Displaying publications 1 - 20 of 25 in total

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  1. Fulltext Revisiting Mitochondria Scored Cancer Progression and Metastasis
    Gundamaraju R, Lu W, Manikam R
    Cancers (Basel), 2021 Jan 23;13(3).
    PMID: 33498743 DOI: 10.3390/cancers13030432
    The Warburg effect has immensely succored the study of cancer biology, especially in highlighting the role of mitochondria in cancer stemness and their benefaction to the malignancy of oxidative and glycolytic cancer cells. Mitochondrial genetics have represented a focal point in cancer therapeutics due to the involvement of mitochondria in programmed cell death. The mitochondrion has been well established as a switch in cell death decisions. The mitochondrion's instrumental role in central bioenergetics, calcium homeostasis, and translational regulation has earned it its fame in metastatic dissemination in cancer cells. Here, we revisit and review mechanisms through which mitochondria influence oncogenesis and metastasis by underscoring the oncogenic mitochondrion that is capable of transferring malignant capacities to recipient cells.
  2. Fulltext CHCHD2: The Power House's Potential Prognostic Factor for Cancer?
    Gundamaraju R, Lu W, Manikam R
    Front Cell Dev Biol, 2020;8:620816.
    PMID: 33537311 DOI: 10.3389/fcell.2020.620816
  3. Fulltext A Novel Computational Method to Reduce Leaky Reaction in DNA Strand Displacement
    Li X, Wang X, Song T, Lu W, Chen Z, Shi X
    J Anal Methods Chem, 2015;2015:675827.
    PMID: 26491602 DOI: 10.1155/2015/675827
    DNA strand displacement technique is widely used in DNA programming, DNA biosensors, and gene analysis. In DNA strand displacement, leaky reactions can cause DNA signals decay and detecting DNA signals fails. The mostly used method to avoid leakage is cleaning up after upstream leaky reactions, and it remains a challenge to develop reliable DNA strand displacement technique with low leakage. In this work, we address the challenge by experimentally evaluating the basic factors, including reaction time, ratio of reactants, and ion concentration to the leakage in DNA strand displacement. Specifically, fluorescent probes and a hairpin structure reporting DNA strand are designed to detect the output of DNA strand displacement, and thus can evaluate the leakage of DNA strand displacement reactions with different reaction time, ratios of reactants, and ion concentrations. From the obtained data, mathematical models for evaluating leakage are achieved by curve derivation. As a result, it is obtained that long time incubation, high concentration of fuel strand, and inappropriate amount of ion concentration can weaken leaky reactions. This contributes to a method to set proper reaction conditions to reduce leakage in DNA strand displacement.
  4. Hybrid transfer learning strategy for cross-subject EEG emotion recognition
    Lu W, Liu H, Ma H, Tan TP, Xia L
    Front Hum Neurosci, 2023;17:1280241.
    PMID: 38034069 DOI: 10.3389/fnhum.2023.1280241
    Emotion recognition constitutes a pivotal research topic within affective computing, owing to its potential applications across various domains. Currently, emotion recognition methods based on deep learning frameworks utilizing electroencephalogram (EEG) signals have demonstrated effective application and achieved impressive performance. However, in EEG-based emotion recognition, there exists a significant performance drop in cross-subject EEG Emotion recognition due to inter-individual differences among subjects. In order to address this challenge, a hybrid transfer learning strategy is proposed, and the Domain Adaptation with a Few-shot Fine-tuning Network (DFF-Net) is designed for cross-subject EEG emotion recognition. The first step involves the design of a domain adaptive learning module specialized for EEG emotion recognition, known as the Emo-DA module. Following this, the Emo-DA module is utilized to pre-train a model on both the source and target domains. Subsequently, fine-tuning is performed on the target domain specifically for the purpose of cross-subject EEG emotion recognition testing. This comprehensive approach effectively harnesses the attributes of domain adaptation and fine-tuning, resulting in a noteworthy improvement in the accuracy of the model for the challenging task of cross-subject EEG emotion recognition. The proposed DFF-Net surpasses the state-of-the-art methods in the cross-subject EEG emotion recognition task, achieving an average recognition accuracy of 93.37% on the SEED dataset and 82.32% on the SEED-IV dataset.
