Displaying publications 1 - 20 of 210 in total

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  1. Darst BF, Shen J, Madduri RK, Rodriguez AA, Xiao Y, Sheng X, et al.
    medRxiv, 2023 May 15.
    PMID: 37292833 DOI: 10.1101/2023.05.12.23289860
    Genome-wide polygenic risk scores (GW-PRS) have been reported to have better predictive ability than PRS based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer risk variants from multi-ancestry GWAS and fine-mapping studies (PRS 269 ). GW-PRS models were trained using a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls used to develop the multi-ancestry PRS 269 . Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California/Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI=0.635-0.677) in African and 0.844 (95% CI=0.840-0.848) in European ancestry men and corresponding prostate cancer OR of 1.83 (95% CI=1.67-2.00) and 2.19 (95% CI=2.14-2.25), respectively, for each SD unit increase in the GW-PRS. However, compared to the GW-PRS, in African and European ancestry men, the PRS 269 had larger or similar AUCs (AUC=0.679, 95% CI=0.659-0.700 and AUC=0.845, 95% CI=0.841-0.849, respectively) and comparable prostate cancer OR (OR=2.05, 95% CI=1.87-2.26 and OR=2.21, 95% CI=2.16-2.26, respectively). Findings were similar in the validation data. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the multi-ancestry PRS 269 constructed with fine-mapping.
  2. Tjader NP, Beer AJ, Ramroop J, Tai MC, Ping J, Gandhi T, et al.
    medRxiv, 2023 Dec 06.
    PMID: 38106140 DOI: 10.1101/2023.12.06.23299442
    BACKGROUND: In breast tumors, somatic mutation frequencies in TP53 and PIK3CA vary by tumor subtype and ancestry. HER2 positive and triple negative breast cancers (TNBC) have a higher frequency of TP53 somatic mutations than other subtypes. PIK3CA mutations are more frequently observed in hormone receptor positive tumors. Emerging data suggest tumor mutation status is associated with germline variants and genetic ancestry. We aimed to identify germline variants that are associated with somatic TP53 or PIK3CA mutation status in breast tumors.

    METHODS: A genome-wide association study was conducted using breast cancer mutation status of TP53 and PIK3CA and functional mutation categories including TP53 gain of function (GOF) and loss of function mutations and PIK3CA activating/hotspot mutations. The discovery analysis consisted of 2850 European ancestry women from three datasets. Germline variants showing evidence of association with somatic mutations were selected for validation analyses based on predicted function, allele frequency, and proximity to known cancer genes or risk loci. Candidate variants were assessed for association with mutation status in a multi-ancestry validation study, a Malaysian study, and a study of African American/Black women with TNBC.

    RESULTS: The discovery Germline x Mutation (GxM) association study found five variants associated with one or more TP53 phenotypes with P values <1×10-6, 33 variants associated with one or more TP53 phenotypes with P values <1×10-5, and 44 variants associated with one or more PIK3CA phenotypes with P values <1×10-5. In the multi-ancestry and Malaysian validation studies, germline ESR1 locus variant, rs9383938, was associated with the presence of TP53 mutations overall (P values 6.8×10-5 and 9.8×10-8, respectively) and TP53 GOF mutations (P value 8.4×10-6). Multiple variants showed suggestive evidence of association with PIK3CA mutation status in the validation studies, but none were significant after correction for multiple comparisons.

    CONCLUSIONS: We found evidence that germline variants were associated with TP53 and PIK3CA mutation status in breast cancers. Variants near the estrogen receptor alpha gene, ESR1, were significantly associated with overall TP53 mutations and GOF mutations. Larger multi-ancestry studies are needed to confirm these findings and determine if these variants contribute to ancestry-specific differences in mutation frequency.

