dataesr/scientific-paragraphs-categorization huggingface dataset:
We carried out bioinformatic annotations for each significantly associated gene. Four open-source databases were queried for prior evidence of a causal role of the genes in breast cancer pathology specifically as well as any cancer pathology. First, the ClinVar database was used to identify any putative pathogenic, single-gene variants reported previously in the context of the phenotypes of interest. The ClinVar database was queried on the 1st of March 2021. Pathogenic, single-gene ClinVar variant entries with at least one star review status were classified as supportive evidence. Second, the aggregated gene-disease database MalaCards  [27]  was used to identify any significant correlation of genes and phenotypes of interest based on 68 different data sources and utilizing NLP (Natural Language Processing) algorithms to include evidence from nonstructured data sources like research publications.
Supportive evidence of causal role of genes was defined as a MalaCards search relevance score over 1. The MalaCard database was queried on the 1st of March 2021. Third, the expert-curated Genetics Home Reference data was queried for all genes of interest and examined for evidence of causal role in breast cancer or any cancer. The queried data version was published on the 28th of July 2020. And fourth, investigating possible roles as driver genes in breast cancer and cancer pathogenicity, we queried the COSMIC Cancer Gene Census data (version 92) which classifies genes as either (1) TIER1: genes with strong evidence of causal role promoting cancer such as documented relevance in cancer and oncogenic mutations, (2) TIER2: genes with substantial indications to play a role in cancer etiology, and (3) untiered genes: genes with no substantial evidence of a causal role.
Gene-based aggregation can help identify the causal genes To assess whether the gene-based approach can help highlight biologically plausible gene candidates, we assessed whether other evidence, such as genetic epidemiological studies or cell models, supports a role for the significantly associated genes in cancer. We queried different public databases for links to breast cancer and other cancer types for the 14 genes found to be associated with breast cancer in the all-European meta-analysis. Two genes, MAP3K1 and FGFR2, in addition to being previously identified in breast cancer-associated genetic region in GWAS (see Table  2 ), are both classified as TIER1 cancer-driving genes in COSMIC Cancer Gene Census. Thus, there is strong evidence that somatic mutations in both genes have a functional involvement in cancer etiology.
To search for previous causal evidence of germline mutations in associated genes, we queried ClinVar, Genetic Home Reference, and MalaCards databases-the last two being an expert-curated genedisease database and an aggregation database of 68 data sources, respectively. Five genes were implicated Table  1  Meta-analysis hits in samples of European ancestry. Results for significant (q < 0. 05) gene associations from the meta-analysis of 12 cohorts of European ancestry. Genes with overlapping coding and/or regulatory regions are summarized as a single locus defined as the intersection of all included genetic regions. Overlap with single-marker association results from Michailidou et al. [10]  are also shown, with new associations identified for FMNL3 and AC058822. In addition, the gene ABRAXAS1 codes for a subunit of the BRCA1-A complex  [31].
Discussion We report the results of a gene-based association analysis in the BCAC resource. Adopting a recently proposed aggregation method that combines variants in coding and regulatory regions, we were able to replicate and extend previously reported findings. This aggregation method Table  2  Support for a Role in Cancer for the 14 Associated Genes. Prior supportive evidence for genes associated with breast cancer in the aggregation test was based on presence of pathogenic cancer mutations in those, based on ClinVar and curated genetic reference database Genetics Home Reference and aggregation database Malacards. In addition, hit genes were queried in the COSMIC Cancer Gene Census database Gene AC058822. 1 was not present in the queried databases a ABRAXAS1 was additionally queried using the alias FAM175A helps identify target genes of previously reported singlemarker associations and uncovers additional associations that were missed by other methods.
No markers in the proximity of this gene were found to be associated with breast cancer in the 2017 GWAS in the same dataset. Features of the method that may facilitate discoveries beyond those identified by other approaches include (i) a reduction of multiple testing burden, (ii) boosting signals by aggregating over all genetic regions affecting individual genes expression and function, (iii) inclusion of lowfrequency variants often underpowered in other studies, and (iv) ability to synthesize evidence for genetic risk factors in different ancestries regardless of differences in non-disease-associated variational background. The inclusion of samples of non-European ancestry in genetic studies can advance our understanding of genetic disease landscapes  [8]. However, differences between populations in terms of allele frequencies and linkage disequilibrium can lead to heterogeneity and false positive associations in single-marker association analyses.
