Lack of hydroxyurea-associated mutagenesis in pediatric sickle cell disease patients.

Hydroxyurea is approved for treating children and adults with sickle cell anemia (SCA). Despite its proven efficacy, concerns remain about its mutagenic and carcinogenic potential that hamper its widespread use. Cell culture- and animal-based investigations indicate that hydroxyurea's genotoxic effects are due to indirect clastogenicity in select cell types when high dose and time thresholds are exceeded (reviewed by Ware & Dertinger, 2021). The current study extends these preclinical observations to pediatric patients receiving hydroxyurea for treatment of SCA. First, proof-of-principle experiments with testicular cancer patients exposed to a cisplatin-based regimen validated the ability of flow cytometric blood-based micronucleated reticulocyte (MN-RET) and PIG-A mutant reticulocyte (MUT RET) assays to detect clastogenicity and gene mutations, respectively. Second, these biomarkers were measured in a cross-sectional study with 26 SCA patients receiving hydroxyurea and 13 SCA patients without exposure. Finally, a prospective study was conducted with 10 SCA patients using pretreatment blood samples and after 6 or 12 months of therapy. Cancer patients exposed to cisplatin exhibited increased MN-RET within days of exposure, while the MUT RET endpoint required more time to reach maximal levels. In SCA patients, hydroxyurea induced MN-RET in both the cross-sectional and prospective studies. However, no evidence of PIG-A gene mutation was found in hydroxyurea-treated children, despite the fact that the two assays use the same rapidly-dividing, highly-exposed cell type. Collectively, these results reinforce the complementary nature of MN-RET and MUT RET biomarkers, and indicate that hydroxyurea can be clastogenic but was not mutagenic in young patients with SCA.

Exploratory study of a KLK2 polymorphism as a prognostic marker in prostate cancer.

OBJECTIVES: An association of a single nucleotide polymorphism (SNP) of the KLK2 gene (rs198977; c.748C>T; R250W) with risk for developing prostate cancer has been observed. We evaluated the role of R250W SNP for prognosis in prostate cancer. METHODS: The c.748C>T SNP was genotyped from blood DNA of 182 patients after completing initial cancer treatments. For evaluating prognosis of genotype groups, associations were performed with Gleason score (GS) and biochemical recurrence free survival (bRFS) in patients demonstrating PSA-recurrence after initial cancer therapy. RESULTS: Overall distribution of the CC, CT and TT genotypes for the SNP was 48%, 44% and 8%, respectively. The distribution of high (8-10), moderate (5-7) and low (2-4) GS among the genotype groups was 17%, 74% and 9% for CC group compared to 25%, 74% and 1% for the CT/TT (P=0.04). Median bRFS time for CT/TT group was 36.5 months compared to 44.5 months for the CC group (P=0.16), while genotype groups combined with morphology revealed significantly different bRFS (P=0.004). CONCLUSIONS: This exploratory analysis in prostate cancer patients revealed the W allele of the KLK2 R250W SNP to be less likely associated with low GS morphology. Further studies will be needed to confirm this observation in larger cohorts.