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Background: Most cancers acquire numerous genetic changes in proto-oncogenes as well as tumor-suppressor genes. Cancer's early diagnosis remains a challenge. Recently, nonlinear polarization has revealed the potential as a promising tool for early cancer diagnosis. Laser-induced nonlinear polarization can offer a novel fingerprint signature. Methods: In this study, nonlinear polarization was adopted for the characterization of both DNA and RNA samples from healthy volunteers. Total DNA and RNA were illuminated with a 656-nm LED source, and the resonance frequencies (scattered and re-emitted signals) were captured and recorded using a hyperspectral camera. Results: Changes in signal frequency as well as phase shift offered a potent means to differentiate DNA (control) from RNA (control). DNA (control) demonstrated characteristic resonance frequencies that differ from total RNA (control) at the 2nd, 3rd, 4th, and 5th harmonics. While DNA demonstrated a phase shift dominating at 0.88 GHz, RNA dominates at 0.106 GHz. The resonance spectral signature of RNA samples from people with hepatocellular carcinoma (HCC) was compared to that of RNA (control). RNA (HCC) demonstrated distinctive frequency signals at 0.014, 0.021, 0.032, and 0.072 GHz. These characteristics feature could facilitate early HCC diagnosis. While RNA (control) dominates at 0.014 and 0.072 MHz, RNA (HCC) dominates at 0.021 and 0.032. Conclusion: As far as we are aware, this is the initial investigation into the use of simple nonlinear polarization to generate spectral fingerprinting signatures of total DNA and RNA. Furthermore, RNA mutations due to HCC were identified via characteristic nonlinear spectral signature. [ABSTRACT FROM AUTHOR]