Widespread forest vertebrate extinctions induced by a mega hydroelectric dam in lowland Amazonia

Mega hydropower projects in tropical forests pose a major emergent threat to terrestrial and freshwater biodiversity worldwide. Despite the unprecedented number of existing, underconstruction and planned hydroelectric dams in lowland tropical forests, long-term effects on biodiversity have yet to be evaluated. We examine how medium and large-bodied assemblages of terrestrial and arboreal vertebrates (including 35 mammal, bird and tortoise species) responded to the drastic 26-year post-isolation history of archipelagic alteration in landscape structure and habitat quality in a major hydroelectric reservoir of Central Amazonia. The Balbina Hydroelectric Dam inundated 3,129 km2 of primary forests, simultaneously isolating 3,546 land-bridge islands. We conducted intensive biodiversity surveys at 37 of those islands and three adjacent continuous forests using a combination of four survey techniques, and detected strong forest habitat area effects in explaining patterns of vertebrate extinction. Beyond clear area effects, edge-mediated surface fire disturbance was the most important additional driver of species loss, particularly in islands smaller than 10 ha. Based on species-area models, we predict that only 0.7% of all islands now harbor a species-rich vertebrate assemblage consisting of ≥80% of all species. We highlight the colossal erosion in vertebrate diversity driven by a man-made dam and show that the biodiversity impacts of mega dams in lowland tropical forest regions have been severely overlooked. The geopolitical strategy to deploy many more large hydropower infrastructure projects in regions like lowland Amazonia should be urgently reassessed, and we strongly advise that long-term biodiversity impacts should be explicitly included in pre-approval environmental impact assessments

Appraising the role of previously reported risk factors in epithelial ovarian cancer risk: A Mendelian randomization analysis

Background Various risk factors have been associated with epithelial ovarian cancer risk in observational epidemiological studies. However, the causal nature of the risk factors reported, and thus their suitability as effective intervention targets, is unclear given the susceptibility of conventional observational designs to residual confounding and reverse causation. Mendelian randomization (MR) uses genetic variants as proxies for risk factors to strengthen causal inference in observational studies. We used MR to evaluate the association of 12 previously reported risk factors (reproductive, anthropometric, clinical, lifestyle, and molecular factors) with risk of invasive epithelial ovarian cancer, invasive epithelial ovarian cancer histotypes, and low malignant potential tumours. Methods and findings Genetic instruments to proxy 12 risk factors were constructed by identifying single nucleotide polymorphisms (SNPs) that were robustly (P < 5 × 10−8) and independently associated with each respective risk factor in previously reported genome-wide association studies. These risk factors included genetic liability to 3 factors (endometriosis, polycystic ovary syndrome, type 2 diabetes) scaled to reflect a 50% higher odds liability to disease. We obtained summary statistics for the association of these SNPs with risk of overall and histotype-specific invasive epithelial ovarian cancer (22,406 cases; 40,941 controls) and low malignant potential tumours (3,103 cases; 40,941 controls) from the Ovarian Cancer Association Consortium (OCAC). The OCAC dataset comprises 63 genotyping project/case–control sets with participants of European ancestry recruited from 14 countries (US, Australia, Belarus, Germany, Belgium, Denmark, Finland, Norway, Canada, Poland, UK, Spain, Netherlands, and Sweden). SNPs were combined into multi-allelic inverse-variance-weighted fixed or random effects models to generate effect estimates and 95% confidence intervals (CIs). Three complementary sensitivity analyses were performed to examine violations of MR assumptions: MR–Egger regression and weighted median and mode estimators. A Bonferroni-corrected P value threshold was used to establish strong evidence (P < 0.0042) and suggestive evidence (0.0042 < P < 0.05) for associations. In MR analyses, there was strong or suggestive evidence that 2 of the 12 risk factors were associated with invasive epithelial ovarian cancer and 8 of the 12 were associated with 1 or more invasive epithelial ovarian cancer histotypes. There was strong evidence that genetic liability to endometriosis was associated with an increased risk of invasive epithelial ovarian cancer (odds ratio [OR] per 50% higher odds liability: 1.10, 95% CI 1.06–1.15; P = 6.94 × 10−7) and suggestive evidence that lifetime smoking exposure was associated with an increased risk of invasive epithelial ovarian cancer (OR per unit increase in smoking score: 1.36, 95% CI 1.04–1.78; P = 0.02). In analyses examining histotypes and low malignant potential tumours, the strongest associations found were between height and clear cell carcinoma (OR per SD increase: 1.36, 95% CI 1.15–1.61; P = 0.0003); age at natural menopause and endometrioid carcinoma (OR per year later onset: 1.09, 95% CI 1.02–1.16; P = 0.007); and genetic liability to polycystic ovary syndrome and endometrioid carcinoma (OR per 50% higher odds liability: 0.89, 95% CI 0.82–0.96; P = 0.002). There was little evidence for an association of genetic liability to type 2 diabetes, parity, or circulating levels of 25-hydroxyvitamin D and sex hormone binding globulin with ovarian cancer or its subtypes. The primary limitations of this analysis include the modest statistical power for analyses of risk factors in relation to some less common ovarian cancer histotypes (low grade serous, mucinous, and clear cell carcinomas), the inability to directly examine the association of some ovarian cancer risk factors that did not have robust genetic variants available to serve as proxies (e.g., oral contraceptive use, hormone replacement therapy), and the assumption of linear relationships between risk factors and ovarian cancer risk. Conclusions Our comprehensive examination of possible aetiological drivers of ovarian carcinogenesis using germline genetic variants to proxy risk factors supports a role for few of these factors in invasive epithelial ovarian cancer overall and suggests distinct aetiologies across histotypes. The identification of novel risk factors remains an important priority for the prevention of epithelial ovarian cancer

