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  1. Fulltext Opinions of the Urban Women on Pap test: Evidence from Bangladesh
    Mustari S, Hossain B, Diah NM, Kar S
    Asian Pac J Cancer Prev, 2019 06 01;20(6):1613-1620.
    PMID: 31244279 DOI: 10.31557/APJCP.2019.20.6.1613
    Each year, many countries from developed world publishes reports on early cancer detection; which is absolutely
    absent in most developing countries like Bangladesh.Very limited evidence is found on the role and acceptance of Pap
    test among the women of Bangladesh in determining cervical cancer. More research and updates are needed relating Pap
    test in early detection of cervical cancer. Thus the purpose of this study is set to assess the opinions of Bangladeshiurban
    womentowardsthe Pap test. A questionnaire-based survey of 400 Bangladeshi urban women was evaluated by on their
    socio-demographic characteristics, knowledgeand attitudes towards Pap testing. In general, the findings reveal that
    respondents havea good understanding of thepurpose of Pap test screening with 3.92 (Mean score). With 3.54 Mean
    score,the respondents believed that Pap tests are recommended to women who are married and with 3.45 mean score
    women believed that Pap tests arerecommended only to those who have children. Generally, respondents possess good
    knowledge of Pap test and its purpose. These findings can be used in identifying prospect cervical cancer screening
    significance populations and trend for future intrusion.
  2. Start-up, performance and optimization of a compost biofilter treating gas-phase mixture of benzene and toluene
    Rene ER, Kar S, Krishnan J, Pakshirajan K, López ME, Murthy DV, et al.
    Bioresour Technol, 2015 Aug;190:529-35.
    PMID: 25827361 DOI: 10.1016/j.biortech.2015.03.049
    The performance of a compost biofilter inoculated with mixed microbial consortium was optimized for treating a gas-phase mixture of benzene and toluene. The biofilter was acclimated to these VOCs for a period of ∼18d. The effects of concentration and flow rate on the removal efficiency (RE) and elimination capacity (EC) were investigated by varying the inlet concentration of benzene (0.12-0.95g/m(3)), toluene (0.14-1.48g/m(3)) and gas-flow rate (0.024-0.072m(3)/h). At comparable loading rates, benzene removal in the mixture was reduced in the range of 6.6-41% in comparison with the individual benzene degradation. Toluene removal in mixture was even more affected as observed from the reductions in REs, ranging from 18.4% to 76%. The results were statistically interpreted by performing an analysis of variance (ANOVA) to elucidate the main and interaction effects.
  3. Comparative evaluation of 50 microgram oral misoprostol and 25 microgram intravaginal misoprostol for induction of labour at term: a randomized trial
    Rahman H, Pradhan A, Kharka L, Renjhen P, Kar S, Dutta S
    J Obstet Gynaecol Can, 2013 May;35(5):408-416.
    PMID: 23756271 DOI: 10.1016/S1701-2163(15)30931-2
    OBJECTIVES: To assess and compare the efficacy and safety of 50 µg oral misoprostol and 25 µg intravaginal misoprostol for induction of labour at term.

    METHODS: This non-blinded, randomized clinical trial included 228 pregnant women at term with obstetric or medical indications for induction of labour. Women either took 50 µg misoprostol orally (two 25 µg tablets) or had one 25 µg tablet of misoprostol inserted in the posterior vaginal fornix. In each group, misoprostol administration was repeated every four hours in the same dose until regular uterine contractions were established or to a maximum of five doses. Time to delivery and outcome data for each group were compared.

    RESULTS: Of the 228 women, eight (3.5%) were excluded from the analysis as they withdrew their consent after randomization. Mean induction-to-delivery interval was similar in both groups (21.22 hours in the oral group vs. 20.15 hours in the vaginal group; P = 0.58). There was no significant difference between the groups with respect to the number of women who delivered within 24 hours or who required oxytocin augmentation of labour, the mode of delivery, and neonatal outcomes (P > 0.05). Uterine hyperstimulation occurred in two women who received misoprostol vaginally, but not in any of the women in the oral misoprostol group.

    CONCLUSION: Oral misoprostol in a dose of 50 µg every four hours, to a maximum of five doses, has the potential to induce labour as safely and effectively as 25 µg misoprostol administered vaginally every four hours.