Third, we were not always able to narrow down associations to a single target gene in loci due to overlapping genetic features. This limitation is affected by the LD structure in a specific region and the amount of prior information available in form of eQTL data and regions of overlapping transcripts. Fourth, although we are able to find plausible target genes applying this method to samples of diverse ancestry, there is potential for further optimisation. Regulatory features for genes have been identified using GTEx data, which predominantly is derived from European ancestry samples. Additionally, variants are weighted using Phred-scaled EigenPC pathogenicity scores  [21]. These scores are derived using unsupervised learning on a labeled training dataset predominantly based on samples of European descent.
Fifth, the current implementation of the method is computationally demanding but nonetheless able to analyze large sample sets (here over 140,000 samples). Sixth, our analysis did not consider different transcripts of genes so our findings are limited to the assigned major transcript. And lastly, the optimal aggregate methods depend on the genetic architecture at a given locus. We used SKAT-O a unified test to capture a range of different architectures. However, the choice of method may impact on the results.
Conclusions Our findings show that usage of extended gene aggregation methods covering coding and regulatory regions in addition to standard single-marker tests (i. e. , GWAS) have the potential to discover novel associations in available datasets. This study helps uncover the role of low-frequency genetic variation in breast cancer susceptibility and empowers gene discovery in ancestrally diverse cohorts. and innovation programme (Grant agreement No. 948561). BCAC is funded by the European Union's Horizon 2020 Research and Innovation Programme (grant numbers 634935 and 633,784 for BRIDGES and B-CAST respectively), and the PERSPECTIVE I&I project, funded by the Government of Canada through Genome Canada and the Canadian Institutes of Health.
Acknowledgements We would like to thank  Dr. Mario Parreno Centeno  for insightful comments regarding the COSMIC database and  Dr. Arthur Gilly  for sharing Phred-scaled EIGEN PC scores. We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians, and administrative staff who have enabled this work to be carried out. ABCS thanks the  Blood bank Sanquin , The Netherlands. ABCTB Investigators:  Christine Clarke ,  Deborah Marsh ,  Rodney Scott ,  Robert Baxter ,  Desmond Yip ,  Jane Carpenter ,  Alison Davis ,  Nirmala Pathmanathan ,  Peter Simpson ,  J. Dinny Graham ,  Mythily Sachchithananthan. Samples are made available to researchers on a non-exclusive basis. The ACP study wishes to thank the participants in the Thai Breast Cancer study. Special thanks also go to the  Thai Ministry of Public Health (MOPH) , doctors and nurses who helped with the data collection process.
A full list of California Teachers Study (CTS) team members is available at https:// www. calte acher sstudy. org/ team. DIETCOM-PLYF thanks the patients, nurses, and clinical staff involved in the study. The DietCompLyf study was funded by the  charity Against Breast Cancer  (Registered Charity Number  1121258 ) and the  NCRN. We thank the participants and the investigators of  EPIC (European Prospective Investigation into Cancer and Nutrition). ESTHER thanks  Hartwig Ziegler ,  Sonja Wolf ,  Volker Hermann ,  Christa Stegmaier , and  Katja Butterbach. FHRISK  and  PROCAS thank NIHR  for funding. GC-HBOC thanks  Stefanie Engert ,  Heide Hellebrand ,  Sandra Hospital. COLBCCC is supported by the  German Cancer Research Center (DKFZ) ,  Heidelberg, Germany. Diana Torres  was in part supported by a postdoctoral fellowship from the  Alexander von Humboldt Foundation.
The opinions, findings, and conclusions expressed herein are those of the author(s) and do not necessarily reflect the official views of the  State of California, Department of Public Health , the  National Cancer Institute , the  National Institutes of Health , the  Centers for Disease Control and Prevention  or their Contractors and Subcontractors, or the  Regents of the University of California , or any of its programs. The University of Westminster curates the DietCompLyf database funded by  Against Breast Cancer Registered Charity  No. 1121258  and the  NCRN. The coordination of EPIC is financially supported by the  European Commission (DG-SANCO)  and the  International Agency for Research on Cancer. The national cohorts are supported by:  Ligue Contre le Cancer ,  Institut Gustave Roussy, Mutuelle Générale de l'Education Nationale ,  Institut National de la Santé et de la Recherche Médicale (INSERM) (France) ;  German Cancer Aid ,  German Cancer Research Center (DKFZ) ,  Federal Ministry of Education and Research (BMBF) (Germany) ; the  Hellenic Health Foundation , the  Stavros Niarchos Foundation (Greece) ;  Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy) ;  Dutch Ministry of Public Health, Welfare and Sports (VWS) ,  Netherlands Cancer Registry (NKR) ,  LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland) ,  World Cancer Research Fund (WCRF) ,  Statistics Netherlands  (The Netherlands);  Health Research Fund (FIS) ,  PI13/00061  to Granada,  PI13/01162  to  EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC  ( RD06/0020 ) (Spain);  Cancer Research UK  ( 14 , 136  to  EPIC-Norfolk ;  C570/A16491  and  C8221/A19170  to  EPIC-Oxford ),  Medical Research Council  (1, 000 , 143  to  EPIC-Norfolk ,  MR/M012190/1  to  EPIC-Oxford) (United Kingdom ).
