Utilizing nullomers in cell-free RNA for early cancer detection

Area of Science:

• Genomics
• Cancer Biology
• Biomarker Discovery

Background:

• Early cancer detection significantly improves patient outcomes.
• Current cancer detection lacks highly sensitive and specific biomarkers.
• Nullomers are novel sequences absent in the human genome but arise from cancer mutations.

Purpose of the Study:

• To characterize the emergence of nullomers in cancer across exonic regions.
• To identify mutational hotspots associated with nullomer formation.
• To evaluate nullomers as biomarkers for detecting cancer in cell-free RNA.

Main Methods:

• Analysis of over 10,000 whole exome sequencing matched tumor-normal samples.
• Identification and characterization of nullomer sequences within exonic regions.
• Detection of nullomers in cell-free RNA from peripheral blood samples.

Main Results:

• Nullomers were characterized across exonic regions in a large cohort of cancer samples.
• Specific mutational hotspots driving nullomer emergence within tumor genes were identified.
• Nullomers were successfully detected in cell-free RNA, enabling multi-tumor classification.
• Developed tumor classification models with AUC > 0.9, including a hepatocellular carcinoma classifier with AUC > 0.99.

Conclusions:

• Nullomers represent a novel class of cancer-specific biomarkers.
• Detection of nullomers in cell-free RNA holds potential for non-invasive cancer diagnostics.
• Nullomer-based approaches demonstrate high accuracy in classifying multiple tumor types, including hepatocellular carcinoma.