Truncated ERG Oncoproteins from TMPRSS2-ERG Fusions Are Resistant to SPOP-Mediated Proteasome Degradation.

SPOP mutations and TMPRSS2-ERG rearrangements occur collectively in up to 65% of human prostate cancers. Although the two events are mutually exclusive, it is unclear whether they are functionally interrelated. Here, we demonstrate that SPOP, functioning as an E3 ubiquitin ligase substrate-binding protein, promotes ubiquitination and proteasome degradation of wild-type ERG by recognizing a degron motif at the N terminus of ERG. Prostate cancer-associated SPOP mutations abrogate the SPOP-mediated degradation function on the ERG oncoprotein. Conversely, the majority of TMPRSS2-ERG fusions encode N-terminal-truncated ERG proteins that are resistant to the SPOP-mediated degradation because of degron impairment. Our findings reveal degradation resistance as a previously uncharacterized mechanism that contributes to elevation of truncated ERG proteins in prostate cancer. They also suggest that overcoming ERG resistance to SPOP-mediated degradation represents a viable strategy for treatment of prostate cancers expressing either mutated SPOP or truncated ERG.

DNA Methyltransferase 3A Is Involved in the Sustained Effects of Chronic Stress on Synaptic Functions and Behaviors.

Emerging evidence suggests that epigenetic mechanisms regulate aberrant gene transcription in stress-associated mental disorders. However, it remains to be elucidated about the role of DNA methylation and its catalyzing enzymes, DNA methyltransferases (DNMTs), in this process. Here, we found that male rats exposed to chronic (2-week) unpredictable stress exhibited a substantial reduction of Dnmt3a after stress cessation in the prefrontal cortex (PFC), a key target region of stress. Treatment of unstressed control rats with DNMT inhibitors recapitulated the effect of chronic unpredictable stress on decreased AMPAR expression and function in PFC. In contrast, overexpression of Dnmt3a in PFC of stressed animals prevented the loss of glutamatergic responses. Moreover, the stress-induced behavioral abnormalities, including the impaired recognition memory, heightened aggression, and hyperlocomotion, were partially attenuated by Dnmt3a expression in PFC of stressed animals. Finally, we found that there were genome-wide DNA methylation changes and transcriptome alterations in PFC of stressed rats, both of which were enriched at several neural pathways, including glutamatergic synapse and microtubule-associated protein kinase signaling. These results have therefore recognized the potential role of DNA epigenetic modification in stress-induced disturbance of synaptic functions and cognitive and emotional processes.

Maximizing the reusability of gene expression data by predicting missing metadata.

Reusability is part of the FAIR data principle, which aims to make data Findable, Accessible, Interoperable, and Reusable. One of the current efforts to increase the reusability of public genomics data has been to focus on the inclusion of quality metadata associated with the data. When necessary metadata are missing, most researchers will consider the data useless. In this study, we developed a framework to predict the missing metadata of gene expression datasets to maximize their reusability. We found that when using predicted data to conduct other analyses, it is not optimal to use all the predicted data. Instead, one should only use the subset of data, which can be predicted accurately. We proposed a new metric called Proportion of Cases Accurately Predicted (PCAP), which is optimized in our specifically-designed machine learning pipeline. The new approach performed better than pipelines using commonly used metrics such as F1-score in terms of maximizing the reusability of data with missing values. We also found that different variables might need to be predicted using different machine learning methods and/or different data processing protocols. Using differential gene expression analysis as an example, we showed that when missing variables are accurately predicted, the corresponding gene expression data can be reliably used in downstream analyses.

Electrostatic Interactions in Protein Structure, Folding, Binding, and Condensation.