  3. Balakrishnan N, Teo SH, Sinnadurai S, Bhoo Pathy NT, See MH, Taib NA, et al.
    World J Surg, 2017 11;41(11):2735-2745.
    PMID: 28653143 DOI: 10.1007/s00268-017-4081-9
    BACKGROUND: Reproductive factors are associated with risk of breast cancer, but the association with breast cancer survival is less well known. Previous studies have reported conflicting results on the association between time since last childbirth and breast cancer survival. We determined the association between time since last childbirth (LCB) and survival of women with premenopausal and postmenopausal breast cancers in Malaysia.

    METHOD: A historical cohort of 986 premenopausal, and 1123 postmenopausal, parous breast cancer patients diagnosed from 2001 to 2012 in University Malaya Medical Centre were included in the analyses. Time since LCB was categorized into quintiles. Multivariable Cox regression was used to determine whether time since LCB was associated with survival following breast cancer, adjusting for demographic, tumor, and treatment characteristics.

    RESULTS: Premenopausal breast cancer patients with the most recent childbirth (LCB quintile 1) were younger, more likely to present with unfavorable prognostic profiles and had the lowest 5-year overall survival (OS) (66.9; 95% CI 60.2-73.6%), compared to women with longer duration since LCB (quintile 2 thru 5). In univariable analysis, time since LCB was inversely associated with risk of mortality and the hazard ratio for LCB quintile 2, 3, 4, and 5 versus quintile 1 were 0.53 (95% CI 0.36-0.77), 0.49 (95% CI 0.33-0.75), 0.61 (95% CI 0.43-0.85), and 0.64 (95% CI 0.44-0.93), respectively; P trend = 0.016. However, this association was attenuated substantially following adjustment for age at diagnosis and other prognostic factors. Similarly, postmenopausal breast cancer patients with the most recent childbirth were also more likely to present with unfavorable disease profiles. Compared to postmenopausal breast cancer patients in LCB quintile 1, patients in quintile 5 had a higher risk of mortality. This association was not significant following multivariable adjustment.

    CONCLUSION: Time since LCB is not independently associated with survival in premenopausal or postmenopausal breast cancers. The apparent increase in risks of mortality in premenopausal breast cancer patients with a recent childbirth, and postmenopausal patients with longer duration since LCB, appear to be largely explained by their age at diagnosis.