  5. Selective toxicity of the mesoionic insecticide, triflumezopyrim, to rice planthoppers and beneficial arthropods
    Zhu J, Li Y, Jiang H, Liu C, Lu W, Dai W, et al.
    Ecotoxicology, 2018 May;27(4):411-419.
    PMID: 29404868 DOI: 10.1007/s10646-018-1904-x
    The novel mesoionic insecticide triflumezopyrim was highly effective in controlling both imidacloprid-susceptible and resistant planthopper populations in Malaysia. However, the toxicity of triflumezopyrim to planthopper populations and their natural enemies has been under-investigated in China. In this study, the median lethal concentrations (LC50) of triflumezopyrim were determined in eight field populations of Nilaparvata lugens and one population of Sogatella furcifera from China under laboratory conditions. Triflumezopyrim showed higher toxicity to planthopper populations than the commonly-used insecticide, imidacloprid. Furthermore, the lethal effect of triflumezopyrim on eight beneficial arthropods of planthoppers was investigated in the laboratory and compared with three commonly-used insecticides, thiamethoxam, chlorpyrifos and abamectin. Triflumezopyrim was harmless to Anagrus nilaparvatae, Cyrtorhinus lividipennis and Paederus fuscipes, while thiamethoxam, chlorpyrifos and abamectin were moderately harmful or harmful to the insect parasitoid and predators. Triflumezopyrim and thiamethoxam were harmless to the predatory spiders Pirata subpiraticus, Ummeliata insecticeps, Hylyphantes graminicola and Pardosa pseudoannulata, and slightly harmful to Theridion octomaculatum. Chlorpyrifos caused slight to high toxicity to four spider species except U. insecticeps. Abamectin was moderately to highly toxic to all five spider species. Our results indicate that triflumezopyrim has high efficacy for rice planthoppers populations and is compatibile with their natural enemies in China.
  6. Progress in phytoremediation of chromium from the environment
    Han L, Gu H, Lu W, Li H, Peng WX, Ling Ma N, et al.
    Chemosphere, 2023 Dec;344:140307.
    PMID: 37769918 DOI: 10.1016/j.chemosphere.2023.140307
    As chromium (Cr) in ecosystems affects human health through food chain exposure, phytoremediation is an environmentally friendly and efficient way to reduce chromium pollution in the environment. Here, we review the mechanism of absorption, translocation, storage, detoxification, and regulation of Cr in plants. The Cr(VI) form is more soluble, mobile, and toxic than Cr(III), reflecting how various valence states of Cr affect environmental risk characteristics, physicochemical properties, toxicity, and plant uptake. Plant root's response to Cr exposure leads to reactive oxygen species (ROS) generation and apoptosis. Cell wall immobilization, vacuole compartmentation, interaction of defense proteins and organic ligand with Cr, and removal of reactive oxygen species by antioxidants continue plant life. In addition, the combined application of microorganisms, genetic engineering, and the addition of organic acids, nanoparticles, fertilization, soil amendments, and other metals could accelerate the phytoremediation process. This review provides efficient methods to investigate and understand the complex changes of Cr metabolism in plants. Preferably, fast-growing, abundantly available biomass species should be modified to mitigate Cr pollution in the environment as these green and efficient remediation technologies are necessary for the protection of soil and water ecology.
  7. Can metagenomics unravel the impact of oral bacteriome in human diseases?
    Chattopadhyay I, Lu W, Manikam R, Malarvili MB, Ambati RR, Gundamaraju R
    Biotechnol Genet Eng Rev, 2023 Apr;39(1):85-117.