Charged and polar groups, through forming ion pairs, hydrogen bonds, and other less specific electrostatic interactions, impart important properties to proteins. Modulation of the charges on the amino acids, e.g., by pH and by phosphorylation and dephosphorylation, have significant effects such as protein denaturation and switch-like response of signal transduction networks. This review aims to present a unifying theme among the various effects of protein charges and polar groups. Simple models will be used to illustrate basic ideas about electrostatic interactions in proteins, and these ideas in turn will be used to elucidate the roles of electrostatic interactions in protein structure, folding, binding, condensation, and related biological functions. In particular, we will examine how charged side chains are spatially distributed in various types of proteins and how electrostatic interactions affect thermodynamic and kinetic properties of proteins. Our hope is to capture both important historical developments and recent experimental and theoretical advances in quantifying electrostatic contributions of proteins.

Influenza A M2 Channel Clustering at High Protein/Lipid Ratios: Viral Budding Implications.

Protein dynamics in crowded environments is important for understanding protein functions in vivo and is especially relevant for membrane proteins because of the roles of protein-protein interactions in membrane protein functions and their regulation. Here, using solid-state NMR spectroscopy in combination with coarse-grained molecular dynamics simulations, we report that the rotational correlation time for the transmembrane domain of the influenza A M2 proton channel in lipid bilayers increases dramatically at an elevated protein/lipid ratio. This increase is attributable to persistent protein-protein interactions, thus revealing for the first time, to the best of our knowledge, extensive cluster formation of the M2 tetrameric channel. Such clustering appears to have direct biological relevance during budding of the nascent influenza virus, which does not use the endosomal sorting complexes required for transport machinery. Indeed, initial coarse-grained molecular dynamics simulations of the longer M2 construct known as the conductance domain suggest clustering-induced membrane curvature formation.

Structural modeling for the open state of an NMDA receptor.

NMDA receptors are tetrameric ligand-gated ion channels that are crucial for neurodevelopment and higher order processes such as learning and memory, and have been implicated in numerous neurological disorders. The lack of a structure for the channel open state has greatly hampered the understanding of the normal gating process and mechanisms of disease-associated mutations. Here we report the structural modeling for the open state of an NMDA receptor. Staring from the crystal structure of the closed state, we repacked the pore-lining helices to generate an initial open model. This model was modified to ensure tight packing between subunits and then refined by a molecular dynamics simulation in explicit membrane. We identify Cα-H…O hydrogen bonds, between the Cα of a conserved glycine in one transmembrane helix and a carbonyl oxygen of a membrane-parallel helix, at the extracellular side of the transmembrane domain as important for stabilizing the open state. This observation explains why mutations of the glycine are associated with neurological diseases and lead to significant decrease in channel open probability.

Mechanism and rate constants of the Cdc42 GTPase binding with intrinsically disordered effectors.

Intrinsically disordered proteins (IDPs) are often involved in signaling and regulatory functions, through binding to cellular targets. Many IDPs undergo disorder-to-order transitions upon binding. Both the binding mechanisms and the magnitudes of the binding rate constants can have functional importance. Previously we have found that the coupled binding and folding of any IDP generally follows a sequential mechanism that we term dock-and-coalesce, whereby one segment of the IDP first docks to its subsite on the target surface and the remaining segments subsequently coalesce around their respective subsites. Here we applied our TransComp method within the framework of the dock-and-coalesce mechanism to dissect the binding kinetics of two Rho-family GTPases, Cdc42 and TC10, with two intrinsically disordered effectors, WASP and Pak1. TransComp calculations identified the basic regions preceding the GTPase binding domains (GBDs) of the effectors as the docking segment. For Cdc42 binding with both WASP and Pak1, the calculated docking rate constants are close to the observed overall binding rate constants, suggesting that basic-region docking is the rate-limiting step and subsequent conformational coalescence of the GBDs on the Cdc42 surface is fast. The possibility that conformational coalescence of the WASP GBD on the TC10 surface is slow warrants further experimental investigation. The account for the differences in binding rate constants among the three GTPase-effector systems and mutational effects therein yields deep physical and mechanistic insight into the binding processes. Our approach may guide the selection of mutations that lead to redesigned binding pathways.