The GESBC was supported by the  Deutsche Krebshilfe  e. V. [70492] and the  German Cancer Research Center (DKFZ). The HABCS study was supported by the  Claudia von Schilling Foundation for Breast Cancer Research , by the  Lower Saxonian Cancer Society , and by the  Rudolf Bartling Foundation. The HEBCS was financially supported by the  Helsinki University Hospital Research Fund , the  Sigrid Juselius Foundation  and the  Cancer Foundation Finland. The HERPACC was supported by  MEXT Kakenhi  (No. 170150181  and  26 , 253 , 041 ) from the  Ministry of Education, Science, Sports, Culture and Technology of Japan , by a  Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control  from  Ministry Health, Labour and Welfare of Japan , by  Health and Labour Sciences Research Grants for Research on Applying Health Technology from Ministry Health, Labour and Welfare of Japan , by  National Cancer Center Research and Development Fund, and "Practical Research for Innovative Cancer Control  ( 15ck0106177h0001  and  20ck0106553 )" from  Japan Agency for Medical Research and development, AMED , and  Cancer Bio Bank Aichi.
The HMBCS was supported by a grant from the  Friends of Hannover Medical School  and by the  Rudolf Bartling Foundation. The HUBCS was supported by a grant from the  German Federal Ministry of Research and Education  ( RUS08/017 ), B. M. was supported by grant  17-44-020 , 498 ,  17-29-06 , 014  of the  Russian Foundation for Basic Research , D. P. was supported by grant  18-29-09 , 129  of the  Russian Foundation for Basic Research , E. K was supported by the program for support the bioresource collections  №007-030 , 164/2  and by the megagrant from the  Government of Russian Federation  ( 2020-220-08-2197 ), and study was performed as part of the assignment of the  Ministry of Science and Higher Education of Russian Federation  ( №AAAA-A16-116 , 020 , 350 , 032-1 ). Financial support for KARBAC was provided through the regional agreement on medical training and clinical research (ALF) between  Stockholm County Council and Karolinska Institutet , the  Swedish Cancer Society , The Gustav V Jubilee foundation and Bert von Kantzows foundation.
The KARMA study was supported by  Märit and Hans Rausings Initiative Against Breast Cancer. The KBCP was financially supported by the special Government Funding (VTR) of  Kuopio University Hospital  grants,  Cancer Fund of North Savo , the  Finnish Cancer Organizations , and by the strategic funding of the  University of Eastern Finland. The KOHBRA study was partially supported by a grant from the  Korea Health Technology R&D Project  through the  Korea Health Industry Development Institute (KHIDI) , and the  National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea  ( HI16C1127 ; 1,020,350; 1,420,190). LMBC is supported by the " Stichting tegen Kanker ". DL is supported by the  FWO. The MABCS study is funded by the  Research Centre for Genetic Engineering and Biotechnology "Georgi D.
The MMHS study was supported by  NIH  grants  CA97396 ,  CA128931 ,  CA116201 ,  CA140286  and  CA177150. MSKCC is supported by grants from the  Breast Cancer Research Foundation and Robert and Kate Niehaus Clinical Cancer Genetics Initiative. MYBRCA is funded by research grants from the  Wellcome Trust  ( v203477/ Z/16/Z ), the  Malaysian Ministry of Higher Education  ( UM. C/HlR/MOHE/06 ) and  Cancer Research Malaysia. MYMAMMO is supported by research grants from  Yayasan Sime Darby LPGA Tournament and Malaysian Ministry of Higher Education  ( RP046B-15HTM ). The NBCS has received funding from the  K. G. Jebsen Centre for Breast Cancer Research ; the  Research Council of Norway  grant  193 , 387/V50  (to  A-L Børresen-Dale  and  V. N. Kristensen ) and grant  193 , 387/H10  (to  A-L Børresen-Dale  and  V.
