A Metastasis or a Second Independent Cancer? Evaluating the Clonal Origin of Tumors Using Array-CGH Data

When a cancer patient develops a new tumor it is necessary to determine if this is a recurrence (metastasis) of the original cancer, or an entirely new occurrence of the disease. This is accomplished by assessing the histo-pathology of the lesions, and it is frequently relatively straightforward. However, there are many clinical scenarios in which this pathological diagnosis is difficult. Since each tumor is characterized by a genetic fingerprint of somatic mutations, a more definitive diagnosis is possible in principle in these difficult clinical scenarios by comparing the fingerprints. In this article we develop and evaluate a statistical strategy for this comparison when the data are derived from array comparative genomic hybridization, a technique designed to identify all of the somatic allelic gains and losses across the genome. Our method involves several stages. First a segmentation algorithm is used to estimate the regions of allelic gain and loss. Then the broad correlation in these patterns between the two tumors is assessed, leading to an initial likelihood ratio for the two diagnoses. This is then further refined by comparing in detail each plausibly clonal mutation within individual chromosome arms, and the results are aggregated to determine a final likelihood ratio. The method is employed to diagnose patients from several clinical scenarios, and the results show that in many cases a strong clonal signal emerges, occasionally contradicting the clinical diagnosis. The “quality” of the arrays can be summarized by a parameter that characterizes the clarity with which allelic changes are detected. Sensitivity analyses show that most of the diagnoses are robust when the data are of high quality. clonality-cgh-jasa 07/31/08 A Metastasis or a Second Independent Cancer? Evaluating the Clonal Origin of Tumors Using ArrayCGH Data Irina Ostrovnaya, Adam B. Olshen, Venkatraman E. Seshan, Irene Orlow, Donna G. Albertson, Colin B. Begg 1. Memorial Sloan-Kettering Cancer Center, New York 2. Columbia University, New York 3. University of California, San Francisco Correspondence to: Colin B. Begg, Department of Epidemiology and Biostatistics, 307 East 63rd Street, New York, NY 10021, [email protected] Hosted by The Berkeley Electronic Press