Disorder-to-Order Transition of an Active-Site Loop Mediates the Allosteric Activation of Sortase A.

Intrinsically disordered proteins and intrinsically disordered regions are implicated in many biological functions and associated with many diseases, but their conformational characterizations are challenging. The disordered ß6/ß7 loop of Staphylococcus aureus sortase A is involved in the binding of both sorting signals and calcium. Calcium binding allosterically activates the enzyme, but the detailed mechanism has been unclear. Here we adapted the replica exchange with solute tempering method to sample the conformations of the ß6/ß7 loop, in apo form and in three liganded forms (bound with a sorting signal or calcium or both). The extensive molecular dynamics simulations yield atomic details of the disordered-to-order transition of the loop and suggest a mechanism for allosteric activation: calcium binding results in partial closure and ordering of the loop, thereby leading to preorganization of the binding pocket for the sorting signal. The approach has general applicability to the study of intrinsically disordered regions.

Distinct mechanisms of a phosphotyrosyl peptide binding to two SH2 domains.

Protein phosphorylation is very common post-translational modification, catalyzed by kinases, for signaling and regulation. Phosphotyrosines frequently target SH2 domains. The spleen tyrosine kinase (Syk) is critical for tyrosine phosphorylation of multiple proteins and for regulation of important pathways. Phosphorylation of both Y342 and Y346 in Syk linker B is required for optimal signaling. The SH2 domains of Vav1 and PLC-γ both bind this doubly phosphorylated motif. Here we used a recently developed method to calculate the effects of Y342 and Y346 phosphorylation on the rate constants of a peptide from Syk linker B binding to the SH2 domains of Vav1 and PLC-γ. The predicted effects agree well with experimental observations. Moreover, we found that the same doubly phosphorylated peptide binds the two SH2 domains via distinct mechanisms, with apparent rigid docking for Vav1 SH2 and dock-and-coalesce for PLC-γ SH2.

Solid-state NMR evidence for ß-hairpin structure within MAX8 designer peptide nanofibers.

MAX8, a designer peptide known to undergo self-assembly following changes in temperature, pH, and ionic strength, has demonstrated usefulness for tissue engineering and drug delivery. It is hypothesized that the self-assembled MAX8 nanofiber structure consists of closed ß-hairpins aligned into antiparallel ß-sheets. Here, we report evidence from solid-state NMR spectroscopy that supports the presence of the hypothesized ß-hairpin conformation within the nanofiber structure. Specifically, our (13)C-(13)C two-dimensional exchange data indicate spatial proximity between V3 and K17, and (13)C-(13)C dipolar coupling measurements reveal proximity between the V3 and V18 backbone carbonyls. Moreover, isotopic dilution of labeled MAX8 nanofibers did not result in a loss of the (13)C-(13)C dipolar couplings, showing that these couplings are primarily intramolecular. NMR spectra also indicate the existence of a minor conformation, which is discussed in terms of previously hypothesized nanofiber physical cross-linking and possible nanofiber polymorphism.

A common model for cytokine receptor activation: combined scissor-like rotation and self-rotation of receptor dimer induced by class I cytokine.

