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Large-scale analysis of acquired chromosomal alterations in non-tumor samples from patients with cancer

Abstract

Mosaicism, the presence of subpopulations of cells bearing somatic mutations, is associated with disease and aging and has been detected in diverse tissues, including apparently normal cells adjacent to tumors. To analyze mosaicism on a large scale, we surveyed haplotype-specific somatic copy number alterations (sCNAs) in 1,708 normal-appearing adjacent-to-tumor (NAT) tissue samples from 27 cancer sites and in 7,149 blood samples from The Cancer Genome Atlas. We find substantial variation across tissues in the rate, burden and types of sCNAs, including those spanning entire chromosome arms. We document matching sCNAs in the NAT tissue and the adjacent tumor, suggesting a shared clonal origin, as well as instances in which both NAT tissue and tumor tissue harbor a gain of the same oncogene arising in parallel from distinct parental haplotypes. These results shed light on pan-tissue mutations characteristic of field cancerization, the presence of oncogenic processes adjacent to cancer cells.

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Fig. 1: Chromosomal alterations, allelic imbalance and mosaicism.
Fig. 2: Summary of results.
Fig. 3: Landscape of sCNAs.
Fig. 4: Arm-level sCNAs in NAT tissues.

Data availability

The results shown are based on data generated by the TCGA Research Network (http://cancergenome.nih.gov/). All datasets used in this work are available in public repositories (https://portal.gdc.cancer.gov/). A list of TCGA disease sites (Supplementary Table 1) and blood and NAT samples used for the analyses (including case IDs) are included (Supplementary Tables 4 and 5, respectively). Reported sCNAs with case IDs are available in Supplementary Tables (6, 7, 10, 11 and 1921).

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Acknowledgements

We thank D. Swartzlander for help with the graphics and reviewers for their helpful comments. We acknowledge the High Performance Research Computing Center at the University of Texas, MD Anderson Cancer Center. This work was supported by National Institutes of Health grants R25CA057730 (to Y.A.J.), R01HG005855 (to P.S.), R01HG005859 (to P.S.), R01CA181244 (to P.S. and C.D.H.) and P30CA016672 (to MD Anderson) and by the following awards from the Cancer Prevention Research Institute of Texas: RP150079 (to H.K.) and RP160668 (to P.S.).

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P.S. and Y.A.J. conceptualized and directed the study. J.F., K.C., M.R.G., P.S., S.S., Y.A.J. and Y.Y. performed data analyses. C.D.H., E.V., H.K., P.S. and Y.A.J. interpreted results. P.S. and Y.A.J. wrote the manuscript.

Corresponding author

Correspondence to Y. A. Jakubek.

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Supplementary Materials

Supplementary Figs. 1–16 and Supplementary Notes 1–8

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Supplementary Tables

Supplementary Tables 1–25

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Jakubek, Y.A., Chang, K., Sivakumar, S. et al. Large-scale analysis of acquired chromosomal alterations in non-tumor samples from patients with cancer. Nat Biotechnol 38, 90–96 (2020). https://doi.org/10.1038/s41587-019-0297-6

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