A New Genetic Risk Score to Predict the Outcome of Locally Advanced or Metastatic Breast Cancer Patients Treated With First-Line Exemestane: Results From a Prospective Study

Currently there are no reliable biomarkers to predict outcome of exemestane treatment. We designed a prospective study to investigate whether constitutive genetic background might affect response to therapy. In a population of 302 advanced breast cancer patients treated with exemestane we showed that a 5-polymorphism-based genetic score could be used to identify patients with different risks of progression and death.Introduction: Approximately 50% of locally advanced or metastatic breast cancer (MBC) patients treated with first-line exemestane do not show objective response and currently there are no reliable biomarkers to predict the outcome of patients using this therapy. The constitutive genetic background might be responsible for differences in the outcome of exemestane-treated patients. We designed a prospective study to investigate the role of germ line polymorphisms as biomarkers of survival. Patients and Methods: Three hundred two locally advanced or MBC patients treated with first-line exemestane were genotyped for 74 germ line polymorphisms in 39 candidate genes involved in drug activity, hormone balance, DNA replication and repair, and cell signaling pathways. Associations with progression-free survival (PFS) and overall survival (OS) were tested with multivariate Cox regression. Bootstrap resampling was used as an internal assessment of results reproducibility. Results: Cytochrome P450 19A1-rs10046TC/CC, solute carrier organic anion transporter 1B1-rs4149056TT, adenosine triphosphate binding cassette subfamily G member 2-rs2046134GG, fibroblast growth factor receptor-4-rs351855TT, and X-ray repair cross complementing 3-rs861539TT were significantly associated with PFS and then combined into a risk score (0-1, 2, 3, or 4-6 risk points). Patients with the highest risk score (4-6 risk points) compared with ones with the lowest score (0-1 risk points) had a median PFS of 10 months versus 26.3 months (adjusted hazard ratio [AdjHR], 3.12 [95% confidence interval (CI), 2.18-4.48]; P < .001) and a median OS of 38.9 months versus 63.0 months (AdjHR, 2.41 [95% CI, 1.22-4.79], P = .012), respectively. Conclusion: In this study we defined a score including 5 polymorphisms to stratify patients for PFS and OS. This score, if validated, might be translated to personalize locally advanced or MBC patient treatment and management

Efficacy of hepatic computed tomography to detect iron overload in chronic hemodialysis

Efficacy of hepatic computed tomography to detect iron overload in chronic hemodialysis. The diagnostic efficacy of hepatic computed tomography density (HCTD) in comparison with serum ferritin for the detection of iron overload was investigated in uremic patients on maintenance hemodialysis (HD) and in patients with idiopathic hemochromatosis (IHC). Ten IHC patients, 38 HD patients and 40 healthy subjects underwent the CT scanning of the liver and determination of percent saturation of transferrin, serum ferritin concentration and HLA typing. Liver iron content was determined by histochemical grading and direct measurement of liver iron concentration either in IHC patients or in HD patients. Nineteen HD patients were considered to have iron overload on the basis of liver iron concentration exceeding 3.6 µmol/100mg dry weight. The mean ± SD values of HCTD in healthy subjects, IHC patients, HD patients with iron overload and without iron overload were 60.2 ± 5.6, 79 ± 5.6, 71.4 ± 3.6, 58 ± 3.8 Hounsfield units, respectively. HCTD showed positive correlations with liver iron concentration and serum ferritin either in IHC patients or in HD patients. The analysis of the diagnostic efficacy of HCTD in comparison with serum ferritin for the detection of excessive hepatic iron in HD patients demonstrated that HCTD had higher sensitivity, specificity, positive and negative predictive values. Cut-off points were arbitrarily fixed to 66 Hounsfield units for HCTD, 400 µ-g/liter for serum ferritin and 3.6 µmol/100mg dry weight for liver iron concentration. Seventeen HD patients who possessed the histocompatibility antigens associated with IHC, namely HLA-A3 and/or HLA-B7 and/or HLA-B14, had liver iron concentration, serum ferritin and HCTD values higher than those of the HD patients without these “hemochromatosis alleles”. The diagnostic approach to the disorders of excessive iron storage of the liver may evolve to a new level of sophistication with the introduction of the CT scanning. HCTD may be an accurate, non-invasive, alternative to liver biopsy for the detection of hepatic iron overload in HD patients and in IHC patients. In HD patients HCTD is more efficient than serum ferritin in diagnosing iron overload. However, liver biopsy, which permits a definition of the presence of fibrosis and cirrhosis, maintains its importance from a standpoint of prognosis and follow-up. In HD patients the presence of any of the histocompatibility antigens of IHC is associated with an increased risk of iron overload and excessive hepatic iron storage

Chlorella vulgaris genome assembly and annotation reveals the molecular basis for metabolic acclimation to high light conditions

International audienc

Structural Refinement by Direct Mapping Reveals Assembly Inconsistencies near Hi-C Junctions

High-throughput chromosome conformation capture (Hi-C) is widely used for scaffolding in de novo assembly because it produces highly contiguous genomes, but its indirect statistical approach can introduce connection errors. We employed optical mapping (Bionano Genomics) as an orthogonal scaffolding technology to assess the structural solidity of Hi-C reconstructed scaffolds. Optical maps were used to assess the correctness of five de novo genome assemblies based on long-read sequencing for contig generation and Hi-C for scaffolding. Hundreds of inconsistencies were found between the reconstructions generated using the Hi-C and optical mapping approaches. Manual inspection, exploiting raw long-read sequencing data and optical maps, confirmed that several of these conflicts were derived from Hi-C joining errors. Such misjoins were widespread, involved the connection of both small and large contigs, and even overlapped annotated genes. We conclude that the integration of optical mapping data after, not before, Hi-C-based scaffolding, improves the quality of the assembly and limits reconstruction errors by highlighting misjoins that can then be subjected to further investigation