Clinical significance of comprehensive genomic profiling tests covered by public insurance in patients with advanced solid cancers in Hokkaido, Japan.

BACKGROUND: Comprehensive cancer genomic profiling has been used recently for patients with advanced solid cancers. Two cancer genomic profiling tests for patients with no standard treatment are covered by Japanese public health insurance since June 2019. METHODS: We prospectively analyzed data of 189 patients with solid cancers who underwent either of the two-cancer genomic profiling tests at Hokkaido University Hospital and its liaison hospitals and whose results were discussed in molecular tumor board at Hokkaido University Hospital between August 2019 and July 2020. RESULTS: All 189 patients had appropriate results. Actionable gene alterations were identified in 93 patients (49%). Frequent mutations included PIK3CA (12%) mutation, BRCA1/2 alteration (7%), ERBB2 amplification (6%) and tumor mutation burden-High (4%). The median turnaround time from sample shipping to acquisition by the expert panel was 26 days. Although 115 patients (61%) were provided with information for genotype-matched therapies, only 21 (11%) received them. Notably, four of eight patients below the age of 20 years were provided information for genotype-matched therapies, and three received them. Their response rates and disease control rates were 29% and 67%, respectively. Most patients who did not undergo the genotype-matched therapies were provided information for only investigational drugs in phases I and II at distant clinical trial sites in central Japan. Twenty-six patients were informed of suspected germline findings, while 11 patients (42%) received genetic counseling. CONCLUSIONS: The publicly reimbursed cancer genomic profilings may lead to the modest but favorable therapeutic efficacy of genotype-matched therapy for solid cancer patients with no standard therapy. However, poor access to genotype-matched therapy needs to be resolved.

Iron-induced epigenetic abnormalities of mouse bone marrow through aberrant activation of aconitase and isocitrate dehydrogenase.

Iron overload remains a concern in myelodysplastic syndrome (MDS) patients. Iron chelation therapy (ICT) thus plays an integral role in the management of these patients. Moreover, ICT has been shown to prolong leukemia-free survival in MDS patients; however, the mechanisms responsible for this effect are unclear. Iron is a key molecule for regulating cytosolic aconitase 1 (ACO1). Additionally, the mutation of isocitrate dehydrogenase (IDH), the enzyme downstream of ACO1 in the TCA cycle, is associated with epigenetic abnormalities secondary to 2-hydroxyglutarate (2-HG) and DNA methylation. However, epigenetic abnormalities observed in many MDS patients occur without IDH mutation. We hypothesized that iron itself activates the ACO1-IDH pathway, which may increase 2-HG and DNA methylation, and eventually contribute to leukemogenesis without IDH mutation. Using whole RNA sequencing of bone marrow cells in iron-overloaded mice, we observed that the enzymes, phosphoglucomutase 1, glycogen debranching enzyme, and isocitrate dehydrogenase 1 (Idh1), which are involved in glycogen and glucose metabolism, were increased. Digital PCR further showed that Idh1 and Aco1, enzymes involved in the TCA cycle, were also elevated. Additionally, enzymatic activities of TCA cycle and methylated DNA were increased. Iron chelation reversed these phenomena. In conclusion, iron activation of glucose metabolism causes an increase of 2-HG and DNA methylation.

Interference of deferasirox with assays for serum iron and serum unsaturated iron binding capacity during iron chelating therapy.

BACKGROUND: Deferasirox (DFX) is an oral iron chelator that is used worldwide for the treatment of iron overload. Although serum ferritin level is usually measured as a marker of the efficacy of DFX, we sometimes experienced unexplainable changes in other serum markers for iron. We hypothesized that photometric assays for serum iron (sFe) and unsaturated iron binding capacity (UIBC) might be affected by DFX. METHODS: Measurement of sFe and UIBC was performed using 4 different assay systems. The samples were prepared by adding 0-300 µM DFX to pooled human serum or 15 randomized human serum samples. In some experiments, DFX-iron complex (DFX-Fe) was prepared by mixing iron ammonium citrate solution and DFX solution. RESULTS: Measurement of sFe was influenced by DFX-Fe, while iron-free DFX showed no effect on the value of sFe; DFX-Fe was measured as sFe, undistinguishable from transferrin-bound iron. On the other hand, measurement of serum UIBC was influenced by DFX itself; DFX might have been bound to iron in the reagent used for the assay, leading to an increase in UIBC values. CONCLUSIONS: DFX affected the sFe and UIBC assay systems. We must be careful in observing these markers during iron chelation therapy with DFX.