{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,3,22]],"date-time":"2025-03-22T10:43:46Z","timestamp":1742640226892,"version":"3.37.3"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2018,9,18]],"date-time":"2018-09-18T00:00:00Z","timestamp":1537228800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","award":["R01HG008759"],"award-info":[{"award-number":["R01HG008759"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008339","name":"Department of Internal Medicine, University of Nebraska Medical Center","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008339","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006928","name":"Ohio State University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006928","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,11,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The intra-tumor heterogeneity is associated with cancer progression and therapeutic resistance, such as in breast cancer. While the existing methods for studying tumor heterogeneity only analyze variant allele frequency (VAF), the genotype of variant is also informative for inferring subclones, which can be detected by long reads or paired-end reads. We developed GenoClone to integrate VAF with the genotype of variant innovatively, so it showed superior performance of inferring the number of subclones, estimating the fractions of subclones and identifying somatic single-nucleotide variants composition of subclones. When GenoClone was applied to 389 TCGA breast cancer samples, it revealed extensive intra-tumor heterogeneity. We further found that a few somatic mutations were relevant to the late stage of tumor evolution, including the ones at the oncogene PIK3CA and the tumor suppress gene TP53. Moreover, 52 subclones that were identified from 167 samples shared high similarity of somatic mutations, which were clustered into three groups with the sizes of 24, 14 and 14. It is helpful for understanding the development of breast cancer in certain subgroups of people and the drug development for population level. Furthermore, GenoClone also identified the tumor heterogeneity in different aliquots of the same samples. The implementation of GenoClone is available at http:\/\/www.healthcare.uiowa.edu\/labs\/au\/GenoClone\/.<\/jats:p>","DOI":"10.1093\/bib\/bby084","type":"journal-article","created":{"date-parts":[[2018,8,22]],"date-time":"2018-08-22T15:17:05Z","timestamp":1534951025000},"page":"2306-2315","source":"Crossref","is-referenced-by-count":4,"title":["Revealing tumor heterogeneity of breast cancer by utilizing the linkage between somatic and germline mutations"],"prefix":"10.1093","volume":"20","author":[{"given":"Meng","family":"Zou","sequence":"first","affiliation":[{"name":"School of Mathematics and Statistics, Huazhong University of Science and Technology"}]},{"given":"Rui","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Statistics, University of Iowa"}]},{"given":"Kin Fai","family":"Au","sequence":"additional","affiliation":[{"name":"School of Mathematics and Statistics, Huazhong University of Science and Technology"},{"name":"Department of Biomedical Informatics, Ohio State University"}]}],"member":"286","published-online":{"date-parts":[[2018,9,18]]},"reference":[{"issue":"4260","key":"2020011102344135100_ref1","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1126\/science.959840","article-title":"The clonal evolution of tumor cell populations","volume":"194","author":"Nowell","year":"1976","journal-title":"Science"},{"issue":"7381","key":"2020011102344135100_ref2","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1038\/nature10762","article-title":"Clonal evolution in cancer","volume":"481","author":"Greaves","year":"2012","journal-title":"Nature"},{"issue":"5","key":"2020011102344135100_ref3","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1038\/nrc3261","article-title":"Intra-tumour heterogeneity: a looking glass for cancer?","volume":"12","author":"Marusyk","year":"2012","journal-title":"Nat Rev Cancer"},{"issue":"7467","key":"2020011102344135100_ref4","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1038\/nature12627","article-title":"Tumour heterogeneity in the clinic","volume":"501","author":"Bedard","year":"2013","journal-title":"Nature"},{"issue":"22","key":"2020011102344135100_ref5","first-page":"5400","article-title":"ERBB-2 (HER2\/neu) gene copy number, p185HER-2 overexpression, and intratumor heterogeneity in human breast cancer","volume":"55","author":"Sz\u00f6ll\u00f6si","year":"1995","journal-title":"Cancer Res"},{"issue":"10","key":"2020011102344135100_ref6","doi-asserted-by":"crossref","first-page":"3786","DOI":"10.1172\/JCI60534","article-title":"Heterogeneity in breast cancer","volume":"121","author":"Polyak","year":"2011","journal-title":"J Clin Invest"},{"issue":"4","key":"2020011102344135100_ref7","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/j.molcel.2015.10.031","article-title":"Breast tumor heterogeneity: source of fitness, hurdle for therapy","volume":"60","author":"Koren","year":"2015","journal-title":"Mol Cell"},{"issue":"4","key":"2020011102344135100_ref8","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1038\/nrclinonc.2013.29","article-title":"Emerging targeted agents in metastatic breast cancer","volume":"10","author":"Zardavas","year":"2013","journal-title":"Nat Rev Clin Oncol"},{"issue":"1","key":"2020011102344135100_ref9","first-page":"105","article-title":"Tumor heterogeneity: causes and consequences. 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