  4. Fulltext Sex Determination and Differentiation in Teleost: Roles of Genetics, Environment, and Brain
    Rajendiran P, Jaafar F, Kar S, Sudhakumari C, Senthilkumaran B, Parhar IS
    Biology (Basel), 2021 Sep 27;10(10).
    PMID: 34681072 DOI: 10.3390/biology10100973
    The fish reproductive system is a complex biological system. Nonetheless, reproductive organ development is conserved, which starts with sex determination and then sex differentiation. The sex of a teleost is determined and differentiated from bipotential primordium by genetics, environmental factors, or both. These two processes are species-specific. There are several prominent genes and environmental factors involved during sex determination and differentiation. At the cellular level, most of the sex-determining genes suppress the female pathway. For environmental factors, there are temperature, density, hypoxia, pH, and social interaction. Once the sexual fate is determined, sex differentiation takes over the gonadal developmental process. Environmental factors involve activation and suppression of various male and female pathways depending on the sexual fate. Alongside these factors, the role of the brain during sex determination and differentiation remains elusive. Nonetheless, GnRH III knockout has promoted a male sex-biased population, which shows brain involvement during sex determination. During sex differentiation, LH and FSH might not affect the gonadal differentiation, but are required for regulating sex differentiation. This review discusses the role of prominent genes, environmental factors, and the brain in sex determination and differentiation across a few teleost species.
  5. Cancer prevention and therapy through the modulation of transcription factors by bioactive natural compounds
    Shanmugam MK, Lee JH, Chai EZ, Kanchi MM, Kar S, Arfuso F, et al.
    Semin Cancer Biol, 2016 10;40-41:35-47.
    PMID: 27038646 DOI: 10.1016/j.semcancer.2016.03.005
    The association between chronic inflammation and cancer development has been well documented. One of the major obstacles in cancer treatment is the persistent autocrine and paracrine activation of pro-inflammatory transcription factors such as nuclear factor-κB, signal transducer and activator of transcription 3, activator protein 1, fork head box protein M1, and hypoxia-inducible factor 1α in a wide variety of tumor cell lines and patient specimens. This, in turn, leads to an accelerated production of cellular adhesion molecules, inflammatory cytokines, chemokines, anti-apoptotic molecules, and inducible nitric oxide synthase. Numerous medicinal plant-derived compounds have made a tremendous impact in drug discovery research endeavors, and have been reported to modulate the activation of diverse oncogenic transcription factors in various tumor models. Moreover, novel therapeutic combinations of standard chemotherapeutic drugs with these agents have significantly improved patient survival by making cancer cells more susceptible to chemotherapy and radiotherapy. In this review, we critically analyze the existing literature on the modulation of diverse transcription factors by various natural compounds and provide views on new directions for accelerating the discovery of novel drug candidates derived from Mother Nature.
  6. Fulltext Cholera prevention and control in Asian countries
    Ahmed MU, Baquilod M, Deola C, Tu ND, Anh DD, Grasso C, et al.
    BMC Proc, 2018;12(Suppl 13):62.
    PMID: 30807619 DOI: 10.1186/s12919-018-0158-1
    Cholera remains a major public health problem in many countries. Poor sanitation and inappropriate clean water supply, insufficient health literacy and community mobilization, absence of national plans and cross-border collaborations are major factors impeding optimal control of cholera in endemic countries. In March 2017, a group of experts from 10 Asian cholera-prone countries that belong to the Initiative against Diarrheal and Enteric Diseases in Africa and Asia (IDEA), together with representatives from the World Health Organization, the US National Institutes of Health, International Vaccine Institute, Agence de médecine préventive, NGOs (Save the Children) and UNICEF, met in Hanoi (Vietnam) to share progress in terms of prevention and control interventions on water, sanitation and hygiene (WASH), surveillance and oral cholera vaccine use. This paper reports on the country situation, gaps identified in terms of cholera prevention and control and strategic interventions to bridge these gaps.
  7. Fulltext Fine scale mapping of the 17q22 breast cancer locus using dense SNPs, genotyped within the Collaborative Oncological Gene-Environment Study (COGs)
    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.
  8. Fulltext Fine-scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer
    Shi J, Zhang Y, Zheng W, Michailidou K, Ghoussaini M, Bolla MK, et al.
    Int J Cancer, 2016 Sep 15;139(6):1303-1317.
    PMID: 27087578 DOI: 10.1002/ijc.30150
    Previous genome-wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. A fine-mapping study across 2.06 Mb (chr8:127,561,724-129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium was conducted. Three additional independent association signals in women of European ancestry, represented by rs35961416 (OR = 0.95, 95% CI = 0.93-0.97, conditional p = 5.8 × 10(-6) ), rs7815245 (OR = 0.94, 95% CI = 0.91-0.96, conditional p = 1.1 × 10(-6) ) and rs2033101 (OR = 1.05, 95% CI = 1.02-1.07, conditional p = 1.1 × 10(-4) ) were found. Integrative analysis using functional genomic data from the Roadmap Epigenomics, the Encyclopedia of DNA Elements project, the Cancer Genome Atlas and other public resources implied that SNPs rs7815245 in Signal 3, and rs1121948 in Signal 5 (in linkage disequilibrium with rs11780156, r(2)  = 0.77), were putatively functional variants for two of the five independent association signals. The results highlighted multiple 8q24 variants associated with breast cancer susceptibility in women of European ancestry.
  9. Fulltext Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression
    Darabi H, McCue K, Beesley J, Michailidou K, Nord S, Kar S, et al.
    Am J Hum Genet, 2015 Jul 02;97(1):22-34.
    PMID: 26073781 DOI: 10.1016/j.ajhg.2015.05.002
    Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82-0.88]) and ER-negative (OR = 0.87 [0.82-0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91-0.95] and OR = 1.06 [1.03-1.09]) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.13]) disease. There was weaker evidence for iCHAV4, located 5' of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer.
  10. Fulltext Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer
    Lawrenson K, Li Q, Kar S, Seo JH, Tyrer J, Spindler TJ, et al.
    Nat Commun, 2015 Sep 22;6:8234.
    PMID: 26391404 DOI: 10.1038/ncomms9234
    Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10(-5)). For three cis-eQTL associations (P<1.4 × 10(-3), FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10(-10) for risk variants (P<10(-4)) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.
  11. Fulltext Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus
    Zeng C, Guo X, Long J, Kuchenbaecker KB, Droit A, Michailidou K, et al.
    Breast Cancer Res, 2016 06 21;18(1):64.
    PMID: 27459855 DOI: 10.1186/s13058-016-0718-0
    BACKGROUND: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk.

