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Hepatocellular carcinoma (HCC) is a major global health problem with about 841,000 new cases and 782,000 deaths annually, due to lacking early biomarker/s, and centralized diagnosis. Transcriptomes research despite its infancy has proved excellence in its implementation in identifying a coherent specific cancer RNAs differential expression. However, results are sometimes overlapped by other cancer types which negatively affecting specificity, plus the high cost of the equipment used. Hyperspectral imaging (HSI) is an advanced tool with unique, spectroscopic features, is an emerging tool that has widely been used in cancer detection. Herein, a pilot study has been performed for HCC diagnosis, by exploiting HIS properties and the analysis of the transcriptome for the development of non-invasive remote HCC sensing. HSI data cube images of the sera extracted total RNA have been analyzed in HCC, normal subject, liver benign tumor, and chronic HCV with cirrhotic/non-cirrhotic liver groups. Data analyses have revealed a specific spectral signature for all groups and can be easily discriminated; at the computed optimum wavelength. Moreover, we have developed a simple setup based on a commercial laser pointer for sample illumination and a Smartphone CCD camera, with HSI consistent data output. We hypothesized that RNA differential expression and its spatial organization/folding are the key players in the obtained spectral signatures. To the best of our knowledge, we are the first to use HSI for sensing cancer based on total RNA in serum, using a Smartphone CCD camera/laser pointer. The proposed biosensor is simple, rapid (2 min), and affordable with specificity and sensitivity of more than 98% and high accuracy.