Comparative evaluation of IS6110 PCR via conventional methods in rapid diagnosis of new and previously treated cases of extrapulmonary tuberculosis

ÖZET Yeni ve önceden tedavi edilmiş ekstrapulmoner tüberkülozlu hastaların hızlı tanısında IS6110 ile konvansiyonel yöntemlerin karşılaştırılmalı değerlendirilmesi Gelişmekte olan ülkelerde ekstrapulmoner tüberküloz (EPTB) tanısı önemli bir problemdir. EPTB&apos;de, az sayıda basil içerme özelliği, yetersiz miktarda örnek gibi birçok sorun bulunmaktadır. Bütün bu kısıtlamalar, konvansiyonel bakteriyolojik tekniklerin EPTB tanısına düşük katkısına neden olmaktadır. Nükleik asit amplifikasyon yöntemleri, mikobakteriyel DNA&apos;nın saptanması amacıyla geliştirilen hızlı ve duyarlı tekniklerdir. Mycobacterium tuberculosis complex&apos;in spesifik genomunda yer alan &quot;insertion sequence&quot; IS6110&apos;a ait 123bp&apos;nin DNA fragmanı, EPTB&apos;nin hızlı tanısı amacıyla polimeraz zincir reaksiyonu (PCR) ile çoğaltıldı. Bu çalışmada, yeni ve önceden tedavi edilmiş EPTB&apos;li hastaların hızlı tanısında IS6110 PCR ile konvansiyonel yöntemler karşılaştırıldı. EPTB şüpheli hastalardan 450 örnek toplandı ve Mycobacteria için Zeihl Neelson (ZN) boyama ve M. tuberculosis için BACTEC kültürü yapıldı. Bütün örnekler ayrıca, M. tuberculosis complex&apos;in insertion element IS6110&apos;un 123bp fragmanını hedefleyen primerlerle PCR amplifikasyonu ile IS6110 için çalışıldı. Testler arasında duyarlılık bakımından anlamlı fark saptandı. Dört yüz elli örnek . Bununla birlikte, testler arasında spesifisite bakımından anlamlı fark yoktu (p&gt; 0.05). IS6110 PCR&apos;nin hem yeni hem de önceden tedavi edilmiş hastalarda, yayma mikroskopi ve BACTEC kültüründen daha duyarlı olduğunu bulduk. IS6110 PCR, yeni ve önceden tedavi edilmiş EPTB&apos;li hastaların tanısında kullanışlı olabilir. Şüpheli EPTB&apos;li hastaların tedavi kararında fayda sağlayabilir. Anahtar Kelimeler: Tüberküloz, ekstrapulmoner tüberküloz, polimeraz zincir reaksiyonu, IS6110. Yazışma Adresi (Address for Correspondence): Dr. Surya KANT, Chhatrapati Shahu Ji Maharaj Medical University UP (Erstwhile King George Medical College), LUCKNOW -INDIA e-mail: [email protected] Tuberculosis (TB) continues to be a major global public health problem. Incidence of extrapulmonary tuberculosis (EPTB) is on increasing worldwide as well as in India (1,2). EPTB compromises 20% of all TB cases in India (3). Diagnosis of EPTB in different clinical presentations has been always as challenge. Smear microscopy and culture lack of sensitivity in EPTB case and culture (solid and liquid media) also takes at least two to four weeks for grow of mycobacteria. A study has reported smear positive is around 10-37% of the patients and mycobacterial culture is positive in variable proportional 12-80% in different biological specimens (3). Studies from many laboratories around the global were using primers most commonly targeting the IS6110 insertion element (4-9). The detection of the IS6110 insertion element present in form of multiple copies to detect of Mycobacterium tuberculosis complex but not other mycobacterial species (9-11). Polymerase chain reaction (PCR) using IS6110 insertion sequences as the target, has potential to conquer limitation of conventional method and to established as rapid, sensitive technique for detecting DNA of M. tuberculosis in different clinical specimens from respiratory and non respiratory sites MATERIALS and METHODS Study Design The study was performed prospectively in a blinded manner. Clinical Specimens and Data Collection 2-5 mL of specimens was collected from 450 specimens, non-repeated specimens from suspected cases of extrapulmonary tuberculosis. The