title: Erythropoietic protoporphyria a clinical and molecular study from Lebanon: Ferrochelatase a potential tumor suppressor gene in colon cancer.
abstract: Erythropoietic protoporphyria (EPP) is a rare cutaneous and systemic disease caused by mutations in the ferrochelatase gene (FECH). The molecular underpinnings of EPP in Middle Eastern populations and relative to other ethnic groups secondary to increased consanguinity are unknown. To understand the molecular pathogenesis of Middle Eastern EPP, we surveyed clinicopathological and molecular features in 6 large consanguineous families from Lebanon and Syria presenting with cutaneous and systemic features consistent with EPP. We observed 30% increased liver disease and 20% elevated end-stage liver complications in our EPP cohort compared to EPP patients previously reported elsewhere. In addition, Middle Eastern EPP patients in our cohort exhibited uniquely an increased incidence of colon cancer. Sequence analysis revealed 2 novel non-synonymous FECH mutations in the studied families designated p.M294T and p.I230M. In addition, FECH activity was significantly decreased (6%) in fibroblasts obtained from sun-exposed sites in a patient with p.M294T mutation, whereas in sharp contrast, protected sites from the same patient exhibited 54% activity for the gene. We also found that sun-exposed fibroblasts, relative to sun-protected and control fibroblasts, exhibited suppressed growth and atypical morphology in vitro, and that these effects were alleviated when the cells were co-cultured with sun-protected fibroblasts. Our findings on the increased incidence of colon cancer in EPP patients prompted us to survey FECH expression patterns in cancer. Using publicly available microarray datasets we found that FECH mRNA was largely significantly decreased in colon adenocarcinomas relative to normal colon tissues. Our findings suggest that families with autosomal recessive EPP should be screened more extensively for systemic involvement including liver diseases and colon cancer, and point to a previously unknown yet plausible tumor suppressor role for FECH in colon malignancy.
authors.affiliation: Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon.
authors.forename: H
authors.initials: H
authors.lastname: Kadara
authors.affiliation: Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon.
authors.forename: G
authors.initials: G
authors.lastname: Nemer
authors.affiliation: Department of Dermatology, American University of Beirut, Beirut, Lebanon.
authors.forename: R
authors.initials: R
authors.lastname: Safi
authors.affiliation: Department of Dermatology, American University of Beirut, Beirut, Lebanon.
authors.forename: N
authors.initials: N
authors.lastname: Rebeiz
authors.affiliation: Department of Pathology, American University of Beirut, Beirut, Lebanon.
authors.forename: L
authors.initials: L
authors.lastname: Daou
authors.affiliation: Department of Dermatology, American University of Beirut, Beirut, Lebanon.
authors.forename: D
authors.initials: D
authors.lastname: Delbani
authors.affiliation: Department of Dermatology, American University of Beirut, Beirut, Lebanon.
authors.forename: W
authors.initials: W
authors.lastname: Btadini
authors.affiliation: Department of Dermatology, American University of Beirut, Beirut, Lebanon.
authors.forename: O
authors.initials: O
authors.lastname: Abbas
authors.affiliation: Department of Dermatology, American University of Beirut, Beirut, Lebanon.
authors.forename: M
authors.initials: M
authors.lastname: Tofaili
authors.affiliation: Department of Pediatrics, American University of Beirut, Beirut, Lebanon.
authors.forename: F
authors.initials: F
authors.lastname: Bitar
authors.affiliation: Department of Dermatology, American University of Beirut, Beirut, Lebanon.
authors.forename: A G
authors.initials: AG
authors.lastname: Kibbi
authors.affiliation: Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Shimomura
authors.affiliation: Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon.|Department of Dermatology, American University of Beirut, Beirut, Lebanon.|Department of Dermatology, Columbia University, New York, New York.
authors.forename: M
authors.identifier: http://orcid.org/0000-0003-1011-0687
authors.initials: M
authors.lastname: Kurban
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D002648:Child; D018920:Coculture Techniques; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000235:genetics*; D003241:Consanguinity; D005190:Family; D005260:Female; D005294:Ferrochelatase / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D007861:Lebanon; D008107:Liver Diseases / Q000150:complications; D008297:Male; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D046351:Protoporphyria, Erythropoietic / Q000201:enzymology* / Q000235:genetics* / Q000401:mortality; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; D005294:Ferrochelatase
keywords: colon cancer; ferrochelatase; liver failure; porphyria