title: Frequent methylation of the KLOTHO gene and overexpression of the FGFR4 receptor in invasive ductal carcinoma of the breast.
abstract: Invasive ductal carcinoma of the breast is the most common cancer affecting women worldwide. The marked heterogeneity of breast cancer is matched only with the heterogeneity in its associated or causative factors. Breast cancer in Saudi Arabia is apparently an early onset with many of the affected females diagnosed before they reach the age of 50 years. One possible rationale underlying this observation is that consanguinity, which is widely spread in the Saudi community, is causing the accumulation of yet undetermined cancer susceptibility mutations. Another factor could be the accumulation of epigenetic aberrations caused by the shift toward a Western-like lifestyle in the past two decades. In order to shed some light into the molecular mechanisms underlying breast cancer in the Saudi community, we identified KLOTHO (KL) as a tumor-specific methylated gene using genome-wide methylation analysis of primary breast tumors utilizing the MBD-seq approach. KL methylation was frequent as it was detected in 55.3 % of breast cancer cases from Saudi Arabia (n = 179) using MethyLight assay. Furthermore, KL is downregulated in breast tumors with its expression induced following treatment with 5-azacytidine. The involvement of KL in breast cancer led us to investigate its relationship in the context of breast cancer, with one of the protagonists of its function, fibroblast growth factor receptor 4 (FGFR4). Overexpression of FGFR4 in breast cancer is frequent in our cohort and this overexpression is associated with poor overall survival. Interestingly, FGFR4 expression is higher in the absence of KL methylation and lower when KL is methylated and presumably silenced, which is suggestive of an intricate relationship between the two factors. In conclusion, our findings further implicate "metabolic" genes or pathways in breast cancer that are disrupted by epigenetic mechanisms and could provide new avenues for understanding this disease in a new context.
authors.affiliation: Center of Excellence in Genomic Medicine Research, King Abdulaziz University, P.O. Box 80216, Jeddah, 21589, Kingdom of Saudi Arabia. adallol@kau.edu.sa.|KACST Technology Innovation Center in Personalized Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia. adallol@kau.edu.sa.
authors.forename: Ashraf
authors.identifier: http://orcid.org/0000-0002-8803-228X
authors.initials: A
authors.lastname: Dallol
authors.affiliation: Center of Excellence in Genomic Medicine Research, King Abdulaziz University, P.O. Box 80216, Jeddah, 21589, Kingdom of Saudi Arabia.
authors.forename: Abdelbaset
authors.initials: A
authors.lastname: Buhmeida
authors.affiliation: Department of Surgery, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Adnan
authors.initials: A
authors.lastname: Merdad
authors.affiliation: Department of Pathology, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Jaudah
authors.initials: J
authors.lastname: Al-Maghrabi
authors.affiliation: Center of Excellence in Genomic Medicine Research, King Abdulaziz University, P.O. Box 80216, Jeddah, 21589, Kingdom of Saudi Arabia.|Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Mamdooh A
authors.initials: MA
authors.lastname: Gari
authors.affiliation: Center of Excellence in Genomic Medicine Research, King Abdulaziz University, P.O. Box 80216, Jeddah, 21589, Kingdom of Saudi Arabia.|Faculty of Science, Zoology Department, Minia University, Minia, Egypt.
authors.forename: Muhammad M
authors.initials: MM
authors.lastname: Abu-Elmagd
authors.affiliation: KACST Technology Innovation Center in Personalized Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.|Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Aisha
authors.initials: A
authors.lastname: Elaimi
authors.affiliation: Center of Excellence in Genomic Medicine Research, King Abdulaziz University, P.O. Box 80216, Jeddah, 21589, Kingdom of Saudi Arabia.
authors.forename: Mourad
authors.initials: M
authors.lastname: Assidi
authors.affiliation: Center of Excellence in Genomic Medicine Research, King Abdulaziz University, P.O. Box 80216, Jeddah, 21589, Kingdom of Saudi Arabia.|Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Adeel G
authors.initials: AG
authors.lastname: Chaudhary
authors.affiliation: Center of Excellence in Genomic Medicine Research, King Abdulaziz University, P.O. Box 80216, Jeddah, 21589, Kingdom of Saudi Arabia.|KACST Technology Innovation Center in Personalized Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.|Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Adel M
authors.initials: AM
authors.lastname: Abuzenadah
authors.affiliation: King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Taoufik
authors.initials: T
authors.lastname: Nedjadi
authors.affiliation: Department of Oncology, National Cancer Institute, Sabratha, Libya.
authors.forename: Eramah
authors.initials: E
authors.lastname: Ermiah
authors.affiliation: King Abdulaziz University Hospital, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Shadi S
authors.initials: SS
authors.lastname: Alkhayyat
authors.affiliation: Center of Excellence in Genomic Medicine Research, King Abdulaziz University, P.O. Box 80216, Jeddah, 21589, Kingdom of Saudi Arabia.|Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Mohammed H
authors.initials: MH
authors.lastname: Al-Qahtani
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D005346:Fibroblast Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005966:Glucuronidase / Q000235:genetics*; D006801:Humans; D000090265:Klotho Proteins; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C117476:FGF19 protein, human; D005346:Fibroblast Growth Factors; C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: Breast cancer; FGF19; FGFR4; KLOTHO; Methylation