{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T01:55:13Z","timestamp":1792893313761,"version":"4.5.0"},"reference-count":25,"publisher":"American Association for Cancer Research (AACR)","issue":"2","content-domain":{"domain":["aacrjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2011,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Timely intervention for cancer requires knowledge of its earliest genetic aberrations. Sequencing of tumors and their metastases reveals numerous abnormalities occurring late in progression. A means to temporally order aberrations in a single cancer, rather than inferring them from serially acquired samples, would define changes preceding even clinically evident disease. We integrate DNA sequence and copy number information to reconstruct the order of abnormalities as individual tumors evolve for 2 separate cancer types. We detect vast, unreported expansion of simple mutations sharply demarcated by recombinative loss of the second copy of TP53 in cutaneous squamous cell carcinomas (cSCC) and serous ovarian adenocarcinomas, in the former surpassing 50 mutations per megabase. In cSCCs, we also report diverse secondary mutations in known and novel oncogenic pathways, illustrating how such expanded mutagenesis directly promotes malignant progression. These results reframe paradigms in which TP53 mutation is required later, to bypass senescence induced by driver oncogenes.<\/jats:p>\n                  <jats:p>Significance: Our approach reveals sequential ordering of oncogenic events in individual cancers, based on chromosomal rearrangements. Identifying the earliest abnormalities in cancer represents a critical step in timely diagnosis and deployment of targeted therapeutics. Cancer Discovery; 1(2); 137\u201343. \u00a9 2011 AACR.<\/jats:p>\n                  <jats:p>This article is highlighted in the In This Issue feature, p. 91<\/jats:p>","DOI":"10.1158\/2159-8290.cd-11-0028","type":"journal-article","created":{"date-parts":[[2011,6,30]],"date-time":"2011-06-30T00:01:53Z","timestamp":1309392113000},"page":"137-143","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":237,"title":["Temporal Dissection of Tumorigenesis in Primary Cancers"],"prefix":"10.1158","volume":"1","author":[{"given":"Steffen","family":"Durinck","sequence":"first","affiliation":[{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Ho","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J.","family":"Wang","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilson","family":"Liao","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lakshmi R.","family":"Jakkula","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric A.","family":"Collisson","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Pons","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sai-Wing","family":"Chan","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernest T.","family":"Lam","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Chu","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyunghee","family":"Park","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung-woo","family":"Hong","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joe S.","family":"Hur","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nam","family":"Huh","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaac M.","family":"Neuhaus","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siegrid S.","family":"Yu","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roy C.","family":"Grekin","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theodora M.","family":"Mauro","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James E.","family":"Cleaver","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pui-Yan","family":"Kwok","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip E.","family":"LeBoit","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gad","family":"Getz","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristian","family":"Cibulskis","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon C.","family":"Aster","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Huang","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Purdom","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Li","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"},{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Bolund","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"},{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah T.","family":"Arron","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joe W.","family":"Gray","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"},{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul T.","family":"Spellman","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond J.","family":"Cho","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Life Sciences Division, Lawrence