The precise mechanism by which the binding of a class I cytokine to the extracellular domain of its corresponding receptor transmits a signal through the cell membrane remains unclear. Receptor activation involves a cytokine-receptor complex with a 1∶2 stoichiometry. Previously we used our transient-complex theory to calculate the rate constant of the initial cytokine-receptor binding to form a 1∶1 complex. Here we computed the binding pathway leading to the 1∶2 activation complex. Three cytokine systems (growth hormone, erythropoietin, and prolactin) were studied, and the focus was on the binding of the extracellular domain of the second receptor molecule after forming the 1∶1 complex. According to the transient-complex theory, translational and rotation diffusion of the binding entities bring them together to form a transient complex, which has near-native relative separation and orientation but not the short-range specific native interactions. Subsequently conformational rearrangement leads to the formation of the native complex. We found that the changes in relative orientations between the two receptor molecules from the transient complex to the 1∶2 native complex are similar for the three cytokine-receptor systems. We thus propose a common model for receptor activation by class I cytokines, involving combined scissor-like rotation and self-rotation of the two receptor molecules. Both types of rotations seem essential: the scissor-like rotation separates the intracellular domains of the two receptor molecules to make room for the associated Janus kinase molecules, while the self-rotation allows them to orient properly for transphosphorylation. This activation model explains a host of experimental observations. The transient-complex based approach presented here may provide a strategy for designing antagonists and prove useful for elucidating activation mechanisms of other receptors.

Prediction and dissection of widely-varying association rate constants of actin-binding proteins.

Actin is an abundant protein that constitutes a main component of the eukaryotic cytoskeleton. Its polymerization and depolymerization are regulated by a variety of actin-binding proteins. Their functions range from nucleation of actin polymerization to sequestering G-actin in 1∶1 complexes. The kinetics of forming these complexes, with rate constants varying at least three orders of magnitude, is critical to the distinct regulatory functions. Previously we have developed a transient-complex theory for computing protein association mechanisms and association rate constants. The transient complex refers to an intermediate in which the two associating proteins have near-native separation and relative orientation but have yet to form short-range specific interactions of the native complex. The association rate constant is predicted as k(a) = k(a0) e(-ΔG(el*)/k(B)T), where k(a0) is the basal rate constant for reaching the transient complex by free diffusion, and the Boltzmann factor captures the bias of long-range electrostatic interactions. Here we applied the transient-complex theory to study the association kinetics of seven actin-binding proteins with G-actin. These proteins exhibit three classes of association mechanisms, due to their different molecular shapes and flexibility. The 1000-fold k(a) variations among them can mostly be attributed to disparate electrostatic contributions. The basal rate constants also showed variations, resulting from the different shapes and sizes of the interfaces formed by the seven actin-binding proteins with G-actin. This study demonstrates the various ways that actin-binding proteins use physical properties to tune their association mechanisms and rate constants to suit distinct regulatory functions.

Patient-Reported Outcome Measures following Coblation Nucleoplasty for Cervical Discogenic Dizziness.

BACKGROUND: There is little research in the literature comparing the efficacy of coblation nucleoplasty with conservative treatment in the treatment of cervical discogenic dizziness and reporting the achieved rate of minimal clinically important differences (MCID) and patient acceptable symptom state (PASS) after surgery. This retrospective study aims to explore the patient-reported outcome measures (PROM) following coblation nucleoplasty for cervical discogenic dizziness and to compare the therapeutic effect of coblation nucleoplasty with prolonged conservative treatment. METHODS: Sixty-one patients with cervical discogenic dizziness and a positive intradiscal diagnostic test eligible for single-level cervical coblation nucleoplasty were included in the study. Among these 61 patients, 40 patients underwent cervical coblation nucleoplasty, while the remaining 21 patients refused surgery and received continued conservative treatment. The primary PROMs were the intensity and frequency of dizziness and secondary PROMs were related to the neck disability index (NDI) and visual analog scale (VAS) for neck pain (VAS-neck) during a 12-month follow-up period. Moreover, the achieved rate of MCID and PASS in both groups was assessed 12 months after surgery. RESULTS: Dizziness intensity, dizziness frequency, VAS-neck score, and NDI score were significantly improved from the baseline at all follow-up time points in both treatment groups, except for showing no significant improvement in dizziness frequency in the conservative treatment group at 6 and 12 months after surgery. However, at each follow-up time point, the above indexes were lower in the surgery group than in the conservative treatment group. In addition, the achieved rates for PASS and MCID in all indexes in the surgery group were significantly higher than those in the conservative treatment group at 12 months after surgery. CONCLUSIONS: Cervical coblation nucleoplasty significantly improved the intensity and frequency of dizziness, neck pain, and NDI in patients with cervical discogenic dizziness, and the results were superior to those from prolonged conservative treatment. Meanwhile, cervical coblation nucleoplasty is a good choice for patients with chronic neck pain and refractory cervical discogenic dizziness who have not demonstrated the indications for open surgery and have not responded well to conservative treatment.

