👤 Henrik Gréen

Persistent taxane-induced peripheral neuropathy (TIPN) is highly prevalent among early-stage breast cancer survivors (ESBCS) and has detrimental effect on quality of life. We leveraged logistic regression models to develop and validate polygenic prediction models to estimate the risk of persistent PN symptoms in a training cohort and validation cohort taking clinical risk factors into account. Based on 337 whole-exome sequenced ESBCS two of five prediction models for individual PN symptoms obtained AUC results above 60% when validated. Using the model for numbness in feet (35 SNVs) in the test cohort, 73% survivors were correctly predicted. For tingling in feet (55 SNVs) 70% were correctly predicted. Both models included SNVs from the ADAMTS20, APT6V0A2, CCDC88C, CYP2C8, EPHA5, NR1H3, PSKH2/APTV0D2, and SCN10A genes. For cramps in feet, difficulty climbing stairs and difficulty opening a jar the validation was unsuccessful. Polygenic prediction models including clinical risk factors can estimate the risk of persistent taxane-induced numbness in feet and tingling in feet in ESBCS. Show less

Chemotherapy-induced hematological toxicities are potentially life-threatening adverse drug reactions that vary between individuals. Recently, JMJD1C has been associated with gemcitabine/carboplatin-induced thrombocytopenia in non-small-cell lung cancer patients, making it a candidate marker for predicting the risk of toxicity. This study investigates if JMJD1C knockdown affects gemcitabine/carboplatin-sensitivity in cell lines. Lentiviral transduction-mediated shRNA knockdown of JMJD1C in the cell lines K562 and MEG-01 were performed using shRNA#32 and shRNA#33. The knockdown was evaluated using qPCR. Cell proliferation, viability, and gemcitabine/carboplatin-sensitivity were subsequently determined using cell counts, trypan blue, and the MTT assay. ShRNA#33 resulted in JMJD1C downregulation by 56.24% in K562 and 68.10% in MEG-01. Despite incomplete knockdown, proliferation (reduction of cell numbers by 61-68%, day 7 post-transduction) and viability (reduction by 21-53%, day 7 post-transduction) were impaired in K562 and MEG-01 cells. Moreover, JMJD1C knockdown reduced the gemcitabine IC50-value for K562 cells (P < 0.01) and MEG-01 cells (P < 0.05) compared to scrambled shRNA control transduced cells. Our results suggest that JMJD1C is essential for proliferation, survival, and viability of K562 and MEG-01 cells. Further, JMJD1C also potentially affects the cells gemcitabine/carboplatin-sensitivity. Although further research is required, the findings show that JMJD1C could have an influential role for gemcitabine/carboplatin-sensitivity. Show less

Chemotherapy-induced myelosuppression, including thrombocytopenia, is a recurrent problem during cancer treatments that may require dose alterations or cessations that could affect the antitumor effect of the treatment. To identify genetic markers associated with treatment-induced thrombocytopenia, we whole-exome sequenced 215 non-small cell lung cancer patients homogeneously treated with gemcitabine/carboplatin. The decrease in platelets (defined as nadir/baseline) was used to assess treatment-induced thrombocytopenia. Association between germline genetic variants and thrombocytopenia was analyzed at single-nucleotide variant (SNV) (based on the optimal false discovery rate, the severity of predicted consequence, and effect), gene, and pathway levels. These analyses identified 130 SNVs/INDELs and 25 genes associated with thrombocytopenia (P-value < 0.002). Twenty-three SNVs were validated in an independent genome-wide association study (GWAS). The top associations include rs34491125 in JMJD1C (P-value = 9.07 × 10 Show less