  4. Yip CH, Taib NA, Choo WY, Rampal S, Thong MK, Teo SH
    World J Surg, 2009 Oct;33(10):2077-81.
    PMID: 19649760 DOI: 10.1007/s00268-009-0146-8
    Mutations in BRCA1 and BRCA2 confer an increased risk to breast and other cancers, but to date there have only been limited numbers of studies of BRCA1- and BRCA2-associated cancers among Asians. Malaysia is a multiracial country with three main races: Malays, Chinese, Indians. We determined whether tumor pathologic features and clinical features differ in patients with and without BRCA mutations in this Asian population.
  5. Rashid SA, Norman N, Teo SH, Tong WY, Leong CR, Tan WN, et al.
    World J Microbiol Biotechnol, 2021 Aug 16;37(9):152.
    PMID: 34398332 DOI: 10.1007/s11274-021-03118-y
    β-lactam antibiotics are the most frequently prescribed class of drugs worldwide, due to its efficacy and good safety profile. However, the emergence of β-lactamase producing bacterial strains eliminated the use of β-lactam antibiotics as a chemotherapeutic choice. To restore their usability, a non-antibiotic adjuvant in conjunction with β-lactam antibiotics is now being utilised. Cholic acid potentially acts as an adjuvant since it can blunt the pro-inflammatory activity in human. Our main objective is to scrutinise the inhibition of β-lactamase-producing bacteria by adjuvant cholic acid, synergism of the test drugs and the primary mechanism of enzymatic reaction. Antibacterial effect of the cholic acid-ampicillin (CA-AMP) on 7 β-lactamase positive isolates were evaluated accordingly to disc diffusion assay, antibiotic susceptibility test, as well as checkerboard analysis. Then, all activities were compared with ampicillin alone, penicillin alone, cholic acid alone and cholic acid-penicillin combination. The CA-AMP displayed notable antibiotic activity on all test bacteria and depicted synergistic influence by representing low fractional inhibitory concentration index (FIC ≤ 0.5). According to kinetic analyses, CA-AMP behaved as an uncompetitive inhibitor against beta lactamase, with reducing values of Michaelis constant (Km) and maximal velocity (Vmax) recorded. The inhibitor constant (Ki) of CA-AMP was equal to 4.98 ± 0.3 µM, which slightly lower than ampicillin (5.00 ± 0.1 µM).
  6. Goh TX, Tan SL, Roebuck MM, Teo SH, Kamarul T
    Tissue Eng Part C Methods, 2022 10;28(10):511-528.
    PMID: 35959742 DOI: 10.1089/ten.TEC.2022.0092
    The state of host cells is reflected in the cargo carried by their extracellular vesicles (EVs). This makes EV a potential source of biomarkers for human diseases. Piwi-interacting RNA (piRNA) regulates gene expression through epigenetic regulation and post-transcriptional gene silencing. Thus, piRNA profiling in EVs derived from human clinical samples could identify markers that characterize disease stages and unveil their roles in disease pathology. This review aimed to report the expression profiles of EV-derived piRNA (EV-piRNA) in various human samples, as well as their role in each pathology. A systematic review was conducted to collate the findings of human EV-piRNA from original research articles published in indexed scientific journals up to February 16, 2022. Article searches were performed in PubMed, Web of Science, and Scopus databases, using a combination of keywords, including "EV" and "piRNA." A total of 775 nonredundant original articles were identified. After subjecting articles to inclusion and exclusion criteria, 34 articles were accepted for this review. The piRNA expression levels among the small RNA profiles of human-derived EVs range from 0.09% to 43.84%, with the lowest expression level reported in urine-derived EVs and the highest percentage in plasma-derived EVs. Differentially expressed EV-piRNAs have been identified in patients with specific disease conditions compared to their counterparts (healthy control), suggesting an association between piRNA and progression in various diseases. Seven articles identified piRNA putative target genes and/or the pathway enrichment of piRNA target genes, and one study demonstrated a direct role of piRNA candidates in disease pathology. In conclusion, EV-piRNA has been isolated successfully from various human body fluids. EV-piRNA is a new research niche in human disease pathology. The expression profiles of EV-piRNA in various tissue types and disease conditions remain largely unexplored. Furthermore, there is currently a lack of guidelines on piRNA bioinformatics analysis, which could lead to inconsistent results and thus hinder the progression of piRNA discoveries. Finally, the lack of published scientific evidence on the role of EV-piRNA supports the need for future research to focus on the functional analysis of EV-piRNA as part of the route in piRNA discoveries.
  7. Jamal J, Roebuck MM, Lee SY, Frostick SP, Abbas AA, Merican AM, et al.
    Int J Biochem Cell Biol, 2020 09;126:105800.
    PMID: 32673644 DOI: 10.1016/j.biocel.2020.105800
    OBJECTIVES: To compare mechanobiological response of synovial fibroblasts (SFb) from OA patient cohorts under mechanical load and inflammatory stressors for better understanding of SFb homeostatic functions.

    METHODS: Primary SFb isolated from knee synovium of OA obese (OA-ob:SFb), OA-pre-obese (OA-Pob:SFb), non-OA arthroscopic (scope:SFb), and non-OA arthroscopic with cartilage damage (scope-CD:SFb) were exposed to OA-conditioned media (OACM), derived from OA obese (OA-ob:CM), OA-pre-obese (OA-Pob:CM), and mechanical stretch at either 0 %, 6 % or 10 % for 24 h. Differences in the mRNA levels of genes involved in extracellular matrix production, inflammation and secretory activity were measured.