specimens were included as Lymph Node Aspirate and Cold Abscesses, Pleural fluid, C.S.F, Synovial Fluid, Ascetic Fluid, Urine, Gastric Aspirate, Pus, Bone Marrow, Wound and Pus swab and Others specimens (biopsies tissues). All specimens were kept in ice box and transported Mycobacteriology Laboratory, Department of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India for smear examination by ZN Staining, BACTEC Culture and PCR test. All patients were signed with due informed consent of the patients from indoor and outward wards of Department of Pulmonary Medicine, Chhatrapati Shahuji Maharaj Medical University, Lucknow, India and Mycobacteriology Laboratory, Department of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India during Jan 2009 to Dec 2010. The clinical history regarding, present and past history of antitubercular treatment (ATT); family history of tuberculosis and any other associated disease were taken in prescribed Performa. Microbiological Analysis of Extra Pulmonary Specimens Specimens was divided in to two part one part was kept at -20 for PCR till processing and another part was processed for mycobacterial smear preparation and BACTEC culture. Smears were stained with Ziehl Neelsen (ZN) method and examined for acid-fast bacilli (AFB) (21). BACTEC vials were incubated and interpreted as per Becton Dickinson (BD, Sparks, MD, USA) manual instructions (22). NAP (p-nitro-α-acetylamino-β-hydroxy propiophenone) (Becton Dickinson, Sparks, MD, USA), identification was done to differentiate M. tuberculosis form non tuberculous mycobacteria (22). A decrease or unchanged growth index (GI) in nap vial indicated presence of M. tuberculosis complex (MTBC), while an increase in GI indicated the presence of Mycobacterium other than tuberculosis (MOTT). Standard H 37 Rv strain of M. tuberculosis complex was used as positive control. Extraction of DNA Extraction of DNA was done by the CTAB (cetyl-trimethyl-ammonium bromide) -phenol chloroform extraction method (23). Specimens were centrifuged at 10.000 rpm for 10 min. The supernatant was discarded and the pellet suspended in 567 µL of TE (Tris EDTA, pH 7.4) buffer, 30 µL 10% SDS (sodium dodecyl sulfate) and 3 µL proteinase K (20 mg/mL), mixed and incubated at 37°C for 1 hour. After incubation, 100 µL of 5 M NaCl and 80 µL of high-salt CTAB buffer (containing 4 M NaCl, 1.8% CTAB was added and mixed followed by incubation at 65°C for 10 min. An approximate equal volume (0.7-0.8 µL) of chloroform-isoamyl alcohol (24.1) was added, mixed thoroughly and centrifuged for 4-5 min in a microcentrifuge at 12.000 rpm. The aqueous viscous supernatant was carefully decanted and transferred to a new tube. An equal volume of phenol: chloroform-isoamyl alcohol (1:1) was added followed by a 5 min spin at 12.000 rpm. The supernatant was separated and then mixed with 0.6 volume of isopropanol to get a precipitate. The precipitated nucleic acids were washed with 75% ethanol, dried and re-suspended in 100 µL of TE buffer. Primer and IS6110 PCR The amplification reaction was performed in a final volume of 20 µL. the reaction mixture contained 10 µL Pyrostart Fast PCR Master Mix 2X (dNTP, Taq polymerase with Mgcl 2 , Fermentas, India), 1 µL (10 pmole) of each primer, 3 µL water (nuclease free) and 5 µL of extracted DNA. The oligonucleotide primers used were IS1 and IS2, are: 5&apos;-CCT GCG AGC GTA GGC GTC GG3&apos; and 5&apos; CTC GTC CAG CGC CGC TTC GG 3&apos; respectively (SBS Gentech Co. Ltd) (24). These primers amplified a target fragment at 123 base pairs (bp) from the insertion, M. tuberculosis sequence element IS6110. The PCR amplification was done in thermal cycler (MJ Research, PTC-100, GMI, Inc, USA), which