    METHOD: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation.

    RESULTS: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P s) for the association observed between variants at 12p11 and breast cancer risk.

  12. Fulltext Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation
    Ghoussaini M, Edwards SL, Michailidou K, Nord S, Cowper-Sal Lari R, Desai K, et al.
    Nat Commun, 2014 Sep 23;4:4999.
    PMID: 25248036 DOI: 10.1038/ncomms5999
    GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology.
  13. Fulltext Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1
    Glubb DM, Maranian MJ, Michailidou K, Pooley KA, Meyer KB, Kar S, et al.
    Am J Hum Genet, 2015 Jan 08;96(1):5-20.
    PMID: 25529635 DOI: 10.1016/j.ajhg.2014.11.009
    Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER(+): odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, ptrend = 5.7 × 10(-44)) and estrogen-receptor-negative (ER(-): OR = 1.10, 95% CI = 1.05-1.15, ptrend = 3.0 × 10(-4)) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [pcond = 1.61 × 10(-5)]) and five variants composing iCHAV3 (lead rs11949391; ER(+): OR = 0.90, 95% CI = 0.87-0.93, pcond = 1.4 × 10(-4)). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival.
  14. 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.
  15. Fulltext Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer
    Couch FJ, Kuchenbaecker KB, Michailidou K, Mendoza-Fandino GA, Nord S, Lilyquist J, et al.
    Nat Commun, 2016 Apr 27;7:11375.
    PMID: 27117709 DOI: 10.1038/ncomms11375
    Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.
  16. Fulltext Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
    Lawrenson K, Kar S, McCue K, Kuchenbaeker K, Michailidou K, Tyrer J, et al.
    Nat Commun, 2016 Sep 07;7:12675.
    PMID: 27601076 DOI: 10.1038/ncomms12675
    A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10(-20)), ER-negative BC (P=1.1 × 10(-13)), BRCA1-associated BC (P=7.7 × 10(-16)) and triple negative BC (P-diff=2 × 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10(-3)) and ABHD8 (P<2 × 10(-3)). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3'-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
  17. Fulltext Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170
    Dunning AM, Michailidou K, Kuchenbaecker KB, Thompson D, French JD, Beesley J, et al.
    Nat Genet, 2016 Apr;48(4):374-86.
    PMID: 26928228 DOI: 10.1038/ng.3521
    We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.
  18. Fulltext Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer
    Milne RL, Kuchenbaecker KB, Michailidou K, Beesley J, Kar S, Lindström S, et al.
    Nat Genet, 2017 Dec;49(12):1767-1778.
    PMID: 29058716 DOI: 10.1038/ng.3785
    Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10-8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.
  19. Fulltext Association analysis identifies 65 new breast cancer risk loci
    Michailidou K, Lindström S, Dennis J, Beesley J, Hui S, Kar S, et al.
    Nature, 2017 Nov 02;551(7678):92-94.
    PMID: 29059683 DOI: 10.1038/nature24284
    Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P 
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