Berkeley National Laboratories; 2Department of Statistics, University of California, Berkeley; 3Department of Dermatology, University of California, San Francisco, and 4San Francisco Dermatopathology Service, San Francisco, California; 5Emerging Technology Research Center, Samsung Advanced Institute of Technology, and 6Samsung Electronics Headquarters, Seoul, Korea; 7The Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge; 8Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; 9Beijing Genomics Institute\u2013Shenzhen, Shenzhen, China; 10Institute of Human Genetics, Aarhus University, Aarhus, Denmark; 11Biomedical Engineering Department, Oregon Health and Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1086","published-online":{"date-parts":[[2011,7,17]]},"reference":[{"key":"2022060622094839400_bib1","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1038\/nature09460","article-title":"The patterns and dynamics of genomic instability in metastatic pancreatic cancer","volume":"467","author":"Campbell","year":"2010","journal-title":"Nature"},{"key":"2022060622094839400_bib2","doi-asserted-by":"crossref","first-page":"18545","DOI":"10.1073\/pnas.1010978107","article-title":"Accumulation of driver and passenger mutations during tumor progression","volume":"107","author":"Bozic","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022060622094839400_bib3","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/S0140-6736(09)61196-X","article-title":"Non-melanoma skin cancer","volume":"375","author":"Madan","year":"2010","journal-title":"Lancet"},{"key":"2022060622094839400_bib4","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1038\/372773a0","article-title":"Sunburn and p53 in the onset of skin cancer","volume":"372","author":"Ziegler","year":"1994","journal-title":"Nature"},{"key":"2022060622094839400_bib5","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1067\/mjd.2000.103340","article-title":"The scientific basis of skin cancer","volume":"42","author":"Leffell","year":"2000","journal-title":"J Am Acad Dermatol"},{"key":"2022060622094839400_bib6","doi-asserted-by":"crossref","first-page":"D652","DOI":"10.1093\/nar\/gkp995","article-title":"COSMIC (the Catalogue of Somatic Mutations in Cancer): a resource to investigate acquired mutations in human cancer","volume":"38","author":"Forbes","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"2022060622094839400_bib7","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1038\/nature08658","article-title":"A comprehensive catalogue of somatic mutations from a human cancer genome","volume":"463","author":"Pleasance","year":"2010","journal-title":"Nature"},{"key":"2022060622094839400_bib8","doi-asserted-by":"crossref","first-page":"2731","DOI":"10.1182\/blood-2009-10-201848","article-title":"Copy neutral loss of heterozygosity: a novel chromosomal lesion in myeloid malignancies","volume":"115","author":"O'Keefe","year":"2010","journal-title":"Blood"},{"key":"2022060622094839400_bib9","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.molmed.2009.01.005","article-title":"Uniparental disomy in cancer","volume":"15","author":"Tuna","year":"2009","journal-title":"Trends Mol Med"},{"key":"2022060622094839400_bib10","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1016\/j.cell.2004.11.004","article-title":"Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome","volume":"119","author":"Olive","year":"2004","journal-title":"Cell"},{"key":"2022060622094839400_bib11","doi-asserted-by":"crossref","first-page":"3602","DOI":"10.1073\/pnas.91.9.3602","article-title":"p53 and E2F-1 cooperate to mediate apoptosis","volume":"91","author":"Wu","year":"1994","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022060622094839400_bib12","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1038\/nrm2450","article-title":"ATR: an essential regulator of genome integrity","volume":"9","author":"Cimprich","year":"2008","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2022060622094839400_bib13","doi-asserted-by":"crossref","first-page":"4905","DOI":"10.1038\/onc.2010.245","article-title":"Genomic analysis of genetic heterogeneity and evolution in high-grade serous ovarian carcinoma","volume":"29","author":"Cooke","year":"2010","journal-title":"Oncogene"},{"key":"2022060622094839400_bib14","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1038\/nature08989","article-title":"Genome remodelling in a basal-like breast cancer metastasis and xenograft","volume":"464","author":"Ding","year":"2010","journal-title":"Nature"},{"key":"2022060622094839400_bib15","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/0092-8674(90)90186-I","article-title":"A genetic model for colorectal tumorigenesis","volume":"61","author":"Fearon","year":"1990","journal-title":"Cell"},{"key":"2022060622094839400_bib16","first-page":"2969","article-title":"Progression model for pancreatic