involved 40 cycles of denaturation at 94°C for 2 minute, annealing of primers at 68°C for 2 minute, and primer extension at 72°C for 1 minute. The amplified products were separated on 2% agarose gels, visualized on a UV-light transilluminator (Bangalore Genei, Bangalore, India). The presence of 123bp fragment indicate as positive test as M. tuberculosis complex. The positive controls included the DNA of H37Rv strain. Negative control included PCR grade water Statistical Analysis Data were analyzed using SPSS 15.0 (Statistical Package for the Social Sciences, Chicago, IL, USA) for Maurya AK, Kant S, Nag VL, Kushwaha RAS, Kumar M, Dhole TN. 215 Tüberküloz ve Toraks Dergisi 2011; 59(3): 213-220 Windows. The significance of difference was taken as significance value (p&lt; 0.05).Sensitivity was calculated as [Tp/(Tp + Fn)] x 100; specificity was calculated as [Tn/(Tn + Fp)] x 100; Tp = total number of positives; Tn = total number of negatives; Fp = total number of false positive, Fn = total number of false negative; respectively. RESULTS Specimen&apos;s Characterization of Extrapulmonary Tuberculosis Cases During the two year study period, 470 clinical specimens were strong clinical suspicion of extrapulmonary tuberculosis were subjected from tertiary care hospitals and all mention test were performed. Out of these, 20 specimens found to be contaminated in BACTEC culture. 450 specimens of results were used in the study. Out of 450 specimens, 153 (34%) lymph node aspirate and cold abscesses, 58 (12.8%) pleural fluid, 44 (9.7%) cerebrum spinal fluid (CSF), 48 (10.7%) urine, 31(6.8%) ascetic fluid, 26 (5.8%) pus, 22 (4.9%) wound and pus swab, 16 (3.5%) gastric aspirate, 10 (2.2%) bone marrow, 10 (2.2%) synovial fluid and 30 (6.7%) others specimens (biopsies tissues). Out of 450 patients, 320 (71.1%) patients were males and 130 (28.9%) females. The mean age of all patients was 39.8 ± 16.1 years. Patients 25-44 years of age accounted for 45% of the total cases. Out of 450 cases, 328 (72.8%) were new cases and 122 (22.2%) were previously treated cases of EPTB. Detection Rate of M. tuberculosis by IS6110 PCR, BACTEC Culture and ZN Smear Microscopy According to New Cases and Previously Treated Cases All specimens were colleted from suspected case of extra pulmonary tuberculosis were found to be AFB positive were 60 (13.4%). On the basis of cases, we found that sensitivity of AFB staining on EPTB were 37 (11.2%) in new cases and 23 (18.8%) in previously treated cases. The sensitivity of AFB staining was higher in comparison to previously treated cases. Overall detection rate of M. tuberculosis by AFB Staining was 60 (13.4%). The detection of M. tuberculosis by BACTEC culture was 202 (45%). Results of BACTEC culture according to cases, 151 (46.03%) were in new cases and 51 (41.8%) were in previously treated cases. We found that sensitivity of BACTEC culture was higher in new cases. All culture isolates obtained were confirmed as mycobacteria with biochemical tests mentioned. Using IS 6110 PCR, 283 (61.8%) were positive for IS6110 PCR for M. tuberculosis. 203 (61.8%) were positive in new cases and 80 (65.5%) were positive in previously treated cases. We found that sensitivity of IS6110 PCR was higher in previously treated cases. Overall comparison of tests, IS6110 PCR was found to have much higComparative evaluation of IS6110 PCR via conventional methods in rapid diagnosis of new and previously treated cases of extrapulmonary tuberculosis 216 Tüberküloz ve Toraks Dergisi 2011; 59(3): 213-220 Comparison of Sensitivity of IS6110 PCR Test Via Others Conventional Tests According to New Cases and Previously Treated Cases IS6110 PCR test was found to be much more sensitive