Anthony Ellis

RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome.

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.

Randomised placebo-controlled trial of rituximab (anti-CD20) in active ulcerative colitis

Objective To assess the safety and efficacy of the B lymphocyte (anti-CD20) antibody, rituximab, in the treatment of steroid-resistant moderately active ulcerative colitis (UC). Methods A double-blinded, randomised controlled trial with a 2:1 ratio of treatment:placebo (phase II) was carried out in the setting of a University teaching hospital. The subjects comprised 24 patients with moderately active UC who have either failed to respond to conventional corticosteroid therapy or who have relapsed during corticosteroid withdrawal. Five of 8 placebo-treated patients and 12 of 16 rituximab-treated patients were receiving azathioprine, 6-mercaptopurine or methotrexate. Two infusions of rituximab 1 g in 500 ml of 0.9% saline intravenously over 4 h (n=16) or saline placebo (n=8) were given at 0 and 2 weeks. Patients still receiving corticosteroids on entry (placebo group 7/8; rituximab group 14/16) continued a standard steroid tapering regimen. The primary end point was remission (Mayo score ≤2) at 4 weeks. Secondary end points included response (Mayo score reduced ≥3) at 4 and 12 weeks. Results Mayo score at entry was higher in rituximab-treated patients (mean 9.19; 95% CI 8.31 to 10.06) than for placebo patients (7.63; 6.63 to 8.62, p=0.03). At week 4 only 1/8 placebo-treated patients and 3/16 rituximab-treated patients were in remission (p=1.0), but 8/16 rituximab-treated patients had responded compared with 2/8 placebo-treated patients, with a median reduction in Mayo score of 2.5 (rituximab) compared with 0 (placebo; p=0.07). This response was only maintained to week 12 in 4/16. Mucosal healing was seen at week 4 in 5/16 rituximab-treated patients and 2/8 placebo-teated patients (non-significant). Rituximab was well tolerated, with one chest infection, three mild infusion reactions plus one case of (probably unrelated) non-fatal pulmonary embolism. Conclusions Rituximab has no significant effect on inducing remission in moderately active UC not responding to oral steroids. There was a possible short-term response that was not sustained. Rituximab is well tolerated in UC. Clinical trial number NCT00261118.

Effect of Systemic Corticosteroid Therapy on Risk for Intra- Abdominal or Pelvic Abscess in Non-operated Crohn's Disease

BACKGROUND & AIMS Systemic corticosteroid therapy increases risk of postoperative sepsis in Crohns disease. This study investigates its effect on risk for sepsis in non-operated patients. METHODS A retrospective case-control study was performed in 432 patients with Crohns disease (the 94% of our database for whom adequate documentation could be retrieved). Two analyses were performed. The first tested the hypothesis that patients with perforating Crohns disease (n = 86) were more likely to develop intra-abdominal or pelvic abscess (n = 29) if they had received systemic corticosteroids during the previous 3 months. The second analysis, confined to interventions since 1998, tested the hypothesis that corticosteroid therapy was more common during the 3 months before presentation with intra-abdominal or pelvic abscess (n = 12) than during the 3 months after presentation with a relapse of nonperforating disease (n = 24 consecutive patients). In both analyses adjustment was made for any other significant variable. RESULTS Systemic corticosteroid therapy was associated with an adjusted odds ratio (OR) for intra-abdominal or pelvic abscess of 9.03 (95% confidence interval [CI], 2.40-33.98) in patients with perforating Crohns disease. Patients receiving prednisolone > or = 20 mg per day had an OR of 2.81 (95% CI, 0.99-7.99) for abscess compared with those receiving a lower dose. In patients with relapsed active disease, corticosteroid therapy was associated with an unadjusted OR of 9.31 (95% CI, 1.03-83.91) for intra-abdominal or pelvic abscess. Neither smoking nor azathioprine usage was associated with increased risk for abscess. CONCLUSIONS Systemic corticosteroid therapy for Crohns disease is associated with increased risk for intra-abdominal or pelvic abscess.

Characterization of a 500 kb region on 17q25 and the exclusion of candidate genes as the familial Tylosis Oesophageal Cancer ( TOC ) locus

The locus for a syndrome of focal palmoplantar keratoderma (Tylosis) associated with squamous cell oesophageal cancer (TOC) has been mapped to chromosome 17q25, a region frequently deleted in sporadic squamous cell oesophageal tumours. Further haplotype analysis described here, based on revised maps of marker order, has reduced the TOC minimal region to a genetic interval of 2 cM limited by the microsatellite markers D17S785 and D17S751. Partial sequence data and complete physical maps estimate the actual size of this region to be only 0.5 Mb. This analysis allowed the exclusion of proposed candidate tumour suppressor genes including MLL septin-like fusion (MSF), survivin, and deleted in multiple human cancer (DMC1). Computer analysis of sequence data from the minimal region identified 13 candidate genes and the presence of 50–70 other ‘gene fragments’ as ESTs and/or predicted exons and genes. Ten of the characterized genes were assayed for mutations but no disease-specific alterations were identified in the coding and promoter sequences. This region of chromosome 17q25 is, therefore, relatively gene-rich, containing 13 known and possibly as many as 50 predicted genes. Further mutation analysis of these predicted genes, and others possibly residing in the region, is required in order to identify the elusive TOC locus.

The genetics of peptic ulcer.

Non-malignant ulceration of the stomach and duodenum was, until relatively recently, considered to be one disease and was known by the all-embracing term peptic ulcer. Evidence from several sources tends to support the idea that even the broad divisions of gastric and duodenal ulcer may themselves be the end results of multiple separate disease processes. Genetic studies have helped considerably in the characterisation of these individual conditions.

Physical and transcript map of the minimally deleted region III on 17p implicated in the early development of Barrett's oesophageal adenocarcinoma

Allelic imbalance (AI) studies on chromosome 17 (C17) in Barretts oesophageal adenocarcinoma (BOA) tumours strongly suggest that a minimally deleted region on C17p harbours a BOA-associated gene with tumour suppressor function. This deleted region, designated minimal region III (MRIII), lies between the two microsatellite markers D17S1852 and D17S954. Computational sequence analysis techniques, BLAST and NIX, were used to assemble a physical map of MRIII, consisting of three overlapping bacterial artificial chromosome (BAC) clones, 297N7, 963H4 and 795F17, from the RPCI-11 library. The 270 kb genomic sequence of MRIII was analysed using the computational gene prediction methods NIX and TAP to identify putative BOA genes. A transcript map of MRIII has been generated and contains 25 candidate BOA genes, four of which are the named genes MYH3, SCO1, x006 and MAGOH-LIKE. The other candidates consist of seven genes predicted by TAP with associated ESTs identified by NIX, two genes predicted by TAP alone and 12 genes/ESTs (or pairs of ESTs) identified by NIX alone. No disease-specific mutations were identified in x006 or MAGOH-LIKE, although expression analysis of these genes suggests that they may show alternative splicing or be altered epigenetically or in regulatory regions in oesophageal cancer.

Oral tylosis: a re-appraisal.

The oral lesions in patients with tylosis (palmoplantar keratoderma) associated with oesophageal cancer, are evaluated, based on their clinical presentation, histological features and long term follow-up. The terminology of these lesions is discussed, together with a proposed reclassification of some forms of palmoplantar keratoderma.

A novel frameshift mutation in the APC gene at exon 15 in familial adenomatous polyposis (FAP) with desmoid tumour

To the Editor: One feature of familial adenomatous polyposis (FAP) is the development of extracolonic manifestations of which the desmoid tumour (DT) is one of the most important. DTs are rare, ben...