Around 50% of the familial breast cancer (BC) cases are estimated to be caused by germline variants in known low-, moderate-, and high-risk susceptibility genes, while the other half is of unknown genetic origin. In the present study, we wanted to evaluate the role of the RECQ helicases, some of which have been studied in the past as candidates, with unclear results about their role in the disease. Using next-generation sequencing (NGS) technology, we analyzed the whole coding sequence of BLM, RECQL1, RECQL4, RECQL5, and WRN in almost 2000 index cases from BC Spanish families that had previously tested negative for the known BC susceptibility genes (BRCAX) and compared the results with the controls extracted from gnomAD. Our results suggest that BLM, RECQL1, RECQL4, and WRN do not play a major role in BC susceptibility. However, in the combined analysis, joining the present results with those previously reported in a series of 1334 BC Spanish patients and controls, we found a statistically significant association between Loss of Function (LoF) variants in RECQL5 and BC risk, with an OR of 2.56 (p = 0.009; 95% CI, 1.18–4.98). Our findings support our previous work and places the RECQL5 gene as a new moderate-risk BC gene.

Multiple myeloma is an incurable plasma cell malignancy. Most patients end up relapsing and developing resistance to antineoplastic drugs, like bortezomib. Antibiotic tigecycline has activity against myeloma. This study analyzed tigecycline and bortezomib combination on cell lines and plasma cells from myeloma patients. Apoptosis, autophagic vesicles, mitochondrial mass, mitochondrial superoxide, cell cycle, and hydrogen peroxide were studied by flow cytometry. In addition, mitochondrial antioxidants and electron transport chain complexes were quantified by reverse transcription real-time PCR (RT-qPCR) or western blot. Cell metabolism and mitochondrial activity were characterized by Seahorse and RT-qPCR. We found that the addition of tigecycline to bortezomib reduces apoptosis in proportion to tigecycline concentration. Supporting this, the combination of both drugs counteracts bortezomib in vitro individual effects on the cell cycle, reduces autophagy and mitophagy markers, and reverts bortezomib-induced increase in mitochondrial superoxide. Changes in mitochondrial homeostasis and MYC upregulation may account for some of these findings. These data not only advise to avoid considering tigecycline and bortezomib combination for treating myeloma, but caution on the potential adverse impact of treating infections with this antibiotic in myeloma patients under bortezomib treatment.

Prognostic uncertainty often leads to overtreatment of differentiated thyroid cancer (DTC) or unspecific management of more aggressive entities. MiR-139-5p (miR-139-5p) has emerged as a promising prognostic factor that may enhance current individual risk assessment systems. Therefore, we aimed to validate miR139-5p expression as a prognostic marker in DTC using a standardized method and to establish expression cutoff values for discriminating prognostic groups. In addition, we explored an in situ approach to analyze this microRNA expression as a potential molecular tool for clinical practice. We collected a tissue series of 132 samples, including thyroid tumors, adjacent normal thyroid tissue, and lymph node metastases from a long-term follow-up retrospective cohort of 60 patients with DTC with either progressive/persistent disease or an excellent response to primary treatment. We first identified recurrent tumor driver mutations and TERT promoter mutations using next-generation sequencing. Through a standardized paired tumor/normal qPCR analysis, we confirmed a significant reduction in miR139-5p expression in progressive/persistent DTCs compared with excellent response DTCs (P value = .002). Further analysis, including thyroid cancer The Cancer Genome Atlas tumor/normal pairs (n = 59), showed a strong association between reduced miR139-5p expression and TERT promoter mutations (P < .001), as well as advanced local or distant metastasis at diagnosis (P = .031). Next, we established miR139-5p^HIGH and miR139-5p^LOW tumor/normal cutoff values to discriminate prognostic groups, with high expression predicting excellent response and low expression predicting disease progression/persistence. Cutoff values were defined through logistic regression and receiver operating characteristic curve analysis and validated in an independent cohort (n = 38). Quantitative image analysis using QuPath software of an automatic chromogenic in situ hybridization assay for miR139 detection further supported the qPCR findings and revealed heterogeneous intratumor miR139 expression, which was lowest in the Ki-67 proliferation index--positive foci. Overall, our data indicate that miR139 expression assessment is a feasible tool for clinical use, potentially reducing overtreatment during primary DTC interventions and supporting a risk-adjusted follow-up schedule.