    PMID: 35861776 DOI: 10.1080/02648725.2022.2102877
    Oral microbial ecosystems are vital in maintaining the health of the oral cavity and the entire body. Oral microbiota is associated with the progression of oral diseases such as dental caries, periodontal diseases, head and neck cancer, and several systemic diseases such as cardiovascular disease, rheumatoid arthritis, adverse pregnancy outcomes, diabetes, lung infection, colorectal cancer, and pancreatic cancer. Buccal mucosa, tongue dorsum, hard palate, saliva, palatine tonsils, throat, keratinized gingiva, supra-gingival plaque, subgingival plaque, dentures, and lips are microbial habitats of the oral cavity. Porphyromonas gingivalis may have a role in the development of periodontal diseases, oral cancer, diabetes, and atherosclerotic disease. Fusobacterium nucleatum showed a higher abundance in periodontal diseases, oral and colon cancer, adverse pregnancy outcomes, diabetes, and rheumatoid arthritis. The higher abundance of Prevotella intermedia is typical in periodontal diseases, rheumatoid arthritis, and adverse pregnancy outcome. S. salivarius displayed higher abundance in both dental caries and OSCC. Oral bacteria may influence systemic diseases through inflammation by releasing pro inflammatory cytokines. Identification of oral bacteria using culture-dependent approaches and next-generation sequencing-based metagenomic approaches is believed to significantly identify the therapeutic targets and non-invasive diagnostic indicators in different human diseases. Oral bacteria in saliva could be exploited as a non-invasive diagnostic indicator for the early detection of oral and systemic disorders. Other therapeutic approaches such as the use of probiotics, green tea polyphenol, cold atmospheric plasma (CAP) therapy, antimicrobial photodynamic therapy, and antimicrobial peptides are used to inhibit the growth of biofilm formation by oral bacteria.
  8. Ascendancy of unfolded protein response over glioblastoma: estimating progression, prognosis and survival
    Gundamaraju R, Wu J, William JNG, Lu W, Jha NK, Ramasamy S, et al.
    Biotechnol Genet Eng Rev, 2023 Apr;39(1):143-165.
    PMID: 35904341 DOI: 10.1080/02648725.2022.2106002
    Glioblastoma (GBM) is presented with a poor prognosis. The endoplasmic reticulum stress (ERS) has been implicated as a major contributor to disease progression and chemoresistance in GBM. Triggering ERS by chemical agents or genetic modulations is identified as some of the reasons for regulating gene expression and the pathogenesis of GBM. ERS initiates unfolded protein response (UPR), an integrated system useful in restoring homeostasis or inducing apoptosis. Modulation of UPR might have positive outcomes in GBM treatment as UPR inducers have been shown to alter cell survival and migration. In the current review, we have utilized GSE7806, a publicly available dataset from Gene Expression Omnibus (GEO), to evaluate the genes expressed during 6.5 hr and 18 hr, which can be comparable to the early and late-onset of the disease. Subsequently, we have elucidated the prognosis and survival information whilst the expression of these genes in the GBM was noted in previous studies. This is the first of its kind review summarizing the most recent gene information correlating UPR and GBM.
  9. Recent progress on phytoremediation of urban air pollution
    Duan X, Gu H, Lam SS, Sonne C, Lu W, Li H, et al.
    Chemosphere, 2024 Feb;349:140821.
    PMID: 38042424 DOI: 10.1016/j.chemosphere.2023.140821
    The rapid growth of population and economy has led to an increase in urban air pollutants, greenhouse gases, energy shortages, environmental degradation, and species extinction, all of which affect ecosystems, biodiversity, and human health. Atmospheric pollution sources are divided into direct and indirect pollutants. Through analysis of the sources of pollutants, the self-functioning of different plants can be utilized to purify the air quality more effectively. Here, we explore the absorption of greenhouse gases and particulate matter in cities as well as the reduction of urban temperatures by plants based on international scientific literature on plant air pollution mitigation, according to the adsorption, dust retention, and transpiration functions of plants. At the same time, it can also reduce the occurrence of extreme weather. It is necessary to select suitable tree species for planting according to different plant functions and environmental needs. In the context of tight urban land use, the combination of vertical greening and urban architecture, through the rational use of plants, has comprehensively addressed urban air pollution. In the future, in urban construction, attention should be paid to the use of heavy plants and the protection and development of green spaces. Our review provides necessary references for future urban planning and research.
  10. Burden of depression in adolescents in the Western Pacific Region from 1990 to 2019: An age-period-cohort analysis of the Global Burden of Disease study
    Li ZB, Lv JJ, Lu W, Yin MY, Li XY, Yang CH
    Psychiatry Res, 2024 Jun;336:115889.