Anterior Cervical Decompression and Fusion Surgery for Cervical Spondylosis with Concomitant Tinnitus: A Multicenter Prospective Cohort Study.

OBJECTIVE: Cervical spondylosis is often accompanied by tinnitus. Up to now, there is a lack of large samples and prospective studies to investigate the effect of anterior cervical decompression and fusion (ACDF) on tinnitus associate with cervical spondylosis. To this end, we performed a prospective cohort study to assess the effectiveness of ACDF on the relief of tinnitus. METHODS: This was a multicenter, prospective, cohort clinical study. Between August 2017 and August 2018, 174 patients with cervical spondylosis accompanied by tinnitus were enrolled, with a follow-up of 12 months. Among the 174 patients, 142 received anterior cervical surgery (surgery group) and 32 received conservative treatment (conservative group). The primary end point was the mean change in scores on the tinnitus functional index (TFI). The secondary end points included tinnitus loudness, modified Japanese orthopaedic association scores (mJOA) for spinal cord function, and visual analogue scale (VAS) for neck pain. All the above indexes were measured before treatments and at 1, 3, 6, and 12 months after treatments. One-way analysis of variance and paired samples t-test was adopted for statistical analysis. RESULTS: The TFI score was reduced immediately after cervical decompression surgery (from 54.7 ± 15.6 to 32.3 ± 12.5, P < 0.001) and this was sustained at 12 months (P < 0.001). The TFI score of the conservative group also decreased (from 53.9 ± 16.8 to 45.2 ± 13.6, P < 0.001), but the effect was not maintained at 12 months (P = 0.069). There was a significant improvement in tinnitus loudness (from 5.2 ± 1.6 to 2.6 ± 1.9, P < 0.001), mJOA (from 12.0 ± 1.6 to 14.2 ± 1.6, P < 0.001), and VAS for neck pain (from 58.5 ± 9.6 to 22.0 ± 16.4, P < 0.001) in the surgical group. Improvements in the surgical group were statistically significantly greater than that in the conservative group (P < 0.001). CONCLUSION: This study indicates that anterior cervical surgery can relieve tinnitus in patients with cervical spondylosis and that tinnitus is an accompanying manifestation of cervical spondylosis.

Rate constants and mechanisms of intrinsically disordered proteins binding to structured targets.

The binding of intrinsically disordered proteins (IDPs) to structured targets is gaining increasing attention. Here we review experimental and computational studies on the binding kinetics of IDPs. Experiments have yielded both the binding rate constants and the binding mechanisms, the latter via mutation and deletion studies and NMR techniques. Most computational studies have aimed at qualitative understanding of the binding rate constants or at mapping the free energy surfaces after the IDPs are engaged with their targets. The experiments and computation show that IDPs generally gain structures after they are engaged with their targets; that is, interactions with the targets facilitate the IDPs' folding. It also seems clear that the initial contact of an IDP with the target is formed by just a segment, not the entire IDP. The docking of one segment to its sub-site followed by coalescing of other segments around the corresponding sub-sites emerges as a recurring feature in the binding of IDPs. Such a dock-and-coalesce model forms the basis for quantitative calculation of binding rate constants. For both disordered and ordered proteins, strong electrostatic attraction with their targets can enhance the binding rate constants by several orders of magnitude. There are now tremendous opportunities in narrowing the gap in our understanding of IDPs relative to ordered proteins with regard to binding kinetics.