    RESULTS: Despite the significant BMI differences between the OA-ob and OA-Pob groups, OA-Pob has more patients with underlying dyslipidaemia, and low-grade synovitis with higher levels of secreted proteins, CXCL8, COL4A1, CCL4, SPARC and FGF2 in OA-Pob:CM. All primary SFb exhibited anti-proliferative activity with both OA-CM. Mechanical stretch stimulated lubricin production in scope:SFb, higher TGFβ1 and COL1A1 expressions in scope-CD:SFb. OA-Pob:CM stimulated greater detrimental effects than the OA-ob:CM, with higher pro-inflammatory cytokines, IL1β, IL6, COX2 and proteases such as aggrecanases, ADAMTS4 and ADAMTS5, and lower ECM matrix, COL1A1 expressions in all SFb. OA-ob:SFb were unresponsive but expressed higher pro-inflammatory cytokines under OA-Pob:CM treatment.

    CONCLUSION: Both mechanical and inflammatory stressors regulate SFb molecular functions with heterogeneity in responses that are dependent on their pathological tissue of origins. While mechanical stretch promotes a favorable effect with enhanced lubricin production in scope:SFb and TGFβ1 and COL1A1 in scope-CD:SFb, the presence of excessively high OA-associated inflammatory mediators in OA-Pob:CM, predominantly SPARC, CXCL8 and FGF2 drive all SFb regardless of pathology, towards greater pro-inflammatory activities.

  8. Breast Cancer Association Consortium, Dorling L, Carvalho S, Allen J, González-Neira A, Luccarini C, et al.
    N Engl J Med, 2021 02 04;384(5):428-439.
    PMID: 33471991 DOI: 10.1056/NEJMoa1913948
    BACKGROUND: Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking.

    METHODS: We used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity.

    RESULTS: Protein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants.

    CONCLUSIONS: The results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.).

  9. Yip CH, Bhoo Pathy N, Teo SH
    Med J Malaysia, 2014 Aug;69 Suppl A:8-22.
    PMID: 25417947 MyJurnal
    Four hundred and nineteen articles related to breast cancer were found in a search through a database dedicated to indexing all original data relevant to medicine published in Malaysia between the years 2000-2013. One hundred and fifty four articles were selected and reviewed on the basis of clinical relevance and future research implications. Overall, Malaysian women have poor survival from breast cancer and it is estimated that half of the deaths due to breast cancer could be prevented. Five-year survival in Malaysia was low and varies among different institutions even within the same disease stage, suggesting an inequity of access to optimal treatment or a lack of compliance to optimal treatment. Malaysian women have poor knowledge of the risk factors, symptoms and methods for early detection of breast cancer, leading to late presentation. Moreover, Malaysian women experience cancer fatalism, belief in alternative medicine, and lack of autonomy in decision making resulting in delays in seeking or avoidance of evidence-based medicine. There are ethnic differences in estrogen receptor status, HER2 overexpression and incidence of triple negative breast cancer which warrant further investigation. Malay women present with larger tumours and at later stages, and even after adjustment for these and other prognostic factors (stage, pathology and treatment), Malay women have a poorer survival. Although the factors responsible for these ethnic differences have not been elucidated, it is thought that pharmacogenomics, lifestyle factors (such as weight-gain, diet and exercise), and psychosocial factors (such as acceptance of 2nd or 3rd line chemotherapy) may be responsible for the difference in survival. Notably, survivorship studies show self-management programmes and exercise improve quality of life, highlighting the need to evaluate the psychosocial impact of breast cancer on Malaysian women, and to design culturally-, religiously- and linguistically-appropriate psycho-education programmes to help women cope with the disease and improve their quality of life. Research done in the Caucasian populations may not necessarily apply to local settings and it is important to embark on local studies particularly prevention, screening, diagnostic, prognostic, therapeutic and psychosocial research.
  10. Ho WK, Hassan NT, Yoon SY, Yang X, Lim JMC, Binte Ishak ND, et al.
    Lancet Reg Health West Pac, 2024 Mar;44:101017.
    PMID: 38333895 DOI: 10.1016/j.lanwpc.2024.101017
    BACKGROUND: Clinical management of Asian BRCA1 and BRCA2 pathogenic variants (PV) carriers remains challenging due to imprecise age-specific breast (BC) and ovarian cancer (OC) risks estimates. We aimed to refine these estimates using six multi-ethnic studies in Asia.

