DNA methylation profiling identified the primary cancer in cases of cancer of unknown primary (CUP), informing tumor-type specific treatment that improved overall survival in these patients, according to a report published in The Lancet Oncology.1

An initial cancer diagnosis usually involves identifying the primary or original tumor and whether it has metastasized. In 5% to 10% of cases, however, a metastasis is diagnosed but no primary tumor is identified, and a diagnosis of cancer of unknown primary is made. Because the cancer type is unknown, treatment is nonspecific resulting in poor patient survival.

Researchers at the Bellvitge Biomedical Research Institute, Barcelona, Spain, used microarray DNA methylation signatures (EPICUP) in a training set of 2790 tumor samples of known cancer types to develop a classifier of cancer type. The training set represented 38 tumor types, including 85 metastases.

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In this study, the classifier was validated by applying it to an independent set of 7691 samples of tumors known to be the same cancer types as in the training set; this set included 534 metastases. In addition, the EPICUP assay was used on 216 well-characterized CUP samples.

Results were confirmed via autopsy examination, clinical detection of the primary cancer in a subsequent follow-up months later, light microscopy, and comprehensive immunohistochemistry profiling.

In the validation set of tumor samples, EPICUP demonstrated a 99.6% specificity (95% CI, 99.5-99.7), 97.7% sensitivity (95% CI, 96.1-99.2), 88.6% positive predictive value (95% CI, 85.8-91.3), and 99.9% negative predictive value (95% CI, 99.9-100.0).

The assay predicted the primary cancer in 188 of 216 (87%) patients with cancer of unknown primary. Tumor-type specific treatment based on EPICUP diagnoses of the primary tumor resulted in improved overall survival compared with empiric therapy (hazard ratio [HR] 3.24, P =.0051 [95% CI, 1.42-7.38]; log rank P =.0029).

These findings demonstrate that DNA methylation–based assay significantly improves diagnoses of primary tumor type in CUP allowing for more precise treatment with better outcomes.


1. Moran S, Martínez-Cardús A, Sayols S, et al. epigenetic profiling to classify cancer of unknown primary: a multicentre, retrospective analysis. Lancet Oncol. doi: 10.1016/S1470-2045(16)30297-2. [Epub ahead of print]