Anterior cervical decompression and fusion surgery for cervicogenic headache: A multicenter prospective cohort study.

Background: Cervicogenic headache (CEH) has long been recognized as a referred pain deriving from pathological changes in the upper cervical nerves. However, previous clinical studies found that anterior lower cervical discectomy for the treatment of cervical myelopathy and/or radiculopathy can also help relieve associated headaches. To date, there is still a lack of large sample and prospective study to investigate the effect of anterior cervical decompression and fusion (ACDF) on CEH associated with cervical spondylosis. Methods: A total of 656 patients with cervical radiculopathy and/or myelopathy were enrolled in three spinal centers. Among them, 221 patients who were diagnosed with CEH were collected in this study, and 204 completed a 1-year follow-up. The primary endpoint was headache intensity during a 12-month follow-up period measured by the numeric pain rating scale (NPRS). The secondary outcome measures included headache frequency, headache duration, and the neck disability index (NDI). Results: Among all 204 patients with CEH who completed a 1-year follow-up, 166 received anterior cervical surgery (surgery group) and 38 received conservative treatment (conservative group). There were statistically significant lower NPRS in the surgical group during follow-up. Between-group differences showed that NPRS in the surgery group was significantly greater improvement at 1 month (2.8, 95% CI: 2.0, 3.6), 3 months (2.6, 95% CI: 1.8, 3.4), 6 months (2.4, 95% CI: 1.6, 3.2), and 12 months (1.5, 95% CI: 0.7, 2.4) (p < 0.05 for all). There were statistically significant lower NDI, less frequent headaches, and lower headache duration in the surgery group during follow-up (p < 0.05 for all). Conclusion: This study indicates that ACDF can effectively relieve CEH associated with cervical myelopathy and/or radiculopathy.

Rationalizing 5000-fold differences in receptor-binding rate constants of four cytokines.

The four cytokines erythropoietin (EPO), interleukin-4 (IL4), human growth hormone (hGH), and prolactin (PRL) all form four-helix bundles and bind to type I cytokine receptors. However, their receptor-binding rate constants span a 5000-fold range. Here, we quantitatively rationalize these vast differences in rate constants by our transient-complex theory for protein-protein association. In the transient complex, the two proteins have near-native separation and relative orientation, but have yet to form the short-range specific interactions of the native complex. The theory predicts the association rate constant as k(a)=k(a0)exp(-ΔG(el)(∗)/k(B)T) where k(a0) is the basal rate constant for reaching the transient complex by random diffusion, and the Boltzmann factor captures the rate enhancement due to electrostatic attraction. We found that the vast differences in receptor-binding rate constants of the four cytokines arise mostly from the differences in charge complementarity among the four cytokine-receptor complexes. The basal rate constants (k(a0)) of EPO, IL4, hGH, and PRL were similar (5.2 × 10(5) M(-1)s(-1), 2.4 × 10(5) M(-1)s(-1), 1.7 × 10(5) M(-1)s(-1), and 1.7 × 10(5) M(-1)s(-1), respectively). However, the average electrostatic free energies (ΔG(e1)(∗)) were very different (-4.2 kcal/mol, -2.4 kcal/mol, -0.1 kcal/mol, and -0.5 kcal/mol, respectively, at ionic strength=160 mM). The receptor-binding rate constants predicted without adjusting any parameters, 6.2 × 10(8) M(-1)s(-1), 1.3 × 10(7) M(-1)s(-1), 2.0 × 10(5) M(-1)s(-1), and 7.6 × 10(4) M(-1)s(-1), respectively, for EPO, IL4, hGH, and PRL agree well with experimental results. We uncover that these diverse rate constants are anticorrelated with the circulation concentrations of the cytokines, with the resulting cytokine-receptor binding rates very close to the limits set by the half-lives of the receptors, suggesting that these binding rates are functionally relevant and perhaps evolutionarily tuned. Our calculations also reproduced well-observed effects of mutations and ionic strength on the rate constants and produced a set of mutations on the complex of hGH with its receptor that putatively enhances the rate constant by nearly 100-fold through increasing charge complementarity. To quantify charge complementarity, we propose a simple index based on the charge distribution within the binding interface, which shows good correlation with ΔG(e1)(∗). Together these results suggest that protein charges can be manipulated to tune k(a) and control biological function.