    METHODS: Data were collected on 271 BRCA1 and 301 BRCA2 families from Malaysia and Singapore, ascertained through population/hospital-based case-series (88%) and genetic clinics (12%). Age-specific cancer risks were estimated using a modified segregation analysis method, adjusted for ascertainment.

    FINDINGS: BC and OC relative risks (RRs) varied across age groups for both BRCA1 and BRCA2. The age-specific RR estimates were similar across ethnicities and country of residence. For BRCA1 carriers of Malay, Indian and Chinese ancestry born between 1950 and 1959 in Malaysia, the cumulative risk (95% CI) of BC by age 80 was 40% (36%-44%), 49% (44%-53%) and 55% (51%-60%), respectively. The corresponding estimates for BRCA2 were 29% (26-32%), 36% (33%-40%) and 42% (38%-45%). The corresponding cumulative BC risks for Singapore residents from the same birth cohort, where the underlying population cancer incidences are higher compared to Malaysia, were higher, varying by ancestry group between 57 and 61% for BRCA1, and between 43 and 47% for BRCA2 carriers. The cumulative risk of OC by age 80 was 31% (27-36%) for BRCA1 and 12% (10%-15%) for BRCA2 carriers in Malaysia born between 1950 and 1959; and 42% (34-50%) for BRCA1 and 20% (14-27%) for BRCA2 carriers of the same birth cohort in Singapore. There was evidence of increased BC and OC risks for women from >1960 birth cohorts (p-value = 3.6 × 10-5 for BRCA1 and 0.018 for BRCA2).

    INTERPRETATION: The absolute age-specific cancer risks of Asian carriers vary depending on the underlying population-specific cancer incidences, and hence should be customised to allow for more accurate cancer risk management.

    FUNDING: Wellcome Trust [grant no: v203477/Z/16/Z]; CRUK (PPRPGM-Nov20∖100002).

  11. Iranpour F, Merican AM, Teo SH, Cobb JP, Amis AA
    Knee, 2017 Jun;24(3):555-563.
    PMID: 28330756 DOI: 10.1016/j.knee.2017.01.011
    BACKGROUND: Patellofemoral instability is a major cause of anterior knee pain. The aim of this study was to examine how the medial and lateral stability of the patellofemoral joint in the normal knee changes with knee flexion and measure its relationship to differences in femoral trochlear geometry.

    METHODS: Twelve fresh-frozen cadaveric knees were used. Five components of the quadriceps and the iliotibial band were loaded physiologically with 175N and 30N, respectively. The force required to displace the patella 10mm laterally and medially at 0°, 20°, 30°, 60° and 90° knee flexion was measured. Patellofemoral contact points at these knee flexion angles were marked. The trochlea cartilage geometry at these flexion angles was visualized by Computed Tomography imaging of the femora in air with no overlying tissue. The sulcus, medial and lateral facet angles were measured. The facet angles were measured relative to the posterior condylar datum.

    RESULTS: The lateral facet slope decreased progressively with flexion from 23°±3° (mean±S.D.) at 0° to 17±5° at 90°. While the medial facet angle increased progressively from 8°±8° to 36°±9° between 0° and 90°. Patellar lateral stability varied from 96±22N at 0°, to 77±23N at 20°, then to 101±27N at 90° knee flexion. Medial stability varied from 74±20N at 0° to 170±21N at 90°. There were significant correlations between the sulcus angle and the medial facet angle with medial stability (r=0.78, p<0.0001).

    CONCLUSIONS: These results provide objective evidence relating the changes of femoral profile geometry with knee flexion to patellofemoral stability.

