Do Protocadherins Show Prognostic Value in the Carcinogenesis of Human Malignant Neoplasms? Systematic Review and Meta-Analysis

Abstract

Background: Protocadherins ( PCDHs ) have been reported as tumor suppressor genes, implying that these genes may be involved in tumor suppression in a variety of cancers. However, a thorough understanding of the functions and mechanisms of PCDHs remains limited. Our aim was to investigate the methylation profile of PCDHs in human malignant neoplasms. Methods: This systematic review has been recorded in PROSPERO (#42019117844) and conducted according to PRISMA’s checklist; search was conducted in LILACS, PubMed, Science Direct, Scopus, and Web of Science databases, manually, with search queries and without date or language restrictions. Results: We found 91 articles, of which 26 were used for this meta-analysis and categorized according to the origin of the neoplasia. In total, 3,377 cases were compiled, with PCDH10, PCDH17 , and PCDH8 being the most studied; males were 2.22 times more affected than females. Studies have shown significant heterogeneity (p <0.001), with the odds ratio varying between cases and controls [2.20 (95% CI = 1.11– 4.35) to 209.05 (95% CI = 12.64– 2,457.18)], and the value of association between methylation and cancers studied was 26.08 (95% CI = 15.42–44.13). Conclusion: In this systematic review, we have demonstrated using meta-analysis that PCDHs could emerge as potential tumor suppressor genes and that a significant increase in methylation may be useful for early detection of different cancers. This work may help in the identification of new prognostic biomarkers in malignant neoplasms.

Methylation of PCDH17 and NEFH as prognostic biomarker for nonmetastatic RCC: A cohort study

“…PCDH17 gene is located in the 13q.21.2 chromosome and belongs to the protocadherins family, which have varied tumor suppression functions such as regulation of cell to cell adhesion, growth control, signal transduction, and are downregulated through methylation in many forms of cancer. [ 26 ] Protocadherin-17 ( PCDH17 ) seems to prevent cancer progression through EMT regulation. [ 27 ] Reduced expression was associated with metastasis and invasion in hepatocellular carcinoma [ 28 ] and predicted resistance to chemotherapy in colorectal cancer, [ 29 ] while PCDH17 gene methylation was correlated with shorter survival in patients with bladder cancer, [ 30 ] prostate cancer, [ 31 ] and with metastasis in breast cancer.…”

Innovative mouse models for the tumor suppressor activity of Protocadherin-10 isoforms

“…In recent years, direct and indirect evidence has accumulated that δ-Pcdhs are important during tumorigenesis, either as tumor-suppressor genes or as oncogenes [ 7 – 10 ]. It has been reported that human PCDH10 , located at chromosome 4q28.3, is frequently inactivated in various human cancers suggesting that PCDH10 acts as tumor suppressor in these malignancies.…”

“…Moreover, PCDH10 was found to be frequently silenced epigenetically by promoter hypermethylation in numerous human malignancies. Since the original report of PCDH10 promoter methylation in breast cancer [ 13 ], this phenomenon has been detected in medulloblastomas, nasopharyngeal and esophageal carcinomas, gastric cancer, colorectal cancer, hepatocellular carcinoma, pancreatic cancer, breast cancer, cervical cancer, testicular cancer, prostate cancer, bladder cancer, non-small cell lung cancer and multiple haematologic malignancies [ 8 – 10 ]. PCDH10 methylation does not occur in normal tissues.…”

“…Importantly, tumor-associated PCDH10 silencing may be quite useful for early detection of occurrence and/or progression of multiple human cancers [ 10 ]. For instance, increased PCDH10 promoter methylation was associated significantly with poorer survival of gastric cancer patients, and identified to be an independent prognostic indicator of this cancer type [ 14 , 15 ].…”