Research Highlights

A mathematical framework to determine the temporal sequence
of somatic genetic events in cancer

Camille Stephan-Otto Attolini, Yu-Kang Cheng, Rameen Beroukhim, Gad Getz, Omar
Abdel-Wahab, Ross L. Levine, Ingo K. Mellinghoff, and Franziska Michor


Human cancer is caused by the accumulation of genetic alterations in cells. Of
special importance are changes that occur early during malignant transformation
because they may result in oncogene addiction and represent promising targets for
therapeutic intervention. Here we describe a computational approach, called Retracing
the Evolutionary Steps in Cancer (RESIC), to deduce the temporal sequence of genetic
events during tumorigenesis from cross-sectional genomic data of tumors at their fully
transformed stage. When applied to a dataset of 70 advanced colorectal cancers, our
algorithm accurately predicts the sequence of APC, KRAS, and TP53 mutations previously
defined by analyzing tumors at different stages of colon cancer formation. We further
validate the method with glioblastoma and leukemia sample data and then apply it
to complex integrated genomics databases, finding that high-level EGFR amplification
appears to be a late event in primary glioblastomas. RESIC represents the first
evolutionary mathematical approach to identify the temporal sequence of mutations
driving tumorigenesis and may be useful to guide the validation of candidate genes
emerging from cancer genome surveys.

Published in the Proceedings of the National Academy of Sciences U S A on October
12th, 2010.

17604–17609 ∣ PNAS ∣ October 12, 2010 ∣ vol. 107 ∣ no. 41

www.pnas.org/cgi/doi/10.1073/pnas.1009117107