  12. Koh SM, Chan CK, Teo SH, Singh S, Merican A, Ng WM, et al.
    Knee, 2020 Jan;27(1):26-35.
    PMID: 31917106 DOI: 10.1016/j.knee.2019.10.028
    PURPOSE: Osteoarthritis (OA) of the knee is a multifactorial degenerative disease typically defined as the 'wear and tear' of articular joint cartilage. However, recent studies suggest that OA is a disease arising from chronic low-grade inflammation. We conducted a study to investigate the relationship between chronic inflammatory mediators present in both the systemic peripheral blood system and localised inflammation in synovial fluid (SF) of OA and non-OA knees; and subsequently made direct comparative analyses to understand the mechanisms that may underpin the processes involved in OA.

    METHODS: 20-Plex proteins were quantified using Human Magnetic Luminex® assay (R&D Systems, USA) from plasma and SF of OA (n = 14) and non-OA (n = 14) patients. Ingenuity Pathway Analysis (IPA) software was used to predict the relationship and possible interaction of molecules pertaining to OA.

    RESULTS: There were significant differences in plasma level for matrix metalloproteinase (MMP)-3, interleukin (IL)-27, IL-8, IL-4, tumour necrosis factor-alpha, MMP-1, IL-15, IL-21, IL-10, and IL-1 beta between the groups, as well as significant differences in SF level for IL-15, IL-8, vascular endothelial growth factor (VEGF), MMP-1, and IL-18. Our predictive OA model demonstrated that toll-like receptor (TLR) 2, macrophage migration inhibitory factor (MIF), TLR4 and IL-1 were the main regulators of IL-1B, IL-4, IL-8, IL-10, IL-15, IL-21, IL-27, MMP-1 and MMP-3 in the plasma system; whilst IL-1B, TLR4, IL-1, and basigin (BSG) were the regulators of IL-4, IL-8, IL-10, IL-15, IL-18, IL-21, IL-27, MMP-1, and MMP-3 in the SF system.

    CONCLUSION: The elevated plasma IL-8 and SF IL-18 may be associated with the pathogenesis of OA via the activation of MMP-3.