The  Carolina Breast Cancer Study (NCBCS)  was funded by  Komen Foundation , the  National Cancer Institute  ( P50 CA058223 ,  U54 CA156733 ,  U01 CA179715 ), and the  North Carolina University Cancer Research Fund. The NGOBCS was supported by the  National Cancer Center Research and Development Fund (Japan). The NHS was supported by  NIH  grants  P01 CA87969 ,  UM1 CA186107 , and  U19 CA148065. The NHS2 was supported by  NIH  grants  UM1 CA176726  and  U19 CA148065. The ORIGO study was supported by the  Dutch Cancer Society  ( RUL 1997-1505 ) and the  Biobanking and Biomolecular Resources Research Infrastructure  ( BBMRI-NL CP16 ). The PBCS was funded by  Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. Genotyping for PLCO was supported by the  Intramural Research Program  of the  National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics.
The PLCO is supported by the  Intramural Research Program of the Division of Cancer Epidemiology and Genetics  and supported by contracts from the  Division of Cancer Prevention, National Cancer Institute, National Institutes of Health. The POSH study is funded by  Cancer Research UK  (grants  C1275/A11699 ,  C1275/C22524 ,  C1275/A19187 ,  C1275/A15956  and  Breast Cancer Campaign   2010PR62 ,  2013PR044. The SBCGS was supported primarily by  NIH  grants  R01CA64277 ,  R01CA148667 ,  UMCA182910 , and  R37CA70867. Biological sample preparation was conducted the  Survey and Biospecimen Shared Resource , which is supported by  P30 CA68485. The scientific development and funding of this project were, in part, supported by the  Genetic Associations and Mechanisms in Oncology (GAME-ON)  Network  U19 CA148065.
The SBCS was supported by  Sheffield Experimental Cancer Medicine Centre and Breast Cancer Now Tissue Bank. SEARCH is funded by  Cancer Research UK  [ C490/A10124 ,  C490/A16561 ] and supported by the  UK National Institute for Health Research Biomedical Research Centre  at the  University of Cambridge. The  University of Cambridge  has received salary support for PDPP from the  NHS in the East of England through the Clinical Academic Reserve. SEBCS was supported by the  BRL (Basic Research Laboratory ) program through the  National Research Foundation of Korea  funded by the  Ministry of Education, Science and Technology  ( 2012-0 , 000 , 347 ). SGBCC is funded by the  National Research Foundation Singapore ,  NUS  start-up Grant,  National University Cancer Institute Singapore (NCIS)   Centre Grant ,  Breast Cancer Prevention Programme, Asian Breast Cancer Research Fund  and the  NMRC   Clinician Scientist Award (SI Category ).
Population-based controls were from the  Multi-Ethnic Cohort (MEC) funded by grants from the  Ministry of Health, Singapore, National University of Singapore and National University Health System, Singapore. The Sister Study (SISTER) is supported by the  Intramural Research Program  of the  NIH, National Institute of Environmental Health Sciences  ( Z01-ES044005  and  Z01-ES049033 ). The  Two Sister Study  ( 2SISTER ) was supported by the  Intramural Research Program  of the  NIH, National Institute of Environmental Health Sciences  ( Z01-ES044005  and  Z01-ES102245 ), and, also by a grant from  Susan G. Komen for the Cure , grant  FAS0703856. SKKDKFZS is supported by the  DKFZ. The SMC is funded by the  Swedish Cancer Foundation  and the  Swedish Research Council  ( VR 2017-00 , 644 ) grant for the  Swedish Infrastructure for Medical Population-based Life-course Environmental Research (SIMPLER).
The TNBCC was supported by: a  Specialized Program of Research Excellence (SPORE) in Breast Cancer  ( CA116201 ), a grant from the  Breast Cancer Research Foundation , a generous gift from the  David F. and Margaret T. Grohne Family Foundation. The TWBCS is supported by the  Taiwan Biobank  project of the  Institute of Biomedical Sciences, Academia Sinica, Taiwan. The UCIBCS component of this research was supported by the  NIH  [ CA58860 ,  CA92044 ] and the  Lon V Smith Foundation  [LVS39420]. The UKBGS is funded by  Breast Cancer Now  and the  Institute of Cancer Research (ICR), London. ICR  acknowledges  NHS  funding to the  NIHR Biomedical Research Centre. The UKOPS study was funded by  The Eve Appeal (The Oak Foundation ) and supported by the  National Institute for Health Research University College London Hospitals Biomedical Research Centre  with contribution to author's salary through MRC core funding  MC_UU_00004/01.