cancer","volume":"6","author":"Hruban","year":"2000","journal-title":"Clin Cancer Res"},{"key":"2022060622094839400_bib17","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/S0092-8674(00)80762-X","article-title":"p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis","volume":"97","author":"Chin","year":"1999","journal-title":"Cell"},{"key":"2022060622094839400_bib18","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1016\/0092-8674(91)90384-B","article-title":"Cotranslation of activated mutant p53 with wild type drives the wild-type p53 protein into the mutant conformation","volume":"65","author":"Milner","year":"1991","journal-title":"Cell"},{"key":"2022060622094839400_bib19","doi-asserted-by":"crossref","first-page":"14025","DOI":"10.1073\/pnas.93.24.14025","article-title":"Frequent clones of p53-mutated keratinocytes in normal human skin","volume":"93","author":"Jonason","year":"1996","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022060622094839400_bib20","first-page":"1791","article-title":"Benign clonal keratinocyte patches with p53 mutations show no genetic link to synchronous squamous cell precancer or cancer in human skin","volume":"150","author":"Ren","year":"1997","journal-title":"Am. J. Pathol."},{"key":"2022060622094839400_bib21","first-page":"7717","article-title":"p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis","volume":"50","author":"Baker","year":"1990","journal-title":"Cancer Res"},{"key":"2022060622094839400_bib22","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1126\/science.1102160","article-title":"Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia","volume":"306","author":"Weng","year":"2004","journal-title":"Science"},{"key":"2022060622094839400_bib23","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1101\/gad.1484707","article-title":"Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1\/2 and MRCK\u03b1 kinases","volume":"21","author":"Lefort","year":"2007","journal-title":"Genes Dev"},{"key":"2022060622094839400_bib24","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1111\/j.1600-0625.1995.tb00224.x","article-title":"Proto-oncogenes and oncogenes in epidermal neoplasia","volume":"4","author":"Simon","year":"1995","journal-title":"Exp Dermatol"},{"key":"2022060622094839400_bib25","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1038\/nature10166","article-title":"Integrated genomic analyses of ovarian carcinoma","volume":"474","author":"The Cancer Genome Atlas Group","year":"2011","journal-title":"Nature"}],"container-title":["Cancer Discovery"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/aacrjournals.org\/cancerdiscovery\/article-pdf\/1\/2\/137\/1712053\/137.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/aacrjournals.org\/cancerdiscovery\/article-pdf\/1\/2\/137\/1712053\/137.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,6]],"date-time":"2022-06-06T18:10:30Z","timestamp":1654539030000},"score":1,"resource":{"primary":{"URL":"https:\/\/aacrjournals.org\/cancerdiscovery\/article\/1\/2\/137\/2262\/Temporal-Dissection-of-Tumorigenesis-in-Primary"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,7,1]]},"references-count":25,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2011,7,17]]},"published-print":{"date-parts":[[2011,7,1]]}},"URL":"https:\/\/doi.org\/10.1158\/2159-8290.cd-11-0028","relation":{"has-preprint":[{"id-type":"doi","id":"10.1158\/2159-8290.c.6545946","asserted-by":"object"},{"id-type":"doi","id":"10.1158\/2159-8290.c.6545946.v1","asserted-by":"object"}],"is-supplemented-by":[{"id-type":"doi","id":"10.1158\/2159-8290.22529481.v1","asserted-by":"object"},{"id-type":"doi","id":"10.1158\/2159-8290.22529475.v1","asserted-by":"object"},{"id-type":"doi","id":"10.1158\/2159-8290.22529490.v1","asserted-by":"object"},{"id-type":"doi","id":"10.1158\/2159-8290.22529484","asserted-by":"object"},{"id-type":"doi","id":"10.1158\/2159-8290.22529493","asserted-by":"object"},{"id-type":"doi","id":"10.1158\/2159-8290.22529481","asserted-by":"object"},{"id-type":"doi","id":"10.1158\/2159-8290.22529490","asserted-by":"object"},{"id-type":"doi","id":"10.1158\/2159-8290.22529493.v1","asserted-by":"object"},{"id-type":"doi","id":"10.1158\/2159-8290.22529478","asserted-by":"object"},{"id-type":"doi","id":"10.1158\/2159-8290.22529487","asserted-by":"object"},{"id-type":"doi","id":"10.1158\/2159-8290.22529487.v1","asserted-by":"object"},{"id-type":"doi","id":"10.1158\/2159-8290.22529475","asserted-by":"object"},{"id-type":"doi","id":"10.1158\/2159-8290.22529484.v1","asserted-by":"object"},{"id-type":"doi","id":"10.1158\/2159-8290.22529478.v1","asserted-by":"object"}],"has-review":[{"id-type":"doi","id":"10.3410\/f.718155592.793485913","asserted-by":"object"}]},"ISSN":["2159-8274","2159-8290"],"issn-type":[{"value":"2159-8274","type":"print"},{"value":"2159-8290","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,7,1]]}}}