    PMID: 38621309 DOI: 10.1016/j.psychres.2024.115889
    BACKGROUND: Depression is a highly prevalent and disabling mental health condition among adolescents. The epidemiology of depression in adolescents has been changing over time, reflecting changes in risk factors as well as disease concepts and diagnosis. However, few studies have characterized the longitudinal epidemiology of depression in adolescents. Understanding trends of disease burden provides key insights to improve resource allocation and design targeted interventions for this vulnerable population. The Western Pacific Region (WPR) is home to over 1.3 billion people with tremendous diversity in culture and socioeconomic development. The epidemiology of adolescent depression in WPR remains largely unknown. In this study, we aimed to estimate trends of disease burden attributable to depressive disorders among adolescents aged 10-24 years in WPR countries between 1990 and 2019, and to investigate period and cohort effects using the Global Burden of Disease (GBD) study database.

    METHODS: The study utilized data from the Global Burden of Disease, Injuries, and Risk Factors Study 2019, concentrating on adolescents aged 10 to 24 years with depression. We conducted an in-depth analysis of depression, including its age-standardized prevalence, incidence, and Disability-Adjusted Life Years (DALYs), across diverse demographics such as regions, ages, genders, and socio-demographic indexes, spanning from 1990 to 2019.

    RESULTS: The analysis found decreasing trends in the prevalence, incidence, and DALYs of adolescent depression in the WPR between 1990-2019, although some countries like Australia and Malaysia showed increases. Specifically, the prevalence of adolescent depression in the region decreased from 9,347,861.6 cases in 1990 to 5,551,341.1 cases in 2019. The incidence rate declined from 2,508.6 per 100,000 adolescents in 1990 to 1,947.9 per 100,000 in 2019. DALYs decreased from 371.9 per 100,000 in 1990 to ASR 299.7 per 100,000 in 2019.

    CONCLUSION: This study found an overall decreasing trend in adolescent depression burden in the Western Pacific Region between 1990 and 2019, with heterogeneity across countries. For 30 years, the 20-24 age group accounted for the majority of depression among adolescents Widening inequality in depression burden requires policy attention. Further analysis of risk factors contributing to epidemiological trends is warranted to inform prevention strategies targeting adolescent mental health in the region.

  11. Exohedral Cuprofullerene: Sequentially Expanding Metal Olefin Up to a C60@Cu24 Rhombicuboctahedron
    Zhan SZ, Zhang GH, Li JH, Liu JL, Zhu SH, Lu W, et al.
    J Am Chem Soc, 2020 Apr 01;142(13):5943-5947.
    PMID: 32187495 DOI: 10.1021/jacs.0c00090
    Exohedral cuprofullerenes with 6-, 12-, or 24-nuclearity were obtained by utilizing fluorocarboxylic/dicarboxylic acid under solvothermal conditions. The 24-nuclear molecule presents a C60@Cu24 core-shell structure with a rhombicuboctahedron Cu24 coated on the C60 core, representing the highest nuclearity in metallofullerene. The resultant complexes show an efficient absorption of visible light as opposed to the pristine C60. TD-DFT calculations revealed the charge transfer from Cu(I) and O atoms to the fullerene moiety dominates the photophysical process.
  12. Designing Calcium Silicate Cements with On-Demand Properties for Precision Endodontics
    Cahyanto A, Rath P, Teo TX, Tong SS, Malhotra R, Cavalcanti BN, et al.
    J Dent Res, 2023 Dec;102(13):1425-1433.
