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. 2023 Sep 14;55(10):1686–1695. doi: 10.1038/s41588-023-01499-4

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© The Author(s) 2023

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Extended Data Fig. 3 — (a-b) Total consequential mutations (nonsynonymous SNVs and indels) per megabase (Mb) DNA for autochthonous lung tumors and cell lines and autochthonous colon tumors, separated by clonal (cancer cell fraction (CCF) ≥ 0.75) (a) and subclonal (CCF ≤ 0.75) (b), with fold-change shown for each comparison. (c) Histograms of total mutations by cancer cell fraction in a representative sgMsh2-targeted lung tumor, cell line, and colon tumor from Fig. 3a,b. (d) Western blot of MSH2 expression in single cell clones with Msh2 re-expression, after 20 passages with puromycin selection, experimentally replicated three times. WT = sgCtl-targeted cell line; MSH2^KO = parental sgMsh2-targeted cell line (09-2). (e) Venn diagrams of mutation overlap between M1-8 clones sequenced at early passage (called passage 0 for convenience) and 20 passages later. (f) Histograms of total mutations by cancer cell fraction in M1-8 clones at passage 0 and 20. (g) Pairwise intersection map of mutations across M1-8 clones. Scale represents fraction of total mutations shared between each pair. (h-i) Total clonal (CCF ≥ 0.75) (h) and subclonal (CCF ≤ 0.5) (i) predicted neoantigens in lung tumors from Fig. 3g–j. (j) Distribution of cancer cell fraction estimates from Fig. 3i with sgMsh2-targeted Pole S415R mutant lung tumor removed. (k-l) Total mutations / Mb (k) and predicted neoantigens (l) in 16–20-week autochthonous MMRd colon tumors from animals with no treatment (blue shades, N = 5 Msh2^KO, 6 Mlh1^KO, 6 Msh3^KO, 2 Msh6^KO) and continuous antibody-mediated T cell depletion (αCD4/8, magenta, N = 7 Msh2^KO). (m-n) CCF distribution (m) and per tumor median (n) of all SNV-derived neoantigens (no expression filter) in colon tumors from (j-k). Significance and smoothing in (i, l) were assessed by two-sided Kolmogorov-Smirnov test and Gaussian kernel density estimation, respectively. Significance in (a-b, h-i, k-l, n) was assessed by Wilcoxon Rank Sum test, with Holm correction for five comparisons in (a-b). P values in (h-j) are uncorrected.

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