Early detection of cancer can significantly improve patient outcomes; however, sensitive and highly specific biomarkers for cancer detection are currently missing. Nullomers are the shortest sequences that are absent from the human genome but can emerge due to somatic mutations in cancer. We examine over 10,000 whole exome sequencing matched tumor-normal samples to characterize nullomer emergence across exonic regions of the genome. We also identify nullomer emerging mutational hotspots within tumor genes. Finally, we provide evidence for the identification of nullomers in cell-free RNA from peripheral blood samples, enabling detection of multiple tumor types. We show multiple tumor classification models with an AUC greater than 0.9, including a hepatocellular carcinoma classifier with an AUC greater than 0.99.

早期发现癌症可以显着改善患者的治疗效果；然而，目前缺乏用于癌症检测的敏感且高度特异性的生物标志物。 Nullomer 是人类基因组中不存在的最短序列，但可能由于癌症的体细胞突变而出现。我们检查了 10,000 多个全外显子组测序匹配的肿瘤正常样本，以表征基因组外显子区域中 nullomer 的出现。我们还确定了肿瘤基因内出现的零聚体突变热点。最后，我们为从外周血样本中鉴定无细胞 RNA 中的 nullomer 提供了证据，从而能够检测多种肿瘤类型。我们展示了多个 AUC 大于 0.9 的肿瘤分类模型，包括 AUC 大于 0.99 的肝细胞癌分类器。