RHBDF2

Gene Summary

Gene:RHBDF2; rhomboid 5 homolog 2 (Drosophila)
Aliases: TEC, TOC, TOCG, RHBDL5, RHBDL6, iRhom2
Location:17q25.1
Summary:-
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:inactive rhomboid protein 2
HPRD
Source:NCBIAccessed: 16 March, 2015

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 16 March 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Serine Proteases
  • Sequence Deletion
  • Genetic Loci
  • Untranslated Regions
  • Promoter Regions
  • Glandular and Epithelial Cancers
  • Pain
  • Genetic Association Studies
  • Chromosomes, Artificial, Yeast
  • Disease Susceptibility
  • Carrier Proteins
  • RHBDF2
  • Amino Acid Sequence
  • Chromosome 17
  • Signal Transduction
  • Analgesics, Opioid
  • Diffuse Palmoplantar Keratoderma (Tylosis)
  • RHBDL2
  • Phenotype
  • Pedigree
  • Missense Mutation
  • Transcription
  • Gene Expression Profiling
  • siRNA
  • Genome-Wide Association Study
  • Cancer Gene Expression Regulation
  • Genes
  • Molecular Sequence Data
  • Keratoderma, Palmoplantar
  • Transglutaminases
  • Sequence Tagged Sites
  • Staphylococcus aureus
  • Mutation
  • Keratinocytes
  • Epidermal Growth Factor Receptor
  • Globins
  • Ovarian Cancer
  • Esophageal Cancer
  • Genotype
  • Membrane Proteins
Tag cloud generated 16 March, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: RHBDF2 (cancer-related)

Brooke MA, Etheridge SL, Kaplan N, et al.
iRHOM2-dependent regulation of ADAM17 in cutaneous disease and epidermal barrier function.
Hum Mol Genet. 2014; 23(15):4064-76 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
iRHOM2 is a highly conserved, catalytically inactive member of the Rhomboid family, which has recently been shown to regulate the maturation of the multi-substrate ectodomain sheddase enzyme ADAM17 (TACE) in macrophages. Dominant iRHOM2 mutations are the cause of the inherited cutaneous and oesophageal cancer-susceptibility syndrome tylosis with oesophageal cancer (TOC), suggesting a role for this protein in epithelial cells. Here, using tissues derived from TOC patients, we demonstrate that TOC-associated mutations in iRHOM2 cause an increase in the maturation and activity of ADAM17 in epidermal keratinocytes, resulting in significantly upregulated shedding of ADAM17 substrates, including EGF-family growth factors and pro-inflammatory cytokines. This activity is accompanied by increased EGFR activity, increased desmosome processing and the presence of immature epidermal desmosomes, upregulated epidermal transglutaminase activity and heightened resistance to Staphylococcal infection in TOC keratinocytes. Many of these features are consistent with the presence of a constitutive wound-healing-like phenotype in TOC epidermis, which may shed light on a novel pathway in skin repair, regeneration and inflammation.

Saarinen S, Vahteristo P, Lehtonen R, et al.
Analysis of a Finnish family confirms RHBDF2 mutations as the underlying factor in tylosis with esophageal cancer.
Fam Cancer. 2012; 11(3):525-8 [PubMed] Related Publications
Tylosis with esophageal cancer (TOC) is a rare familial cancer syndrome inherited in an autosomal-dominant manner and characterized by esophageal cancer susceptibility and hyperkeratotic skin lesions. Two heterozygous missense mutations in the RHBDF2 gene were recently reported to be associated with TOC in three families: a p.Ile186Thr mutation was found in families from the UK and the US and a p.Pro189Leu mutation was detected in a German TOC family. We aimed to validate these novel results in an independent material by screening RHBDF2 in a previously unreported Finnish TOC family. We identified a new missense mutation, p.Asp188Asn, segregating with TOC in the Finnish family, and interestingly the detected mutation alters a codon located between the two previously reported mutation sites. Thus, we confirmed RHBDF2 mutations as the underlying cause of the TOC syndrome and our results suggest that the TOC associated mutations might be specific for this particular site in the RHBDF2 gene. These results enable the genetic counseling and diagnostic mutation screening of the members of TOC families.

Wojnarowicz PM, Provencher DM, Mes-Masson AM, Tonin PN
Chromosome 17q25 genes, RHBDF2 and CYGB, in ovarian cancer.
Int J Oncol. 2012; 40(6):1865-80 [PubMed] Related Publications
It has been proposed that the frequent loss of heterozygosity (LOH) of an entire chromosome 17 contig in epithelial ovarian cancers (EOC) is the consequence of the inactivation of multiple tumour suppressor genes on this chromosome. We report the characterization of a 453 Kb 17q25 locus shown previously to exhibit a high frequency of LOH in EOC samples. LOH analysis further defined the minimal region of deletion to a 65 Kb interval flanked by D17S2239 and D17S2244, which contains RHBDF2, CYGB and PRCD as tumour suppressor gene candidates. Tissue specific expression excluded PRCD as a candidate. RHBDF2 was expressed at low levels in the majority of benign and low malignant potential (LMP) tumours, and in a subset of malignant ovarian tumour samples, as compared with primary cultures of normal ovarian surface epithelial cell (NOSE) samples. CYGB was expressed at low levels in the majority of LMP and malignant samples compared with benign and NOSE samples. In contrast to CYGB expression, RHBDF2 was expressed at low or undetectable levels in EOC cell lines exhibiting tumourigenic characteristics and up-regulated in a genetically modified EOC cell line rendered non-tumourigenic. DNA sequence analysis identified variants but no apparent deleterious mutations in either gene. Methylation-specific PCR analysis suggested that promoter methylation of CYGB but not RHBDF2 occurred in 6 of 31 malignant samples. The results combined suggest that RHBDF2 and CYGB may play distinctive roles in ovarian cancer and could be added to the growing roster of chromosome 17 genes implicated in this disease.