The  USRT Study  was funded by  Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The WAABCS study was supported by grants from the  National Cancer Institute of the National Institutes of Health  ( R01 CA89085  and  P50 CA125183  and the  D43 TW009112  grant),  Susan G. Komen  ( SAC110026 ), the  Dr. Ralph and Marian Falk Medical Research Trust , and the  Avon Foundation for Women.
Funding This result is part of a project that has received funding from the  European Research Council (ERC)  under the European Union's  Horizon 2020 research Research , the  Ministère de l'Économie et de l'Innovation du Québec through Genome Québec , the  Quebec Breast Cancer Foundation. The  EU Horizon 2020 Research and Innovation Programme  funding source had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Additional funding for BCAC is provided via the  Confluence  project which is funded with intramural funds from the  National Cancer Institute Intramural Research Program, National Institutes of Health. Genotyping of the OncoArray was funded by the  NIH  Grant  U19 CA148065 , and  Cancer UK  Grant  C1287/A16563  and the  PERSPECTIVE  project supported by the  Government of Canada through Genome Canada  and the  Canadian Institutes of Health Research  (grant  GPH-129344 ), and the  Ministère de l'Économie, Science et Innovation du Québec through Genome Québec  and the  PSRSIIRI-701  grant, and the  Quebec Breast Cancer Foundation.
Funding for iCOGS came from: the  European Community 's  Seventh Framework Programme  under grant agreement n°  223 , 175  ( HEALTH-F2-2009-223 , 175 ) (COGS),  Cancer Research UK  ( C1287/A10118 ,  C1287/A10710 ,  C12292/A11174 ,  C1281/A12014 ,  C5047/A8384 ,  C5047/A15007 ,  C5047/A10692 ,  C8197/A16565 ), the  National Institutes of Health  ( CA128978 ) and  Post-Cancer GWAS initiative  ( 1U19 CA148537 ,  1U19 CA148065  and  1U19 CA148112 -the  GAME-ON initiative ), the  Department of Defence  ( W81XWH-10-1-0341 ), the  Canadian Institutes of Health Research (CIHR)  for the  CIHR Team in Familial Risks of Breast Cancer , and  Komen Foundation  for the Cure, the  Breast Cancer Research Foundation , and the  Ovarian Cancer Research Fund. The BRIDGES panel sequencing was supported by the  European Union   Horizon 2020 research and innovation program  BRIDGES (grant number,  634 , 935 ) and the  Wellcome Trust  ( v203477/Z/16/Z ).
The ABCS study was supported by the  Dutch Cancer Society  [grants NKI 2007-3839; 2009 4363]. The  Australian Breast Cancer Tissue Bank (ABCTB)  was supported by the  National Health and Medical Research Council of Australia , The  Cancer Institute NSW  and the  National Breast Cancer Foundation. The ACP study is funded by the  Breast Cancer Research Trust, UK. KM and AL are supported by the  NIHR Manchester Biomedical Research Centre , the  Allan Turing Institute  under the  EPSRC grant   EP/N510129/1. The AHS study is supported by the intramural research program of the  National Institutes of Health , the  National Cancer Institute  (grant number  Z01-CP010119 ), and the  National Institute of Environmental Health Sciences  (grant number  Z01-ES049030 ). The work of the BBCC was partly funded by  ELAN-Fond of the University Hospital of Erlangen.
The BBCS is funded by  Cancer Research UK  and  Breast Cancer Now and acknowledges NHS  funding to the  NIHR Biomedical Research Centre , and the  National Cancer Research Network (NCRN). For the BCFR-NY, BCFR-ON, BCFR-PA, BCFR-UT this work was supported by grant  UM1 CA164920  from the  National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the  National Cancer Institute  or any of the collaborating centers in the  Breast Cancer Family Registry (BCFR) , nor does mention of trade names, commercial products, or organizations imply endorsement by the  US Government  or the BCFR. The BCINIS study is supported in part by the  Breast Cancer Research Foundation (BCRF). The  BREast Oncology GAlician Network (BREOGAN)  is funded by  Acción Estratégica de Salud del Instituto de Salud Carlos III   FIS PI12/02125/Cofinanciado  and  FEDER PI17/00918 / Cofinanciado FEDER ;  Acción Estratégica de Salud del Instituto de Salud Carlos III FIS Intrasalud  ( PI13/01136 );  Programa Grupos Emergentes ,  Cancer Genetics Unit, Instituto de Investigacion Biomedica Galicia Sur.