Genome-wide cfDNA Mutation Profiles Allow for Noninvasive Cancer Detection

Cell-free DNA (cfDNA) presents an opportunity for early cancer screening, but the low frequency of cancer-associated mutations found in cfDNA fragments renders it difficult to distinguish tumor-specific mutations from background noise. In this study, Bruhm and colleagues developed an approach called GEnome-wide Mutational Incidence for Non-Invasive detection of cancer (GEMINI) that enriches for tumor-specific somatic mutations and effectively accounts for background mutations. Whole-genome sequencing (WGS) data from more than 2,500 patients with cancer spanning 25 cancer types were compared with matched normal tissues to identify cancer-specific somatic mutation frequencies across the genome. These mutations were distinguished from background alterations including common germline mutations, sequencing artifacts, and mutations in white blood cells, which are sources of potential confounding cfDNA mutations. Binning WGS data identified regions across tumor genomes that harbored elevated mutation frequencies, which remained enriched for mutations after subtracting sources of background alterations. When applied to cfDNA sequenced from a prospective lung cancer diagnostic cohort, GEMINI was able to identify similar regions of high-frequency mutations. Key regional differences in mutational profiles were converted to GEMINI scores that could effectively distinguish patients with cancer from high-risk patients without cancer or those with benign lesions. Elevated GEMINI scores were also evident in a cohort of patients without a cancer diagnosis at the time of sample collection but who later developed lung cancer, demonstrating that this method may be utilized to detect cancer before conventional diagnosis. Moreover, analysis of another cohort of individuals from lung cancer screening programs revealed that GEMINI scores positively correlated with cancer stage and could distinguish between histologic subtypes of lung cancer. GEMINI scores in patients with liver cancer were also elevated compared to those in patients with cirrhosis, demonstrating the utility of GEMINI in the detection of other cancer types. Additionally, GEMINI also demonstrated its ability to noninvasively track therapeutic responses in patients with lung cancer. In summary, these results suggest that the GEMINI approach developed in this study can be utilized to noninvasively detect cancer using low-coverage WGS of cfDNA.

Bruhm DC, Mathios D, Foda ZH, Annapragada AV, Medina JE, Adleff V, et al. Single-molecule genome-wide mutation profiles of cell-free DNA for non-invasive detection of cancer. Nat Genet 2023 Jul 27 [Epub ahead of print].

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