Cell-free DNA captures tumor heterogeneity and driver alterations in rapid autopsies with pre-treated metastatic cancer

Bernard Pereira, Christopher T. Chen, Lipika Goyal, Charlotte Walmsley, Christopher J. Pinto, Islam Baiev, Read Allen, Laura Henderson, Supriya Saha, Stephanie Reyes, Martin S. Taylor, Donna M. Fitzgerald, Maida Williams Broudo, Avinash Sahu, Xin Gao, Wendy Winckler, A. Rose Brannon, Jeffrey A. Engelman, Rebecca Leary, James R. Stone, Catarina D. Campbell () and Dejan Juric ()
Additional contact information
Bernard Pereira: Novartis Institutes for Biomedical Research
Christopher T. Chen: Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School
Lipika Goyal: Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School
Charlotte Walmsley: Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School
Christopher J. Pinto: Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School
Islam Baiev: Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School
Read Allen: Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School
Laura Henderson: Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School
Supriya Saha: Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School
Stephanie Reyes: Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School
Martin S. Taylor: Department of Pathology, Massachusetts General Hospital
Donna M. Fitzgerald: Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School
Maida Williams Broudo: Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School
Avinash Sahu: Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School
Xin Gao: Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School
Wendy Winckler: Novartis Institutes for Biomedical Research
A. Rose Brannon: Novartis Institutes for Biomedical Research
Jeffrey A. Engelman: Novartis Institutes for Biomedical Research
Rebecca Leary: Novartis Institutes for Biomedical Research
James R. Stone: Department of Pathology, Massachusetts General Hospital
Catarina D. Campbell: Novartis Institutes for Biomedical Research
Dejan Juric: Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract In patients with metastatic cancer, spatial heterogeneity of somatic alterations may lead to incomplete assessment of a cancer’s mutational profile when analyzing a single tumor biopsy. In this study, we perform sequencing of cell-free DNA (cfDNA) and distinct metastatic tissue samples from ten rapid autopsy cases with pre-treated metastatic cancer. We show that levels of heterogeneity in genetic biomarkers vary between patients but that gene expression signatures representative of the tumor microenvironment are more consistent. Across nine patients with plasma samples available, we are able to detect 62/62 truncal and 47/121 non-truncal point mutations in cfDNA. We observe that mutation clonality in cfDNA is correlated with the number of metastatic lesions in which the mutation is detected and use this result to derive a clonality threshold to classify truncal and non-truncal driver alterations with reasonable specificity. In contrast, mutation truncality is more often incorrectly assigned when studying single tissue samples. Our results demonstrate the utility of a single cfDNA sample relative to that of single tissue samples when treating patients with metastatic cancer.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23394-4

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DOI: 10.1038/s41467-021-23394-4

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