  13. Saunus JM, Quinn MC, Patch AM, Pearson JV, Bailey PJ, Nones K, et al.
    J Pathol, 2015 Nov;237(3):363-78.
    PMID: 26172396 DOI: 10.1002/path.4583
    Treatment options for patients with brain metastases (BMs) have limited efficacy and the mortality rate is virtually 100%. Targeted therapy is critically under-utilized, and our understanding of mechanisms underpinning metastatic outgrowth in the brain is limited. To address these deficiencies, we investigated the genomic and transcriptomic landscapes of 36 BMs from breast, lung, melanoma and oesophageal cancers, using DNA copy-number analysis and exome- and RNA-sequencing. The key findings were as follows. (a) Identification of novel candidates with possible roles in BM development, including the significantly mutated genes DSC2, ST7, PIK3R1 and SMC5, and the DNA repair, ERBB-HER signalling, axon guidance and protein kinase-A signalling pathways. (b) Mutational signature analysis was applied to successfully identify the primary cancer type for two BMs with unknown origins. (c) Actionable genomic alterations were identified in 31/36 BMs (86%); in one case we retrospectively identified ERBB2 amplification representing apparent HER2 status conversion, then confirmed progressive enrichment for HER2-positivity across four consecutive metastatic deposits by IHC and SISH, resulting in the deployment of HER2-targeted therapy for the patient. (d) In the ERBB/HER pathway, ERBB2 expression correlated with ERBB3 (r(2)  = 0.496; p < 0.0001) and HER3 and HER4 were frequently activated in an independent cohort of 167 archival BM from seven primary cancer types: 57.6% and 52.6% of cases were phospho-HER3(Y1222) or phospho-HER4(Y1162) membrane-positive, respectively. The HER3 ligands NRG1/2 were barely detectable by RNAseq, with NRG1 (8p12) genomic loss in 63.6% breast cancer-BMs, suggesting a microenvironmental source of ligand. In summary, this is the first study to characterize the genomic landscapes of BM. The data revealed novel candidates, potential clinical applications for genomic profiling of resectable BMs, and highlighted the possibility of therapeutically targeting HER3, which is broadly over-expressed and activated in BMs, independent of primary site and systemic therapy.
  14. Teo SH, Yap DKY, Mansir N, Islam A, Taufiq-Yap YH
    Sci Rep, 2019 11 08;9(1):16358.
    PMID: 31705011 DOI: 10.1038/s41598-019-52857-4
    A γ-NA5 catalyst in the form of pellet was first to be reported and was pioneering in gasification to accelerate the production of syngas through biomass (palm empty fruit brunch) conversion. The synthesised γ-NA5 pellet possesses a high surface area of 212.32 m2 g-1, which renders more active sites for hydrocarbon cracking, subsequently leading to high H2 production (0.0716 m3 kg-1). Additionally, the pellet exhibits remarkable reversibility and reusability with 91% H2 production efficiency being retained after five consecutive gasification cycles. Distinctively, the feature of the synthesised γ-NA5 pellet from the conventional powder-like catalyst is that it eases the separation of the used catalyst from the biomass ash, and subsequently facilitates regeneration solely by calcination process. The loading of 20 wt.% optimised amount of catalyst itself has successfully shorten the completion of gasification process up to 135 min, which is highly feasible for a large scale industrial usage after considering the cost of the catalyst, facile preparation method, and catalyst's effectiveness towards gasification.
  15. Chow YP, Tan LP, Chai SJ, Abdul Aziz N, Choo SW, Lim PV, et al.
    Sci Rep, 2017 03 03;7:42980.
    PMID: 28256603 DOI: 10.1038/srep42980
    In this study, we first performed whole exome sequencing of DNA from 10 untreated and clinically annotated fresh frozen nasopharyngeal carcinoma (NPC) biopsies and matched bloods to identify somatically mutated genes that may be amenable to targeted therapeutic strategies. We identified a total of 323 mutations which were either non-synonymous (n = 238) or synonymous (n = 85). Furthermore, our analysis revealed genes in key cancer pathways (DNA repair, cell cycle regulation, apoptosis, immune response, lipid signaling) were mutated, of which those in the lipid-signaling pathway were the most enriched. We next extended our analysis on a prioritized sub-set of 37 mutated genes plus top 5 mutated cancer genes listed in COSMIC using a custom designed HaloPlex target enrichment panel with an additional 88 NPC samples. Our analysis identified 160 additional non-synonymous mutations in 37/42 genes in 66/88 samples. Of these, 99/160 mutations within potentially druggable pathways were further selected for validation. Sanger sequencing revealed that 77/99 variants were true positives, giving an accuracy of 78%. Taken together, our study indicated that ~72% (n = 71/98) of NPC samples harbored mutations in one of the four cancer pathways (EGFR-PI3K-Akt-mTOR, NOTCH, NF-κB, DNA repair) which may be potentially useful as predictive biomarkers of response to matched targeted therapies.
