Can gene therapy be used to prevent cancer? Gene therapy for aldehyde dehydrogenase 2 deficiency.

Approximately 8% of the world population and 35-45% of East Asians are carriers of the hereditary disorder aldehyde dehydrogenase 2 (ALDH2) deficiency. ALDH2 plays a central role in the liver to metabolize ethanol. With the common E487K variant, there is a deficiency of ALDH2 function; when ethanol is consumed, there is a systemic accumulation of acetaldehyde, an intermediate product in ethanol metabolism. In ALDH2-deficient individuals, ethanol consumption acutely causes the "Alcohol Flushing Syndrome" with facial flushing, tachycardia, nausea, and headaches. With chronic alcohol consumption, ALDH2 deficiency is associated with a variety of disorders, including a remarkably high risk for aerodigestive tract cancers. Acetaldehyde is a known carcinogen. The epidemiologic data relating to the association of ALDH2 deficiency and cancer risk are striking: ALDH2 homozygotes who are moderate-to-heavy consumers of ethanol have a 7-12-fold increased risk for esophageal cancer, making ALDH2 deficiency the most common hereditary disorder associated with an increased cancer risk. In this review, we summarize the genetics and biochemistry of ALDH2, the epidemiology of cancer risk associated with ALDH2 deficiency, the metabolic consequences of ethanol consumption associated with ALDH2 deficiency, and gene therapy strategies to correct ALDH2 deficiency and its associated cancer risk. With the goal of reducing the risk of aerodigestive tract cancers, in the context that ALDH2 is a hereditary disorder and ALDH2 functions primarily in the liver, ALDH2 deficiency is an ideal target for the application of adeno-associated virus-mediated liver-directed gene therapy to prevent cancer.

Synthetic Antibody Mimics Based on Cancer-Targeting Immunostimulatory Peptides.

De novo cancer-targeting immunostimulatory peptides have been designed and developed as synthetic antibody mimics. A series of bifunctional peptides incorporating NKp30-binding and NK-cell-activating domains were synthesized as linear dimers and then extended into branching trimeric peptides by the incorporation of GRP78-targeting and tumor-cell-binding sequences. A selected trimeric peptide from this small set of peptides displayed binding capabilities on GRP78+ HepG2 and A549 target cells. Cell binding diminished in the presence of an anti-GRP78 peptide blocker, thus suggesting GRP78-binding dependence. Similarly, the selected trimeric peptide was also found to exhibit NK cell binding in an NKp30-dependent manner, which translated into NK cell activation as indicated by cytokine secretion. In co-culture, fluorescence microscopy revealed that the target GFP-expressing A549 cells were visibly associated with the effector NK cells when pre-activated with lead trimeric peptide. Accordingly, A549 cells were found to be compromised, as evidenced by the loss of GFP signal and notable detection of early-/late-stage apoptosis. Investigation of the immunological markers related to toxicity revealed detectable secretion of pro-inflammatory cytokines and chemokines, including IFN-γ, TNF-α, and IL-8. Furthermore, administration of peptide-activated NK cells into A549-tumor-bearing mice resulted in a consistent decrease in tumor growth when compared to the untreated control group. Taken together, the identification of a lead trimeric peptide capable of targeting and activating NK cells' immunotoxicity directly towards GRP78+ /B7H6- tumors provides a novel proof-of-concept for the development of cancer-targeting immunostimulatory peptide ligands that mimic antibody-targeting and -activating functions related to cancer immunotherapy applications.

Genetic variants as biomarkers for progression and resistance in multiple myeloma.

Technical advances in genome sequencing, in particular whole-genome sequencing (WGS), provide adequate tools to understanding cancer at the molecular level while specifically focusing on genetic variants that contribute to the causation and progression of pathogenic cancers. Multiple myeloma (MM), a malignant disease of plasma cells that is marked as rare yet incurable, may be diagnosed by WGS tools, as this cancer is associated with chromosomal translocations and mutations in specific protein-coding genes. Among these protein-coding genes, many are known to be responsible for cell cycle regulation in MM. The initial significant protein-coding mutations were found in NRAS, KRAS and TP53 and later reported in FAM46C, DIS3, CCND1, PNRC1, ALOX12B, HLA-A and MAGED1. Here, we report gene network associations of MM using Qiagen's Ingenuity Pathway Analysis (IPA) software and compared biomarker information reported in IPA for these protein-coding genes (NRAS, TP53 and KRAS). Using Qiagen's Ingenuity Variant Analysis (IVA), we characterized cancer driver variants in MT-ND1 as likely pathogenic or variants of uncertain significance.

Assessment of the Association of D2 Dopamine Receptor Gene and Reported Allele Frequencies With Alcohol Use Disorders: A Systematic Review and Meta-analysis.

Importance: The association between the D2 dopamine receptor gene (DRD2) Taq1A locus (rs1800497) and alcohol use disorder (AUD) is enduring but the subject of long-standing controversy; meta-analysis of studies across 3 decades shows an association between rs1800497 and AUD, but genome-wide analyses have detected no role for rs1800497 in any phenotype. No evidence has emerged that rs1800497, which is located in ANKK1, perturbs the expression or function of DRD2. Objective: To resolve contradictions in previous studies by identifying hidden confounders and assaying for functional effects of rs1800497 and other loci in the DRD2 region. Data Sources: PubMed (882 studies), Embase (1056 studies), and Web of Science (501 studies) databases were searched through August 2018. Three clinical populations-Finnish, Native American, and African American participants-were genotyped for 208 to 277 informative single-nucleotide polymorphisms (SNPs) across the DRD2 region to test the associations of SNPs in this region with AUD. Study Selection: Eligible studies had diagnosis of AUD made by accepted criteria, reliable genotyping methods, sufficient genotype data to calculate odds ratios and 95% CIs, and availability of control allele frequencies or genotype frequencies. Data Extraction and Synthesis: After meta-analysis of 62 studies, metaregression was performed to detect between-study heterogeneity and to explore the effects of moderators, including deviations of cases and controls from allele frequencies in large population databases (ExAC and 1000 Genomes). Linkage to AUD and the effect on gene expression of rs1800497 were evaluated in the context of other SNPs in the DRD2 region. Data analysis was performed from August 2018 to March 2019. This study follows the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline. Main Outcomes and Measures: The effects of rs1800497 and other SNPs in the DRD2 region on gene expression were measured in human postmortem brain samples via differential allelic expression and evaluated in other tissues via publicly available expression quantitative locus data. Results: A total of 62 studies of DRD2 and AUD with 16 294 participants were meta-analyzed. The rs1800497 SNP was associated with AUD (odds ratio, 1.23; 95% CI, 1.14-1.31; P < .001). However, the association was attributable to spuriously low allele frequencies in controls in positive studies, which also accounted for some between-study heterogeneity (I2 = 43%; 95% CI, 23%-58%; Q61 = 107.20). Differential allelic expression of human postmortem brain and analysis of expression quantitative loci in public data revealed that a cis-acting locus or loci perturb the DRD2 transcript level; however, rs1800497 does not and is not in strong disequilibrium with such a locus. Across the DRD2 region, other SNPs are more strongly associated with AUD than rs1800497, although no DRD2 SNP was significantly associated in these 3 clinical samples. Conclusions and Relevance: In this meta-analysis, the significant association of DRD2 with AUD was reassessed. The DRD2 association was attributable to anomalously low control allele frequencies, not function, in positive studies. For genetic studies, statistical replication is not verification.