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.

SLURP‐1 is mutated in Mal de Meleda, a potential molecular signature for melanoma and a putative squamous lineage tumor suppressor gene

“…Currently, there are no available treatments for genodermatoses, such as MDM, causing patients to abandon long‐term clinical follow‐up, which result in missing some features of the condition that present late in the disease. Our group among others has had a long standing interest in understanding the molecular pathogenesis of genodermatoses in addition to unraveling uncommon clinical features of these diseases . In this report, we sought to study a consanguineous Middle Eastern family with clinical features of MDM, a rare autosomal recessive genodermatoses.…”

FECH Expression Correlates with the Prognosis and Tumor Immune Microenvironment in Clear Cell Renal Cell Carcinoma

“…In addition, the RAS/MEK pathway increased PpIX accumulation in cancer cells by regulating the FECH activity mechanism, which would facilitate precise recognition of tumor boundaries and small satellite tumors [ 25 ]. Relevant studies have shown that changes in FECH expression were detected in human colon cancers and that loss of FECH has a tumor-suppressive effect on colon carcinogenesis in vitro [ 26 ], which was a potential tumor-suppressor gene for colon cancer [ 27 ]. The FECH gene may be a switch gene involved in the invasiveness of pituitary nonfunctioning adenomas [ 28 ].…”

Comparative characterization of sun exposed and sun protected skin‐derived mesenchymal‐like stem cells in variegate porphyria and healthy individuals

“…The activity of ferrochelatase, a terminal enzyme of the heme biosynthetic pathway, was markedly reduced in sun‐exposed fibroblasts relative to matched sun‐protected fibroblasts. Furthermore, SE fibroblasts were able to restore a normal phenotype when co‐cultured with SP fibroblasts 18 . Here, we studied a second form of cutaneous porphyria in an individual with severe autosomal recessive variegate porphyria.…”

“…Furthermore, SE fibroblasts were able to restore a normal phenotype when co-cultured with SP fibroblasts. 18 Here, we studied a second form of cutaneous porphyria in an individual with severe autosomal recessive variegate porphyria. The aim of this study was to isolate and characterize the human skin-derived mesenchymal-like stem cells from different areas of the skin in autosomal recessive variegate porphyria patient (SE and SP) in comparison with the skin-derived mesenchymal-like stem cells from healthy individual and to determine whether stem cells in sun-protected region could be used to regenerate areas in the skin that are damaged.…”