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Fulltext Diversity of endophytic bacteria in Malaysian plants as revealed by 16S rRNA encoding gene sequence based method of bacterial identification

Loh CY, Tan YY, Rohani R, Weber JF, Bhore SJ

J Young Pharm, 2013 Sep;5(3):95-7.
PMID: 24396249 DOI: 10.1016/j.jyp.2013.07.001

Bacterial endophytes do have several potential applications in pharmacy, medicine and agricultural biotech industry. The main objective of this study was to understand types of bacterial endophytes associated with dicotyledonous (dicot) and monocotyledonous (monocot) plant species. Isolation of the endophytic bacteria was performed using surface-sterilized various tissue samples, and identification of the endophytic bacterial isolates (EBIs) was completed using 16S rRNA encoding gene sequence similarity based method. In total, 996 EBIs were isolated and identified from 1055 samples of 31 monocot and 65 dicot plant species from Peninsular Malaysia. The 996 EBIs represented 71 different types of bacterial species. Twelve (12) out of 71 species are reported as endophytes for the first time. We conclude that diverse types of bacterial endophytes are associated with dicot and monocot plants, and could be useful in pharmacy, medicine and agricultural biotechnology for various potential applications.
Perspectives and advancements in the design of nanomaterials for targeted cancer theranostics

Tan YY, Yap PK, Xin Lim GL, Mehta M, Chan Y, Ng SW, et al.

Chem Biol Interact, 2020 Sep 25;329:109221.
PMID: 32768398 DOI: 10.1016/j.cbi.2020.109221

Cancer continues to be one of the most challenging diseases to be treated and is one of the leading causes of deaths around the globe. Cancers account for 13% of all deaths each year, with cancer-related mortality expected to rise to 13.1 million by the year 2030. Although, we now have a large library of chemotherapeutic agents, the problem of non-selectivity remains the biggest drawback, as these substances are toxic not only to cancerous cells, but also to other healthy cells in the body. The limitations with chemotherapy and radiation have led to the discovery and development of novel strategies for safe and effective treatment strategies to manage the menace of cancer. Researchers have long justified and have shed light on the emergence of nanotechnology as a potential area for cancer therapy and diagnostics, whereby, nanomaterials are used primarily as nanocarriers or as delivery agents for anticancer drugs due to their tumor targeting properties. Furthermore, nanocarriers loaded with chemotherapeutic agents also overcome biological barriers such as renal and hepatic clearances, thus improving therapeutic efficacy with lowered morbidity. Theranostics, which is the combination of rationally designed nanomaterials with cancer-targeting moieties, along with protective polymers and imaging agents has become one of the core keywords in cancer research. In this review, we have highlighted the potential of various nanomaterials for their application in cancer therapy and imaging, including their current state and clinical prospects. Theranostics has successfully paved a path to a new era of drug design and development, in which nanomaterials and imaging contribute to a large variety of cancer therapies and provide a promising future in the effective management of various cancers. However, in order to meet the therapeutic needs, theranostic nanomaterials must be designed in such a way, that take into account the pharmacokinetic and pharmacodynamics properties of the drug for the development of effective carcinogenic therapy.
Antiretroviral agents in pre-exposure prophylaxis: emerging and advanced trends in HIV prevention

Yap PK, Loo Xin GL, Tan YY, Chellian J, Gupta G, Liew YK, et al.

J Pharm Pharmacol, 2019 Sep;71(9):1339-1352.
PMID: 31144296 DOI: 10.1111/jphp.13107

