Oesophageal candidiasis and squamous cell cancer in patients with gain-of-function STAT1 gene mutation

Abstract

Background: Oesophageal candidiasis is a common, usually self-limiting opportunistic infection, but long-term infection with Candida is known to predispose to oral and oesophageal squamous cell cancer (SCC). Permissive factors that lead to immune deficiencies can underlie persistent or recurring candidiasis, called chronic mucocutaneous candidiasis (CMC). Secondary immune deficiencies are most often due to human immunodeficiency virus (HIV) infection, antibiotic use and immunosuppressive treatment (steroids, chemotherapy). Inborn errors of the immune system (primary immune deficiencies) can present with isolated CMC known as CMC disease (CMCD), which is most often found in patients with autoimmune polyendocrinopathy syndrome type 1 (APS1)/APECED or in patients with an underlying gain-of-function STAT1 mutation (GOF-STAT1).

Objective: To describe a new form of inherited/familial CMC with a high risk for developing squamous cell carcinoma of the oesophagus, due to a gain-of-function mutation in the STAT1 gene.

Methods and results: This report describes a family of patients with CMC with confirmed GOF-STAT1 mutation. These patients usually present with CMCD in childhood, have severe oral and oesophageal candidiasis accompanied by severe difficulty swallowing, chest pain, heartburn, and are at risk of developing oral and/or oesophageal SCC. This case series describes six patients in three generations of the same family, two of whom developed and died of SCC. We recommend regular endoscopic surveillance to detect early oesophageal neoplasia in patients with CMCD as well as urgent endoscopy in symptomatic patients.

Conclusion: CMC is not a well-recognised condition in gastroenterology practice and clinicians need to be aware of the genetics of the condition as well as the risk for oesophageal cancer so that they can counsel their patients and arrange surveillance appropriately.

Keywords: Chronic mucocutaneous candidiasis; gain-of-function STAT1 mutation; primary immune deficiency; squamous cell carcinoma.

Figure 1.

Family tree of CMC patients.

Figure 2.

Appearance of the nails in CMC.

Figure 3.

Appearance of the tongue in CMC.

Figure 4.

STAT1 gain-of-function in CMC patient 5. (a) STAT1 phosphorylation following stimulation with interferon (IFN) was assessed by flow cytometry. Whole blood from a healthy control and CMC patient 5 was stimulated with 10³IU/ml interferon (IFN)α (IFN-α2b Intron A, Merck Sharp & Dohme) for 30 minutes, cells were fixed, permeablised and stained with Alexa Fluor R 647 STAT1 (pY701) for pSTAT1 and CD3 Pacific Blue antibody for CD3 + T cells (all reagents from BD). Data were collected with a FACSCaliber (BD) and analysed with FlowJo software. Grey = healthy control; black = CMC patient; clear peaks = unstimulated cells; full peaks = IFNα stimulated cells. Median fluorescence intensity (MFI) is shown. (b) qRT-PCR of STAT1-dependent gene expression for CXCL10 and IRF1. In a healthy control and CMC patient 5, peripheral blood mononuclear cells were isolated and cultured in RPMI medium for 4 h with 1 × 10³IU/ml IFNα (IFN-α2b Intron A, Merck Sharp & Dohme), 1 µg/ml IFNγ (R&D Systems). Total RNA was purified using RNeasy Mini Kit (Qiagen) and reverse-transcribed into cDNA. Gene expression analysis for CXCL1o and IRF1 mRNA was performed with custom TaqMan gene expression assays (ABI). Gene expression was normalised to the housekeeping gene 18S rRNA. Data is expressed in the 2 − Ct format, where Ct = Ct (target) – Ct (18S). Results are for n = 3 replicates. Statistical significance was assessed by unpaired, two-tailed t test using Prism software. * = p > 0.05; ** = p > 0.01.