  16. Dörk T, Peterlongo P, Mannermaa A, Bolla MK, Wang Q, Dennis J, et al.
    Sci Rep, 2019 08 29;9(1):12524.
    PMID: 31467304 DOI: 10.1038/s41598-019-48804-y
    Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44-1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.
  17. Ng CH, Ripolles TS, Hamada K, Teo SH, Lim HN, Bisquert J, et al.
    Sci Rep, 2018 02 06;8(1):2482.
    PMID: 29410450 DOI: 10.1038/s41598-018-20228-0
    Perovskite solar cells based on series of inorganic cesium lead bromide and iodide mixture, CsPbBr3-xI x , where x varies between 0, 0.1, 0.2, and 0.3 molar ratio were synthesized by two step-sequential deposition at ambient condition to design the variations of wide band gap light absorbers. A device with high overall photoconversion efficiency of 3.98 % was obtained when small amount of iodide (CsPbBr2.9I0.1) was used as the perovskite and spiro-OMeTAD as the hole transport material (HTM). We investigated the origin of variation in open circuit voltage, Voc which was shown to be mainly dependent on two factors, which are the band gap of the perovskite and the work function of the HTM. An increment in Voc was observed for the device with larger perovskite band gap, while keeping the electron and hole extraction contacts the same. Besides, the usage of bilayer P3HT/MoO3 with deeper HOMO level as HTM instead of spiro-OMeTAD, thus increased the Voc from 1.16 V to 1.3 V for CsPbBr3 solar cell, although the photocurrent is lowered due to charge extraction issues. The stability studies confirmed that the addition of small amount of iodide into the CsPbBr3 is necessarily to stabilize the cell performance over time.
  18. Liu J, Prager-van der Smissen WJC, Collée JM, Bolla MK, Wang Q, Michailidou K, et al.
    Sci Rep, 2020 Jun 16;10(1):9688.
    PMID: 32546843 DOI: 10.1038/s41598-020-65665-y
    In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR = 1.035, 95% CI = 0.859-1.246, P = 0.718 and OR = 0.798, 95% CI = 0.482-1.322, P = 0.381 respectively), nor in specific high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene.
  19. Liu J, Lončar I, Collée JM, Bolla MK, Dennis J, Michailidou K, et al.
    Sci Rep, 2016 Nov 15;6:36874.
    PMID: 27845421 DOI: 10.1038/srep36874
    NBS1, also known as NBN, plays an important role in maintaining genomic stability. Interestingly, rs2735383 G > C, located in a microRNA binding site in the 3'-untranslated region (UTR) of NBS1, was shown to be associated with increased susceptibility to lung and colorectal cancer. However, the relation between rs2735383 and susceptibility to breast cancer is not yet clear. Therefore, we genotyped rs2735383 in 1,170 familial non-BRCA1/2 breast cancer cases and 1,077 controls using PCR-based restriction fragment length polymorphism (RFLP-PCR) analysis, but found no association between rs2735383CC and breast cancer risk (OR = 1.214, 95% CI = 0.936-1.574, P = 0.144). Because we could not exclude a small effect size due to a limited sample size, we further analyzed imputed rs2735383 genotypes (r2 > 0.999) of 47,640 breast cancer cases and 46,656 controls from the Breast Cancer Association Consortium (BCAC). However, rs2735383CC was not associated with overall breast cancer risk in European (OR = 1.014, 95% CI = 0.969-1.060, P = 0.556) nor in Asian women (OR = 0.998, 95% CI = 0.905-1.100, P = 0.961). Subgroup analyses by age, age at menarche, age at menopause, menopausal status, number of pregnancies, breast feeding, family history and receptor status also did not reveal a significant association. This study therefore does not support the involvement of the genotype at NBS1 rs2735383 in breast cancer susceptibility.
  20. Darabi H, Beesley J, Droit A, Kar S, Nord S, Moradi Marjaneh M, et al.
    Sci Rep, 2016 Sep 07;6:32512.
    PMID: 27600471 DOI: 10.1038/srep32512
    Genome-wide association studies have found SNPs at 17q22 to be associated with breast cancer risk. To identify potential causal variants related to breast cancer risk, we performed a high resolution fine-mapping analysis that involved genotyping 517 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of genotypes for 3,134 SNPs in more than 89,000 participants of European ancestry from the Breast Cancer Association Consortium (BCAC). We identified 28 highly correlated common variants, in a 53 Kb region spanning two introns of the STXBP4 gene, that are strong candidates for driving breast cancer risk (lead SNP rs2787486 (OR = 0.92; CI 0.90-0.94; P = 8.96 × 10(-15))) and are correlated with two previously reported risk-associated variants at this locus, SNPs rs6504950 (OR = 0.94, P = 2.04 × 10(-09), r(2) = 0.73 with lead SNP) and rs1156287 (OR = 0.93, P = 3.41 × 10(-11), r(2) = 0.83 with lead SNP). Analyses indicate only one causal SNP in the region and several enhancer elements targeting STXBP4 are located within the 53 kb association signal. Expression studies in breast tumor tissues found SNP rs2787486 to be associated with increased STXBP4 expression, suggesting this may be a target gene of this locus.
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