    PMID: 37861249 DOI: 10.1177/00220345231198185
    Calcium silicate (C3S) cements are available in kits that do not account for patients' specific needs or clinicians' preferences regarding setting time, radiopacity, mechanical, and handling properties. Moreover, slight variations in powder components and liquid content affect cement's properties and bioactivity. Unfortunately, it is virtually impossible to optimize several cement properties simultaneously via the traditional "one variable at a time" strategy, as inputs often induce trade-offs in properties (e.g., a higher water-to-powder ratio [W/P] increases flowability but decreases mechanical properties). Herein, we used Taguchi's methods and genetic algorithms (GAs) to simultaneously analyze the effect of multiple inputs (e.g., powder composition, radiopacifier concentration, and W/P) on setting time, pH, flowability, diametral tensile strength, and radiopacity, as well as prescribe recipes to produce cements with predicted properties. The properties of cements designed with GAs were experimentally tested, and the results matched the predictions. Finally, we show that the cements increased the genetic expression of odonto/osteogenic genes, alkaline phosphatase activity, and mineralization potential of dental pulp stem cells. Hence, GAs can produce cements with tailor-made properties and differentiation potential for personalized endodontic treatment.
  13. Helicobacter pylori overcomes natural immunity in repeated infections
    Stenström B, Windsor HM, Fulurija A, Benghezal M, Kumarasinghe MP, Kimura K, et al.
    Clin Case Rep, 2016 11;4(11):1026-1033.
    PMID: 27830066
    Repeated experimental reinfection of two subjects indicates that Helicobacter pylori infection does not promote an immune response protective against future reinfection. Our results highlight the importance of preventing reinfection after eradication, through public health initiatives, and possibly treatment of family members. They indicate difficulties for vaccine development, especially therapeutic vaccines.
  14. Fulltext Peritoneal dialysis first policy in Hong Kong for 35 years: Global impact
    Li PK, Lu W, Mak SK, Boudville N, Yu X, Wu MJ, et al.
    Nephrology (Carlton), 2022 Oct;27(10):787-794.
    PMID: 35393750 DOI: 10.1111/nep.14042
    Peritoneal dialysis (PD) first policy has been established in Hong Kong since 1985. After 35 years of practice, the PD first policy in Hong Kong has influenced many countries around the world including governments, health ministries, nephrologists and renal nurses on the overall health policy structure and clinical practice in treating kidney failure patients using PD as an important dialysis modality. In 2021, the International Association of Chinese Nephrologists and the Hong Kong Society of Nephrology jointly held a symposium celebrating the 35 years of PD first policy in Hong Kong. In that symposium, experts and opinion leaders from around the world have shared their perspectives on how the PD first policy has grown and how it has affected PD and home dialysis practice globally. The advantages of PD during COVID-19 pandemic were highlighted and the use of telemedicine as an important adjunct was discussed in treating kidney failure patients to improve the overall quality of care. Barriers to PD and the need for sustainability of PD first policy were also emphasized. Overall, the knowledge awareness of PD as a home dialysis for patients, families, care providers and learners is a prerequisite for the success of PD first. A critical mass of PD regional hubs is needed for training and mentorship. Importantly, the alignment of policy and clinical goals are enablers of PD first program.
  15. Icosidodecahedral Coordination-Saturated Cuprofullerene
    Zhan SZ, Liu YL, Cai H, Li MD, Huang Q, Wang XD, et al.
    Angew Chem Int Ed Engl, 2023 Oct 23;62(43):e202312698.
    PMID: 37682089 DOI: 10.1002/anie.202312698
    The first coordination-saturated buckyball with a C60 molecule totally encased in an icosidodecahedral Cu30 in a (μ30 -(η2 )30 )-fashion, namely C60 @Cu30 @Cl36 N12 , has been successfully realized by a C60 -templated assembly. The 48 outmost coordinating atoms (36Cl+12N) comprise a new simple polyhedron that is described by a ccf topology. Charge transfer from (CuI , Cl) to C60 explains the expansion of the light absorption up to 700 nm, and accounts for an ultrafast photophysical process that underpins its high photothermal conversion efficiency. This work makes a giant step forward in exohedral metallofullerene (ExMF) chemistry.
  16. Symmetry-Driven Assembly of a Penta-Shell Keplerate Cuprofullerene for Metallofullerene Frameworks
    Liu YL, Zhan SZ, Sun JX, Cai H, Yuan ZL, Zhang HF, et al.
    Angew Chem Int Ed Engl, 2023 Aug 14;62(33):e202306748.