OBJECTIVES: Antiretroviral agents (ARVs) have been the most promising line of therapy in the management of human immunodeficiency virus (HIV) infections. Some of these ARVs are used in the pre-exposure prophylaxis (PrEP) to suppress the transmission of HIV. Prophylaxis is primarily used in uninfected people, before exposure, to effectively prevent HIV infection. Several studies have shown that ART PrEP prevents HIV acquisition from sexual, blood and mother-to-child transmissions. However, there are also several challenges and limitations to PrEP. This review focuses on the current antiretroviral therapies used in PrEP.
KEY FINDINGS: Among ARVs, the most common drugs employed from the class of entry inhibitors are maraviroc (MVC), which is a CCR5 receptor antagonist. Other entry inhibitors like emtricitabine (FTC) and tenofovir (TFV) are also used. Rilpivirine (RPV) and dapivirine (DPV) are the most common drugs employed from the Non-nucleoside reverse transcriptase inhibitor (NNRTIs) class, whereas, tenofovir disoproxil fumarate (TDF) is primarily used in the Nucleoside Reverse Transcriptase Inhibitor (NRTIs) class. Cabotegravir (CAB) is an analog of dolutegravir, and it is an integrase inhibitor. Some of these drugs are also used in combination with other drugs from the same class.
SUMMARY: Some of the most common pre-exposure prophylactic strategies employed currently are the use of inhibitors, namely entry inhibitors, non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors, integrase and protease inhibitors. In addition, we have also discussed on the adverse effects caused by ART in PrEP, pharmacoeconomics factors and the use of antiretroviral prophylaxis in serodiscordant couples.
Demographics and outcome of patients with congenital haemophilia in Sarawak, Malaysia

Tang ASO, Wong QY, Tan YY, Chieng CH, Ko CT, Ong GB, et al.

Med J Malaysia, 2021 Jan;76(1):51-55.
PMID: 33510109

INTRODUCTION: Sarawak has a population that is geographically and characteristically widely varied. This study aimed to determine the demographic profile of patients in Sarawak, Malaysia. Materials and Methods - A cross-sectional study was conducted in 2019 at four major haemophilia treatment centres in Kuching, Sibu, Bintulu and Miri Hospitals, Sarawak. Demographic and clinical data were collected with consents from patients.
RESULTS AND DISCUSSION: Ninety-six haemophilia patients were identified - 79(82.3%) haemophilia A(HA) and 17(17.7%) haemophilia B(HB). Severe haemophilia patients were noted in 45.6% (36/79) of HA and 64.7% (11/17) of HB. In all 44.3% of the HA and 52.9% of the HB population had no identifiable family history of haemophilia. Two-thirds of the patients with severe HA were on prophylaxis [24/36 (66.7%)] and only onethird [4/11 (36.4%)] in severe HB. Inhibitors developed in 9/79 (11.4%) of the HA population [3/79 (3.8%) high responders]. The median inhibitor titre was not significantly different between the different treatment groups - on demand versus prophylaxis (1.0BU versus 2.0BU; z statistic -1.043, p-value 0.297, Mann-Whitney test). None of the patients developed inhibitory alloantibodies to factor IX. Four HA patients (5.1%) underwent immune tolerance induction where one case had a successful outcome. Three severe HA patients received emicizumab prophylaxis and showed remarkable reduction in bleeding events with no thromboembolic events being reported. One female moderate HA patient received PEGylated recombinant anti-haemophilic factor. Eleven patients underwent radiosynovectomy. One mild HB patient succumbed to traumatic intracranial bleeding. Our data reported a prevalence (per 100,000 males) of 5.40 cases for all severities of HA, 2.46 cases for severe HA; 1.16 cases for all severities of HB, and 0.75 cases for severe HB. The overall incidence of HA and HB was 1 in 11,500 and 1 in 46,000, respectively.
CONCLUSION: This study outlines the Sarawakian haemophilia landscape and offers objective standards for forward planning. Shared responsibilities among all parties are of utmost importance to improve the care of our haemophilia population.
Fulltext Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

Barnes DR, Rookus MA, McGuffog L, Leslie G, Mooij TM, Dennis J, et al.

Genet Med, 2020 10;22(10):1653-1666.
PMID: 32665703 DOI: 10.1038/s41436-020-0862-x

PURPOSE: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers.
METHODS: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort.
RESULTS: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10-72). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10-50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10-22) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10-12) carriers. The associations in the prospective cohort were similar.
CONCLUSION: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.
Fulltext Development and Evaluation of Topical Zinc Oxide Nanogels Formulation Using Dendrobium anosmum and Its Effect on Acne Vulgaris

Tan YY, Wong LS, Nyam KL, Wittayanarakul K, Zawawi NA, Rajendran K, et al.

