstrated low Claudin-4 expression. In contrary Saad et al [ 19 ] and Abd El-Fattah et al [ 14 ] reported high Claudin-4 expression in 44% and 46.7% and low Claudin-4 in 56% and 53.3% of carcinoma cases included in their studies respectively. The difference observed in these results may be attributed to the difference in the number of studied cases conducted in their studies.…”

“…Similarly, Törzsök et al [ 27 ] reported significantly lower expression of Claudin-1 in high-grade tumours in comparison to low grade ones (P- value <0.035). In contrast, Saad et al [ 19 ] and Abd El-Fattah et al [ 14 ] found that high Claudin-1 expression was significantly associated with high grade urothelial carcinomas (P-value = 0.009) and (P-value= 0.012) respectively. Also, a study done by Kokenek-Unal, et al [6] showed that Claudin-1 had significantly lower expression in low grade non-invasive papillary urothelial carcinoma (NPUCs) compared to high grade and invasive papillary urothelial carcinoma (PUCs).…”

“…Immunodetection was performed, using a labeled streptavidin-biotin (LSAB) system. A skin section with a histologically normal epidermis was used as a positive control for Claudin-1 and a section from colonic mucosa normal epithelium was used as a positive control for Claudin-4 [ 6 , 19 ]. For negative control of both Claudin-1 and Claudin-4, omitting the primary antibodies was done.…”

“…Accordingly, it is evaluated as follows: 0 indicated negative results, 1–2 represented weak expression, 3–6 denoted moderate expression, and 9 meant strong expression. Additionally and weak expressions were classified as low, while moderate and strong were considered as high expressions [ 6 , 19 ].…”