Somatic Substitution Signature as an Innovative Tool in Lung Cancer Diagnosis

Diagnosis of lung cancer can sometimes be challenging and is of major interest since effective molecular-guided therapies are available. Compounds of tobacco smoke may generate a specific substitutional signature in lung, which is the most exposed organ. To predict whether a tumor is of lung origin or not, we developed and validated the EASILUNG (Exome And SIgnature LUNG) test based on the relative frequencies of somatic substitutions on coding non-transcribed DNA strands from whole-exome sequenced tumors. Data from 7,796 frozen tumor samples (prior to any treatment) from 32 TCGA solid cancer groups were used for its development. External validation was carried out on a local dataset of 196 consecutive routine exome results. The EASILUNG test demonstrated good calibration and good discriminative power with a sensitivity of 80% and a specificity of 94.3%. Similar results were obtained from external validation. This innovative test may be helpful in medical decision-making in patients with unknown primary tumors potentially of lung origin and in the diagnosis of lung cancer in smokers. Funding Statement: The authors state: "No funding." Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: All patients gave their consent and the study was approved by the CGFL ethical board.