Blaydon DC, Etheridge SL, Risk JM, et al.
RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome.
Am J Hum Genet. 2012; 90(2):340-6 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
Tylosis esophageal cancer (TOC) is an autosomal-dominant syndrome characterized by palmoplantar keratoderma, oral precursor lesions, and a high lifetime risk of esophageal cancer. We have previously localized the TOC locus to a small genomic interval within chromosomal region 17q25. Using a targeted capture array and next-generation sequencing, we have now identified missense mutations (c.557T>C [p.Ile186Thr] and c.566C>T [p.Pro189Leu] in RHBDF2, which encodes the inactive rhomboid protease RHBDF2 (also known as iRhom2), as the underlying cause of TOC. We show that the distribution of RHBDF2 in tylotic skin is altered in comparison with that in normal skin, and immortalized tylotic keratinocytes have decreased levels of total epidermal growth factor receptor (EGFR) and display an increased proliferative and migratory potential relative to normal cells, even when normal cells are stimulated with exogenous epidermal growth factor. It would thus appear that EGFR signaling is dysregulated in tylotic cells. Furthermore, we also show an altered localization of RHBDF2 in both tylotic and sporadic squamous esophageal tumors. The elucidation of a role of RHBDF2 in growth-factor signaling in esophageal cancer will help to determine whether targeting this pathway in chemotherapy for this and other squamous cell carcinomas will be effective.

Galvan A, Skorpen F, Klepstad P, et al.
Multiple Loci modulate opioid therapy response for cancer pain.
Clin Cancer Res. 2011; 17(13):4581-7 [PubMed] Related Publications
PURPOSE: Patients treated with opioid drugs for cancer pain experience different relief responses, raising the possibility that genetic factors play a role in opioid therapy outcome. In this study, we tested the hypothesis that genetic variations may control individual response to opioid drugs in cancer patients.
EXPERIMENTAL DESIGN: We tested 1 million single-nucleotide polymorphisms (SNP) in European cancer patients, selected in a first series, for extremely poor (pain relief ≤40%; n = 145) or good (pain relief ≥90%; n = 293) responses to opioid therapy using a DNA-pooling approach. Candidate SNPs identified by SNP-array were genotyped in individual samples constituting DNA pools as well as in a second series of 570 patients.
RESULTS: Association analysis in 1,008 cancer patients identified eight SNPs significantly associated with pain relief at a statistical threshold of P < 1.0 × 10⁻³, with rs12948783, upstream of the RHBDF2 gene, showing the best statistical association (P = 8.1 × 10⁻⁹). Functional annotation analysis of SNP-tagged genes suggested the involvement of genes acting on processes of the neurologic system.
CONCLUSION: Our results indicate that the identified SNP panel can modulate the response of cancer patients to opioid therapy and may provide a new tool for personalized therapy of cancer pain.

Ruhrberg C, Williamson JA, Sheer D, Watt FM
Chromosomal localisation of the human envoplakin gene (EVPL) to the region of the tylosis oesophageal cancer gene (TOCG) on 17q25.
Genomics. 1996; 37(3):381-5 [PubMed] Related Publications
Envoplakin is a membrane-associated precursor of the epidermal cornified envelope. Envoplakin is homologous to desmoplakin I and desmoplakin II (DPI/II), bullous pemphigoid antigen 1 (BPAG1), and plectin and is proposed to link desmosomes and keratin filaments to the cornified envelope. We describe the isolation of cosmids and yeast artificial chromosomes containing the complete human envoplakin gene (EVPL) and show, by analysis of somatic cell hybrids and chromosomal in situ hybridisation, that the envoplakin gene, unlike the genes encoding BPAG1 and DPI/II, maps to 17q25 and is physically linked to D17S1603. This sequence-tagged site segregates with the autosomal dominant human disease focal nonepidermolytic palmoplantar keratosis (NEPKK; "tylosis"), which is associated with an increased risk of oesophageal cancer. The chromosomal localisation of the envoplakin gene, the homology of the encoded protein to keratin-binding proteins, and its expression in epidermal and oesophageal keratinocytes all raise the possibility that loss of envoplakin function could be responsible for this form of palmoplantar keratoderma.

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Cite this page: Cotterill SJ. TOC, Cancer Genetics Web: http://www.cancer-genetics.org/TOC.htm Accessed:

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