Temporal dissection of tumorigenesis in primary cancers

Steffen Durinck, Christine Ho, Nicholas J. Wang, Wilson Liao, Lakshmi R. Jakkula, Eric A. Collisson, Jennifer Pons, Sai Wing Chan, Ernest T. Lam, Catherine Chu, Kyunghee Park, Sung woo Hong, Joe S. Hur, Nam Huh, Isaac M. Neuhaus, Siegrid S. Yu, Roy C. Grekin, Theodora M. Mauro, James E. Cleaver, Pui Yan KwokPhilip E. LeBoit, Gad Getz, Kristian Cibulskis, Jon C. Aster, Haiyan Huang, Elizabeth Purdom, Jian Li, Lars Bolund, Sarah T. Arron, Joe W. Gray, Paul T. Spellman, Raymond J. Cho

Research output: Contribution to journalArticle

157 Scopus citations

Abstract

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. 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.

Original languageEnglish (US)
Pages (from-to)137-143
Number of pages7
JournalCancer discovery
Volume1
Issue number2
DOIs
StatePublished - Jun 29 2011

ASJC Scopus subject areas

  • Oncology

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    Durinck, S., Ho, C., Wang, N. J., Liao, W., Jakkula, L. R., Collisson, E. A., Pons, J., Chan, S. W., Lam, E. T., Chu, C., Park, K., Hong, S. W., Hur, J. S., Huh, N., Neuhaus, I. M., Yu, S. S., Grekin, R. C., Mauro, T. M., Cleaver, J. E., ... Cho, R. J. (2011). Temporal dissection of tumorigenesis in primary cancers. Cancer discovery, 1(2), 137-143. https://doi.org/10.1158/2159-8290.CD-11-0028