Molecules, 2023 Sep 22;28(19).
PMID: 37836592 DOI: 10.3390/molecules28196749

Zinc oxide nanoparticles have high levels of biocompatibility, a low impact on environmental contamination, and suitable to be used as an ingredient for environmentally friendly skincare products. In this study, biogenically synthesized zinc oxide nanoparticles using Dendrobium anosum are used as a reducing and capping agent for topical anti-acne nanogels, and the antimicrobial effect of the nanogel is assessed on Cutibacterium acne and Staphylococcus aureus. Dendrobium anosmum leaf extract was examined for the presence of secondary metabolites and its total amount of phenolic and flavonoid content was determined. Both the biogenically and chemogenic-synthesized zinc oxide nanoparticles were compared using UV-Visible spectrophotometer, FE-SEM, XRD, and FTIR. To produce the topical nanogel, the biogenic and chemogenic zinc oxide nanoparticles were mixed with a carbomer and hydroxypropyl-methyl cellulose (HPMC) polymer. The mixtures were then tested for physical and chemical characteristics. To assess their anti-acne effectiveness, the mixtures were tested against C. acne and S. aureus. The biogenic zinc oxide nanoparticles have particle sizes of 20 nm and a high-phase purity. In comparison to chemogenic nanoparticles, the hydrogels with biogenically synthesized nanoparticles was more effective against Gram-positive bacteria. Through this study, the hybrid nanogels was proven to be effective against the microbes that cause acne and to be potentially used as a green product against skin infections.
Fulltext Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes

Fachal L, Aschard H, Beesley J, Barnes DR, Allen J, Kar S, et al.

Nat Genet, 2020 01;52(1):56-73.
PMID: 31911677 DOI: 10.1038/s41588-019-0537-1

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.
Effect of training on time efficiency and marginal adaptation of computer-aided design/computer-aided manufacturing crowns among dental students

Tan YY, Ho TK, Goo CL

Eur J Dent Educ, 2021 Sep 19.
PMID: 34541757 DOI: 10.1111/eje.12722

INTRODUCTION: The computer-aided design/computer-aided manufacturing (CAD/CAM) technology has revolutionised dentistry at present. An operator's skills can affect the overall clinical duration and marginal accuracy of the prosthesis fabricated through this workflow. The aim of this study was to assess the effect of CAD/CAM hands-on training compared with that of a self-instructional video on the performance of dental students in digital impression and fabrication of a CAD/CAM crown.
METHODS: In this cross-sectional study, 30 undergraduate dental students were shown a CEREC demonstration video. Each operator then captured a digital impression using the intra-oral scanner, and a crown was subsequently milled. All participants underwent a training course before repeating the process. Marginal discrepancy for each crown on its abutment tooth was measured before and after training using a stereomicroscope and was evaluated using Wilcoxon signed rank test. The duration taken for the process was recorded before and after training and evaluated using paired t-test.
RESULTS: The overall mean ±standard deviation marginal adaptation for the CEREC crowns was 78.15 ± 42.83 μm before training and 52.41 ± 17.12 μm after training. The Wilcoxon signed rank test found significant difference (p
Diffuse axonal injury A clinical and computerised tomography study of 128 patients

Selladurai BM, Sherazi ZA, Nair RC, Tan YY, Khadar MA

J Clin Neurosci, 1995 Jul;2(3):216-23.
PMID: 18638817

A study of clinical, computerised tomography (CT) profile and outcome was made of 128 patients, diagnosed to have diffuse axonal injury based on CT criteria. The mean age was 26 years. A lucid interval was present in 37 patients and hypoxia and/or hypotension was present in 43 patients. The depth of "marker lesions" in CT correlated with Glasgow Coma Score (GCS) (p<0.02) and duration of coma (p<0.01). The presence of associated intracranial haematoma >25 ml portended an adverse outcome. A logistic regression analysis revealed age, GCS, state of perimesencephalic cisterns and pupillary dilation to be independent predictors of poor outcome. Residual sequelae (focal deficits, cognitive deficits, postconcussion syndrome) were evident in nearly half of patients with diffuse axonal injury (DAI) and a lucid interval.
Fulltext Advanced oxidation and biological integrated processes for pharmaceutical wastewater treatment: A review

Adeoye JB, Tan YH, Lau SY, Tan YY, Chiong T, Mubarak NM, et al.

