The PIG-A mutation test in disease
Whilst the applicability of this mutation assay has mostly been investigated in humans exposed to defined mutagenic agents, the application of the PIG-A test in disease detection has also been explored. Reports by Nichols et al., showed that patients with pancreatic cancer had elevated levels of PIG-A mutant erythrocytes (5.775 × 10-6 (95% CI 4.777-10) compared to non-cancer controls (4.211 × 10-6 (95% CI 1.39-5.16)) (Nichols et al., 2023). Although this difference was subtle, it may indicate an underlying individual susceptibility to mutation and hence risk of malignancy. In a larger cohort studied by Haboubi et al, oesophageal adenocarcinoma patients had elevated levels of mutant erythrocytes (9.75 x 10-6 (95% CI 4.36-17.52)) compared to healthy volunteers (2.8 x 10-6 (95% CI 2.21-3.57)), patients with gastro-oesophageal reflux disease (3.44 x 10-6 (95% CI 1.56-5.43)) and patients with the pre-malignant condition Barrett’s oesophagus (4.35 x 10-6 (95% CI 2.49-6.09)). Moreover, the number ofPIG-A mutant cells was associated with tumour staging and metastatic disease. Elevated PIG-A mutant frequency was identified as risk factor for oesophageal cancer independent of age and gender using general linear model analyses (Haboubi et al., 2019). Two publications have assessed PIG-A mutant cells in IBD patients. Firstly, Baig and colleagues found no significant increase in mutant reticulocytes in paediatric IBD patients although 10 patients with higher micronucleus frequencies all had established disease (Baig et al., 2020). Secondly, Cao et al., found significantly elevated erythrocyte mutant cell number in adult Chinese IBD patients, although these were all undergoing azathioprine treatment (Cao, Wang, Liu, et al., 2020). Whilst the mechanistic link between solid tumour development and induction of circulating PIG-A mutation levels remain unclear, with inflammatory driven malignancies such as oesophageal cancer and IBD, circulating blood cells (RETs or immature red blood cells) may be exposed to inflammatory mediators and subsequently accumulate DNA damage which results in a PIG-A mutant phenotype in erythrocytes.