    PMID: 37366116 DOI: 10.1002/anie.202306748
    Two metallofullerene frameworks (MFFs) constructed from a penta-shell Keplerate cuprofullerene chloride, C60 @Cu24 @Cl44 @Cu12 @Cl12 , have been successfully prepared via a C60 -templated symmetry-driven strategy. The icosahedral cuprofullerene chloride is assembled on a C60 molecule through [η2 -(C=C)]-CuI and CuI -Cl coordination bonds, resulting in the penta-shell Keplerate with the C60 core canopied by 24 Cu, 44 Cl, 12 Cu and 12 Cl atoms that fulfill the tic@rco@oae@ico@ico penta-shell polyhedral configuration. By sharing the outmost-shell Cl atoms, the cuprofullerene chlorides are connected into 2D or 3D (snf net) frameworks. TD-DFT calculations reveal that the charge transfer from the outmost CuI and Cl to C60 core is responsible for their light absorption expansion to near-infrared region, implying anionic halogenation may be an effective strategy to tune the light absorption properties of metallofullerene materials.
  17. 2018 Kidney Disease: Improving Global Outcomes (KDIGO) Hepatitis C in Chronic Kidney Disease Guideline Implementation: Asia Summit Conference Report
    Li PK, Bavanandan S, Mohamed R, Szeto CC, Wong VW, Chow KM, et al.
    Kidney Int Rep, 2020 Aug;5(8):1129-1138.
    PMID: 32775812 DOI: 10.1016/j.ekir.2020.05.001
    In 2018, Kidney Disease: Improving Global Outcomes (KDIGO) published a clinical practice guideline on the prevention, diagnosis, evaluation, and treatment of hepatitis C virus (HCV) infection in chronic kidney disease (CKD). The guideline synthesized recent advances, especially in HCV therapeutics and diagnostics, and provided clinical recommendations and suggestions to aid healthcare providers and improve care for CKD patients with HCV. To gain insight into the extent that the 2018 guideline has been adopted in Asia, KDIGO convened an HCV Implementation Summit in Hong Kong. Participants included nephrologists, hepatologists, and nurse consultants from 8 Southeast Asian countries or regions with comparable high-to-middle economic ranking by the World Bank: mainland China, Hong Kong, Japan, Malaysia, Singapore, South Korea, Taiwan, and Thailand. Through presentations and discussions, meeting participants described regional practice patterns related to the KDIGO HCV in CKD guideline, identified barriers to implementing the guideline, and developed strategies for overcoming the barriers in Asia and around the world.
  18. Fulltext Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1
    Cai Q, Zhang B, Sung H, Low SK, Kweon SS, Lu W, et al.
    Nat Genet, 2014 Aug;46(8):886-90.
    PMID: 25038754 DOI: 10.1038/ng.3041
    In a three-stage genome-wide association study among East Asian women including 22,780 cases and 24,181 controls, we identified 3 genetic loci newly associated with breast cancer risk, including rs4951011 at 1q32.1 (in intron 2 of the ZC3H11A gene; P=8.82×10(-9)), rs10474352 at 5q14.3 (near the ARRDC3 gene; P=1.67×10(-9)) and rs2290203 at 15q26.1 (in intron 14 of the PRC1 gene; P=4.25×10(-8)). We replicated these associations in 16,003 cases and 41,335 controls of European ancestry (P=0.030, 0.004 and 0.010, respectively). Data from the ENCODE Project suggest that variants rs4951011 and rs10474352 might be located in an enhancer region and transcription factor binding sites, respectively. This study provides additional insights into the genetics and biology of breast cancer.
  19. Fulltext Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus
    Horne HN, Chung CC, Zhang H, Yu K, Prokunina-Olsson L, Michailidou K, et al.
    PLoS One, 2016;11(8):e0160316.
    PMID: 27556229 DOI: 10.1371/journal.pone.0160316
    The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000-120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08-1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive.
  20. Fulltext Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium
    Milne RL, Burwinkel B, Michailidou K, Arias-Perez JI, Zamora MP, Menéndez-Rodríguez P, et al.
    Hum Mol Genet, 2014 Nov 15;23(22):6096-111.
    PMID: 24943594 DOI: 10.1093/hmg/ddu311
    Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 × 10(-6)], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 × 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 × 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 × 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 × 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.
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