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.