PurposeVariability in pharmacokinetics and drug response is shaped by single-nucleotide variants (SNVs) as well as copy-number variants (CNVs) in genes with importance for drug absorption, distribution, metabolism, and excretion (ADME). While SNVs have been extensively studied, a systematic assessment of the CNV landscape in ADME genes is lacking.MethodsWe integrated data from 2,504 whole genomes from the 1000 Genomes Project and 59,898 exomes from the Exome Aggregation Consortium to identify CNVs in 208 relevant pharmacogenes.ResultsWe describe novel exonic deletions and duplications in 201 (97%) of the pharmacogenes analyzed. The deletions are population-specific and frequencies range from singletons up to 1%, accounting for >5% of all loss-of-function alleles in up to 42% of the genes studied. We experimentally confirmed novel deletions in CYP2C19, CYP4F2, and SLCO1B3 by Sanger sequencing and validated their allelic frequencies in selected populations.ConclusionCNVs are an additional source of pharmacogenetic variability with important implications for drug response and personalized therapy. This, together with the important contribution of rare alleles to the variability of pharmacogenes, emphasizes the necessity of comprehensive next-generation sequencing-based genotype identification for an accurate prediction of the genetic variability of drug pharmacokinetics.
Renal cell carcinoma (RCC) is the most frequent kidney solid tumor, the clear cell RCC (ccRCC) being the major histological subtype. The probability of recurrence and the clinical behavior of ccRCC will greatly depend on the different clinical and histopathological features, already incorporated to different scoring systems, and on the genomic landscape of the tumor. In this sense, ccRCC has for a long time been known to be associated to the biallelic inactivation of Von Hippel-Lindau (VHL) gene which causes aberrant hypoxia inducible factor (HIF) accumulation. Recently, next generation-sequencing technologies have provided the bases for an in-depth molecular characterization of ccRCC, identifying additional recurrently mutated genes, such as PBRM1 (≈40-50%), SETD2 (≈12%), or BAP1 (≈10%). PBRM1, the second most common mutated gene in ccRCC after VHL, is a component of the SWI/SNF chromatin remodeling complex. Different studies have investigated the biological consequences and the potential role of PBRM1 alterations in RCC prognosis and as a drug response modulator, although some results are contradictory. In the present article, we review the current evidence on PBRM1 as potential prognostic and predictive marker in both localized and metastatic RCC.
Gene therapy for inherited retinal diseases has been shown to ameliorate functional and structural defects in both animal models and in human clinical trials. X-linked retinoschisis (XLRS) is an early-age onset macular dystrophy resulting from loss of an extracellular matrix protein (RS1). In preparation for a human clinical gene therapy trial, we conducted a dose-range efficacy study of the clinical vector, a self-complementary AAV delivering a human retinoschisin (RS1) gene under control of the RS1 promoter and an interphotoreceptor binding protein enhancer (AAV8-scRS/IRBPhRS), in the retinoschisin knockout (Rs1-KO) mouse. The therapeutic vector at 1 × 10(6) to 2.5 × 10(9) (1E6-2.5E9) vector genomes (vg)/eye or vehicle was administered to one eye of 229 male Rs1-KO mice by intravitreal injection at 22 ± 3 days postnatal age (PN). Analysis of retinal function (dark-adapted electroretinogram, ERG), structure (cavities and outer nuclear layer thickness) by in vivo retinal imaging using optical coherence tomography, and retinal immunohistochemistry (IHC) for RS1 was done 3-4 months and/or 6-9 months postinjection (PI). RS1 IHC staining was dose dependent across doses ≥1E7 vg/eye, and the threshold for significant improvement in all measures of retinal structure and function was 1E8 vg/eye. Higher doses, however, did not produce additional improvement. At all doses showing efficacy, RS1 staining in Rs1-KO mouse was less than that in wild-type mice. Improvement in the ERG and RS1 staining was unchanged or greater at 6-9 months than at 3-4 months PI. This study demonstrates that vitreal administration of AAV8 scRS/IRBPhRS produces significant improvement in retinal structure and function in the mouse model of XLRS over a vector dose range that can be extended to a human trial. It indicates that a fully normal level of RS1 expression is not necessary for a therapeutic effect.
Rationale : Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that present variable outcomes. To date, no effective therapies or reliable prognostic markers are available for patients who develop metastatic PPGL (mPPGL). Our aim was to discover robust prognostic markers validated through in vitro models, and define specific therapeutic options according to tumor genomic features. Methods : We analyzed three PPGL miRNome datasets (n=443), validated candidate markers and assessed them in serum samples (n=36) to find a metastatic miRNA signature. An integrative study of miRNome, transcriptome and proteome was performed to find miRNA targets, which were further characterized in vitro . Results : A signature of six miRNAs (miR-21-3p, miR-183-5p, miR-182-5p, miR-96-5p, miR-551b-3p, and miR-202-5p) was associated with metastatic risk and time to progression. A higher expression of five of these miRNAs was also detected in PPGL patients' liquid biopsies compared with controls. The combined expression of miR-21-3p/miR-183-5p showed the best power to predict metastasis (AUC=0.804, P =4.67·10 -18 ), and was found associated in vitro with pro-metastatic features, such as neuroendocrine-mesenchymal transition phenotype, and increased cell migration rate. A pan-cancer multi-omic integrative study correlated miR-21-3p levels with TSC2 expression, mTOR pathway activation, and a predictive signature for mTOR inhibitor-sensitivity in PPGLs and other cancers. Likewise, we demonstrated in vitro a TSC2 repression and an enhanced rapamycin sensitivity upon miR-21-3p expression. Conclusions : Our findings support the assessment of miR-21-3p/miR-183-5p, in tumors and liquid biopsies, as biomarkers for risk stratification to improve the PPGL patients' management. We propose miR-21-3p to select mPPGL patients who may benefit from mTOR inhibitors.
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