than ZN staining and BACTEC culture results individually as well as in combination are shown in 217 Tüberküloz ve Toraks Dergisi 2011; 59(3): 213-220 DISCUSSION Tuberculosis (TB) is a major public health dilemma in India. India is the highest TB burden country accounting for one fifth of the global incidence. Global annual incidence estimate is 9.4 million cases out of which it is estimated that 1.98 million cases are from India (26). In India, EPTB comprises 20% of all TB cases. Its prevalence in the country varies between 8.3-13.1% in different districts according to cohort analysis by Central TB Division, Ministry of Health and Family Welfare in 2002 (27,28). The diagnosis of extrapulmonary tuberculosis is till now challenging for diagnostic routine laborites. Numeric reasons are showing that, lack of adequate specimens amounts or volumes; distribute of the specimens for different diagnostic tests (histology/cytology, biochemical analysis, microbiology, and PCR), non-uniform distribution of microorganisms; paucibacillary nature of the specimens; presence of inhibitors that undermine the performance of nucleic acid amplification-based techniques; and the lack of an efficient sample processing technique universally applicable on all types of extrapulmonary samples (29). The poor performance of conventional M. tuberculosis detection techniques, based on microscopic examination of Ziehl-Neelsen stained and culture of M. tuberculosis (LJ Medium and BACTEC Radiometric culture) are still in widespread use for diagnostic purposes, still though they fail to provide the required sensitivity and specificity. The PCR test would be particularly useful in the diagnosis of EPTB where conventional microbiological techniques for M. tuberculosis are showing poor performance of sensitivity. The specificity, sensitivity and speed of PCR test in diagnosis of M. tuberculosis infection shown in this study should encourage the use of this method in routine diagnosis of EPTB. Previously studies shown the success of microscopy is highly variable from 22% to 96% and most authors rate it at round 60% (30-32). Our results shown that sensitivity of smear microscopy was 13.7% and specificity was 100%. The sensitivity of microscopy depends on the clinical presentation and more than 10.000 bacilli per milliliter are necessary for secure microscopic positivity (33). Our studies shown that conventional bacteriological technique were positive in 202 (45%) specimens, where as IS6110 PCR showed that 283 (63%) specimens were positive for M. tuberculosis. The difference was found that to be statistical significant (p&lt; 0.05). Several studies have been reported on PCR to detect M. tuberculosis (34-39). The detection of the IS6110 insertion element present in multiple copies to detect M. tuberculosis complex, but not other mycobacterial species 218 Tüberküloz ve Toraks Dergisi 2011; 59(3): 213-220 tion and PCR results were positive but BACTEC culture was negative; these could be the presence of nonviable mycobacteria in the sample as patients were receiving antitubercular treatment. IS6110 PCR test is higher sensitivity than microscopy and the culture and could help in therapeutic decision for patients with clinical suspicion of EPTB. CONCLUSION IS6110 PCR test for DNA specific M. tuberculosis may be hopes of a rapid and accurate diagnostic test for EPTB and it will help where conventional diagnosis fails and provisional diagnosis of tuberculosis is made on the basis of clinical presentation and histology/cytology examination without evidence of AFB. IS6110 PCR may be great potential to improve the clinician vision for the early diagnosis, treatment and prevention of EPTB. ACKNOWLEDGEMEN

Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk

BACKGROUND: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. METHODS: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). RESULTS: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. CONCLUSION: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. IMPACT: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization

Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

BACKGROUND: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. METHODS: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. RESULTS: The most significant global associations for all genes in the pathway were seen in endometrioid (p = 0.082) and clear cell (p = 0.083), with the most significant gene level association seen with TGFBR2 (p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 (p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA (p = 0.035, endometrioid and mucinous), LGALS1 (p = 0.03, mucinous), STAT5B (p = 0.022, clear cell), TGFBR1 (p = 0.021 endometrioid) and TGFBR2 (p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). CONCLUSIONS: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients

Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR=1.33, p=4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR=1.07, p=0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR=0.90, p=0.00033; rs927062, OR =0.94, p=0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations

Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer.

BACKGROUND: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. METHODS: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. RESULTS: The most significant global associations for all genes in the pathway were seen in endometrioid ( p = 0.082) and clear cell ( p = 0.083), with the most significant gene level association seen with TGFBR2 ( p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 ( p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA ( p = 0.035, endometrioid and mucinous), LGALS1 ( p = 0.03, mucinous), STAT5B ( p = 0.022, clear cell), TGFBR1 ( p = 0.021 endometrioid) and TGFBR2 ( p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). CONCLUSIONS: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients

Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry

Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes. We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry. In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 × 10 ) and AC058822.1 (P = 1.47 × 10 ), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C. Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 × 10 ), demonstrating the importance of diversifying study cohorts. [Abstract copyright: © 2023. The Author(s).

PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS

Background: The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study.Methods: We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T&gt;G and c.3113G&gt;A, CHEK2c.349A&gt;G, c.538C&gt;T, c.715G&gt;A, c.1036C&gt;T, c.1312G&gt;T, and c.1343T&gt;G and ATM c.7271T&gt;G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant.Results: For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10−5), PALB2 c.3113G&gt;A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10−8) and ATM c.7271T&gt;G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A&gt;G OR 2.26 (95% CI 1.29 to 3.95), c.1036C&gt;T OR 5.06 (95% CI 1.09 to 23.5) and c.538C&gt;T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T&gt;G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G&gt;T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants.Conclusions: This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.</p