Attention Deficit Hyperactivity Disorder (ADHD) among elementary students in rural China: Prevalence, correlates, and consequences.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a widely recognized mental health problem in developed countries but remains under-investigated in developing settings. This study examines the prevalence, correlates, and consequences of ADHD symptoms among elementary school students in rural China. METHODS: Cross-sectional data were collected from 6,719 students across 120 rural primary schools in China on ADHD symptoms, demographic characteristics, and academic performance in reading and math. ADHD symptoms were evaluated using the caregiver-reported ADHD Rating Scale-IV. RESULTS: The prevalence of ADHD symptoms was 7.5% in our sample. Male students, students in lower grade levels, and students with lower cognitive ability showed a significantly higher prevalence of ADHD symptoms (ORs = 2.56, 2.06, and 1.84, respectively; p<0.05). Left-behind children showed a significantly lower prevalence of ADHD symptoms than did children who were living with their parents (OR = 0.74, p < 0.05). Adjusted regressions show that students with ADHD symptoms scored 0.12 standardized deviations lower in reading (p < 0.05) and 0.19 standardized deviations lower in math (p < 0.01). LIMITATIONS: The ADHD Rating Scale-IV is a screening scale rather than a diagnostic test. Caregiver self-report measures also may underestimate ADHD symptoms for our sample. CONCLUSIONS: ADHD is a common disorder among rural students in China and appears to be contributing to poor academic outcomes. The higher prevalence of ADHD among students with low cognitive ability also suggests that many rural children in China face multifactorial learning challenges. Taken together, the findings indicate a need for educators and policymakers in rural China to develop programs to reduce risk and support students with ADHD symptoms.

Cytochrome P450-2D6: A novel biomarker in liver cancer health disparity.

Liver cancer morbidity and mortality rates differ among ethnic groups. In the United States, the burden of liver cancer in Asian Americans (AS) is higher compared to Caucasian Americans (CA). Research on liver cancer health disparities has mainly focused on environmental and socioeconomic factors yet has ignored the genotypic differences among various racial/ethnic groups. This lack of molecular level understanding has hindered the development of personalized medical approaches for liver cancer treatment. To understand the genetic heterogeneity of liver cancer between AS and CA, we performed a systematic analysis of RNA-seq data of AS and CA patients from The Cancer Genome Atlas (TCGA). We used four differential gene expression analysis packages; DESeq2, limma, edgeR, and Superdelta2, to identify the differentially expressed genes. Our analysis identified cytochrome P450-2D6 enzyme (CYP2D6) as the gene with the greatest differential expression with higher levels in AS compared to CA. To scrutinize the underlying mechanism of CYP2D6, Ingenuity Pathway Analysis (IPA) and Cytoscape were conducted and found hepatocyte nuclear factor-4α (HNF4A) and interleukin-6 (IL6) in direct association with CYP2D6. IL6 is downregulated in AS compared to CA, while HNF4A is not significantly different. Herein, we report that CYP2D6 may serve as a putative biomarker in liver cancer health disparities. Its negative association with IL6 proclaims an intricate relationship between CYP2D6 and inflammation in the ethnic differences seen in AS and CA liver cancer patients. The goal of the present study was to understand how genetic factors may contribute to the interethnic variability of liver cancer prevalence and outcomes in AS and CA patients. Identifying ethnic-specific genes may help ameliorate detection, diagnosis, surveillance, and treatments of liver cancer, as well as reduce disease-related incidence and mortality rates in the vulnerable population.