Erythrocyte PIG-A mutant frequencies in cancer patients receiving cisplatin

Abstract

Background: Cisplatin is a primary chemotherapy choice for various solid tumors. DNA damage caused by cisplatin results in apoptosis of tumor cells. Cisplatin-induced DNA damage, however, may also result in mutations in normal cells and the initiation of secondary malignancies. In the current study, we have used the erythrocyte PIG-A assay to evaluate mutagenesis in non-tumor hematopoietic tissue of cancer patients receiving cisplatin chemotherapy.

Methods: Twenty-one head and neck cancer patients undergoing treatment with cisplatin were monitored for the presence of PIG-A mutant total erythrocytes and the young erythrocytes, reticulocytes (RETs), in peripheral blood for up to five and a half months from the initiation of the anti-neoplastic chemotherapy.

Results: PIG-A mutant frequency (MF) in RETs increased at least two-fold in 15 patients at some point of the monitoring, while the frequency of total mutant RBCs increased at least two-fold in 6 patients. A general trend for an increase in the frequency of mutant RETs and total mutant RBCs was observed in 19 and 18 patients, respectively. Only in one patient did both RET and total RBC PIG-A MFs did not increase at any time-point over the monitoring period.

Conclusion: Cisplatin chemotherapy induces moderate increases in the frequency of PIG-A mutant erythrocytes in head and neck cancer patients. Mutagenicity measured with the flow cytometric PIG-A assay may serve as a tool for predicting adverse outcomes of genotoxic antineoplastic therapy.

Keywords: Phosphatidylinositol glycan class-A (PIG-A) gene; chemotherapy; erythrocytes; head and neck cancer (HNC); mutations.

FIGURE 1

Blood drawing and cisplatin infusion timing relative to day of the study. Not all subjects submitted the requested four blood samples; not all subjects completed cisplatin chemotherapy course. The therapy course was not the same for all subjects. The vertical order of patients is based on the number of donated blood samples and the number of cisplatin infusions. Groups were based on office visits for blood sampling. The 11 patients highlighted in bold received the standard 3‐infusion cisplatin therapy course and submitted the requested four blood samples. For details, see Results and Table 1.

FIGURE 2

Box and whiskers percentile charts for reticulocyte (RET) and total RBC absolute PIG‐A mutant frequencies (MF) measured in cancer patients receiving cisplatin. The boundaries of the box represent the 25th and 75th percentiles; the horizontal line within the box marks the median; and the whiskers indicate the 10th and 90th percentiles. MFs were determined at scheduled office visits for cisplatin infusions or for follow‐up post‐therapy visits at which blood samples were collected (Groups 1, 2, 3, and 4; see Table 1 and Materials & Methods for details on timing of office visits). MFs are shown for all 21 patients (fewer blood samples were collected at the third and the fourth office visits as some patients withdrew from the study; see Table 1). Data for the charts are taken from Table 2.

FIGURE 3

Time‐dependent relative fold‐increases in RET and total RBC PIG‐A MFs in cancer patients receiving cisplatin chemotherapy. Each data point was calculated as the ratio of the PIG‐A MF determined at a specific day of study and the MF determined at Day 0 (the first office visit) before cisplatin infusion (data for the charts are taken from Table 2). Only the numerical index of the patient ID and the disease status at the end of the study are shown in the charts. Data points for each patient are traced by lines. Dotted lines represent patients with unknown status of disease at the end of the study.