J Environ Manage, 2024 Feb 27;353:120170.
PMID: 38308991 DOI: 10.1016/j.jenvman.2024.120170

The stress of pharmaceutical and personal care products (PPCPs) discharging to water bodies and the environment due to increased industrialization has reduced the availability of clean water. This poses a potential health hazard to animals and human life because water contamination is a great issue to the climate, plants, humans, and aquatic habitats. Pharmaceutical compounds are quantified in concentrations ranging from ng/Lto μg/L in aquatic environments worldwide. According to (Alsubih et al., 2022), the concentrations of carbamazepine, sulfamethoxazole, Lutvastatin, ciprofloxacin, and lorazepam were 616-906 ng/L, 16,532-21635 ng/L, 694-2068 ng/L, 734-1178 ng/L, and 2742-3775 ng/L respectively. Protecting and preserving our environment must be well-driven by all sectors to sustain development. Various methods have been utilized to eliminate the emerging pollutants, such as adsorption and biological and advanced oxidation processes. These methods have their benefits and drawbacks in the removal of pharmaceuticals. Successful wastewater treatment can save the water bodies; integrating green initiatives into the main purposes of actor firms, combined with continually periodic awareness of the current and potential implications of environmental/water pollution, will play a major role in water conservation. This article reviews key publications on the adsorption, biological, and advanced oxidation processes used to remove pharmaceutical products from the aquatic environment. It also sheds light on the pharmaceutical adsorption capability of adsorption, biological and advanced oxidation methods, and their efficacy in pharmaceutical concentration removal. A research gap has been identified for researchers to explore in order to eliminate the problem associated with pharmaceutical wastes. Therefore, future study should focus on combining advanced oxidation and adsorption processes for an excellent way to eliminate pharmaceutical products, even at low concentrations. Biological processes should focus on ideal circumstances and microbial processes that enable the simultaneous removal of pharmaceutical compounds and the effects of diverse environments on removal efficiency.
Fulltext Reducing scanning electron microscope charging by using exponential contrast stretching technique on post-processing images

Sim KS, Tan YY, Lai MA, Tso CP, Lim WK

J Microsc, 2010 Apr 1;238(1):44-56.
PMID: 20384837 DOI: 10.1111/j.1365-2818.2009.03328.x

An exponential contrast stretching (ECS) technique is developed to reduce the charging effects on scanning electron microscope images. Compared to some of the conventional histogram equalization methods, such as bi-histogram equalization and recursive mean-separate histogram equalization, the proposed ECS method yields better image compensation. Diode sample chips with insulating and conductive surfaces are used as test samples to evaluate the efficiency of the developed algorithm. The algorithm is implemented in software with a frame grabber card, forming the front-end video capture element.
Real-time image quality assessment with mixed Lagrange time delay estimation autoregressive (MLTDEAR) model

Sim KS, Tso CP, Tan YY, Lim WK

J Microsc, 2007 Jun;226(Pt 3):230-43.
PMID: 17535262

A proposal to assess the quality of scanning electron microscope images using mixed Lagrange time delay estimation technique is presented. With optimal scanning electron microscope scan rate information, online images can be quantified and improved. The online quality assessment technique is embedded onto a scanning electron microscope frame grabber card for real-time image processing. Different images are captured using scanning electron microscope and a database is built to optimally choose filter parameters. An optimum choice of filter parameters is obtained. With the optimum choice of scan rate, noise can be removed from real-time scanning electron microscope images without causing any sample contamination or increasing scanning time.
Fulltext Sentiment Analysis and Sarcasm Detection using Deep Multi-Task Learning

Tan YY, Chow CO, Kanesan J, Chuah JH, Lim Y

Wirel Pers Commun, 2023;129(3):2213-2237.
PMID: 36987507 DOI: 10.1007/s11277-023-10235-4

Social media platforms such as Twitter and Facebook have become popular channels for people to record and express their feelings, opinions, and feedback in the last decades. With proper extraction techniques such as sentiment analysis, this information is useful in many aspects, including product marketing, behavior analysis, and pandemic management. Sentiment analysis is a technique to analyze people's thoughts, feelings and emotions, and to categorize them into positive, negative, or neutral. There are many ways for someone to express their feelings and emotions. These sentiments are sometimes accompanied by sarcasm, especially when conveying intense emotion. Sarcasm is defined as a positive sentence with underlying negative intention. Most of the current research work treats them as two distinct tasks. To date, most sentiment and sarcasm classification approaches have been treated primarily and standalone as a text categorization problem. In recent years, research work using deep learning algorithms have significantly improved performance for these standalone classifiers. One of the major issues faced by these approaches is that they could not correctly classify sarcastic sentences as negative. With this in mind, we claim that knowing how to spot sarcasm will help sentiment classification and vice versa. Our work has shown that these two tasks are correlated. This paper proposes a multi-task learning-based framework utilizing a deep neural network to model this correlation to improve sentiment analysis's overall performance. The proposed method outperforms the existing methods by a margin of 3%, with an F1-score of 94%.
Outcome prediction in early management of severe head injury: an experience in Malaysia

