CDH22hypermethylation is an independent prognostic biomarker in breast cancer.
Cadherin-like protein 22 (CDH22) is a transmembrane glycoprotein involved in cell-cell adhesion and metastasis. Its role in cancer is controversial because it has been described as being upregulated in colorectal cancer, whereas it is downregulated in metastatic melanoma. However, its status in breast cancer (BC) is unknown. The purpose of our study was to determine the molecular status and clinical value ofCDH22in BC.



We observed by immunohistochemistry that the level of CDH22 expression was lower in BC tissues than in their matched adjacent-to-tumour and non-neoplastic tissues from reduction mammoplasties. Since epigenetic alteration is one of the main causes of gene silencing, we analysed the hypermethylation of 3 CpG sites in theCDH22promoter by pyrosequencing in a series of 142 infiltrating duct BC cases.CDH22was found to be hypermethylated in tumoral tissues relative to non-neoplastic mammary tissues. Importantly, this epigenetic alteration was already present in adjacent-to-tumour tissues, although to a lesser extent than in tumoral samples. Furthermore,CDH22gene regulation was dynamically modulated in vitro by epigenetic drugs. Interestingly,CDH22hypermethylation in all 3 CpG sites simultaneously, but not expression, was significantly associated with shorter progression-free survival (p =0.015) and overall survival (p= 0.021) in our patient series. Importantly,CDH22hypermethylation was an independent factor that predicts poor progression-free survival regardless of age and stage (p= 0.006).



Our results are the first evidence thatCDH22is hypermethylated in BC and that this alteration is an independent prognostic factor in BC. Thus,CDH22hypermethylation could be a potential biomarker of poor prognosis in BC.
Cancer Epigenetics Group, Navarrabiomed. Departmento de Salud-UPNA. IdiSNA, Irunlarrea Road, 3, 31008 Pamplona, Spain.
Esperanza
E
Martín-Sánchez
Cancer Epigenetics Group, Navarrabiomed. Departmento de Salud-UPNA. IdiSNA, Irunlarrea Road, 3, 31008 Pamplona, Spain.
Saioa
S
Mendaza
Cancer Epigenetics Group, Navarrabiomed. Departmento de Salud-UPNA. IdiSNA, Irunlarrea Road, 3, 31008 Pamplona, Spain.
Ane
A
Ulazia-Garmendia
Cancer Epigenetics Group, Navarrabiomed. Departmento de Salud-UPNA. IdiSNA, Irunlarrea Road, 3, 31008 Pamplona, Spain.
Iñaki
I
Monreal-Santesteban
Department of Pathology, Complejo Hospitalario de Navarra, Irunlarrea Road, 3, 31008 Pamplona, Spain.
Alicia
A
Córdoba
Department of Surgery, Complejo Hospitalario de Navarra, Pamplona, Spain.
Francisco
F
Vicente-García
Immunomodulation Group, Navarrabiomed. Departmento de Salud-UPNA. IdiSNA, Pamplona, Spain.
Idoia
I
Blanco-Luquin
Department of Medical Oncology, Complejo Hospitalario de Navarra, Pamplona, Spain.
Susana
S
De La Cruz
Biobank of Navarrabiomed. Departmento de Salud-UPNA. IdiSNA, Pamplona, Spain.
Ana
A
Aramendia
Cancer Epigenetics Group, Navarrabiomed. Departmento de Salud-UPNA. IdiSNA, Irunlarrea Road, 3, 31008 Pamplona, Spain.|Department of Pathology, Complejo Hospitalario de Navarra, Irunlarrea Road, 3, 31008 Pamplona, Spain.
David
D
Guerrero-Setas
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D015820:Cadherins / Q000235:genetics*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016019:Survival Analysis
D015820:Cadherins; C099417:CDH22 protein, human
Breast cancer; CDH22; DNA methylation; Predictive biomarker