Selladurai BM, Jayakumar R, Tan YY, Low HC

Br J Neurosurg, 1992;6(6):549-57.
PMID: 1472321

The outcome of 109 patients with severe head injury was studied in relation to clinical and computed tomographic (CT) criteria on admission, after resuscitation. Age, Glasgow Coma Score (GCS) and state of pupils strongly correlated with outcome. The presence of hypothalamic disturbances, hypoxia and hypotension were associated with an adverse outcome. The CT indicators associated with poor outcome were perimesencephalic cistern (PMC) obliteration, subarachnoid haemorrhage, diffuse axonal injury and acute subdural haematoma. The prognostic value of midline shift and mass effect were influenced by concomitant presence of diffuse brain injury. For the subset of patients aged < 20 years, with GCS 6-8 and patent PMC (n = 21), 71.4% correct predictions were made for a good outcome. For the subset of patients aged > 20 years, with GCS 3-5 and partial or complete obliteration of PMC (n = 28), 89.3% correct predictions were made for a poor outcome.
Fulltext Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations

Rebbeck TR, Friebel TM, Friedman E, Hamann U, Huo D, Kwong A, et al.

Hum Mutat, 2018 05;39(5):593-620.
PMID: 29446198 DOI: 10.1002/humu.23406

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.
Fulltext Fine-needle aspiration to improve diagnosis of melioidosis of the head and neck in children: a study from Sarawak, Malaysia

Mohan A, Podin Y, Liew DW, Mahendra Kumar J, Lau PS, Tan YY, et al.

BMC Infect Dis, 2021 Oct 15;21(1):1069.
PMID: 34654392 DOI: 10.1186/s12879-021-06754-9

BACKGROUND: Melioidosis, the infection caused by Burkholderia pseudomallei, is associated with a high case fatality rate, due in part to difficulties in clinical recognition and diagnostic confirmation of the disease. Although head and neck involvement is common in children, specific disease manifestations differ between geographic regions. The aim of this study was to provide a detailed description of melioidosis of the head and neck among children in Sarawak, Malaysia, and determine if fine-needle aspiration of suspected head or neck lesions could improve melioidosis diagnosis.
METHODS: We conducted a retrospective descriptive study of all children aged
Fulltext Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores

Lecarpentier J, Silvestri V, Kuchenbaecker KB, Barrowdale D, Dennis J, McGuffog L, et al.

J Clin Oncol, 2017 Jul 10;35(20):2240-2250.
PMID: 28448241 DOI: 10.1200/JCO.2016.69.4935

Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 × 10-6). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 × 10-9). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.
Fulltext Characterization of the Cancer Spectrum in Men With Germline BRCA1 and BRCA2 Pathogenic Variants: Results From the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)

Silvestri V, Leslie G, Barnes DR, CIMBA Group, Agnarsson BA, Aittomäki K, et al.

JAMA Oncol, 2020 Aug 01;6(8):1218-1230.
PMID: 32614418 DOI: 10.1001/jamaoncol.2020.2134

IMPORTANCE: The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population.
OBJECTIVE: To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers.
DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected.
MAIN OUTCOMES AND MEASURES: BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview.
RESULTS: Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P
Polygenic risk modeling for prediction of epithelial ovarian cancer risk

Dareng EO, Tyrer JP, Barnes DR, Jones MR, Yang X, Aben KKH, et al.

Eur J Hum Genet, 2022 Jan 14.
PMID: 35027648 DOI: 10.1038/s41431-021-00987-7

Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
Fulltext Correction: Polygenic risk modeling for prediction of epithelial ovarian cancer risk

Dareng EO, Tyrer JP, Barnes DR, Jones MR, Yang X, Aben KKH, et al.

Eur J Hum Genet, 2022 May;30(5):630-631.
PMID: 35314806 DOI: 10.1038/s41431-022-01085-y

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