Abstract
Nuclear organization of genomic DNA affects processes of DNA damage and repair, yet its effects on mutational landscapes in cancer genomes remain unclear. Here we analyzed genome-wide somatic mutations from 366 samples of six cancer types. We found that lamina-associated regions, which are typically localized at the nuclear periphery, displayed higher somatic mutation frequencies than did the interlamina regions at the nuclear core. This effect was observed even after adjustment for features such as GC percentage, chromatin, and replication timing. Furthermore, mutational signatures differed between the nuclear core and periphery, thus indicating differences in the patterns of DNA-damage or DNA-repair processes. For instance, smoking and UV-related signatures, as well as substitutions at certain motifs, were more enriched in the nuclear periphery. Thus, the nuclear architecture may influence mutational landscapes in cancer genomes beyond the previously described effects of chromatin structure and replication timing.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
De, S. & Michor, F. DNA secondary structures and epigenetic determinants of cancer genome evolution. Nat. Struct. Mol. Biol. 18, 950–955 (2011).
De, S. & Michor, F. DNA replication timing and long-range DNA interactions predict mutational landscapes of cancer genomes. Nat. Biotechnol. 29, 1103–1108 (2011).
Helleday, T., Eshtad, S. & Nik-Zainal, S. Mechanisms underlying mutational signatures in human cancers. Nat. Rev. Genet. 15, 585–598 (2014).
Liu, L., De, S. & Michor, F. DNA replication timing and higher-order nuclear organization determine single-nucleotide substitution patterns in cancer genomes. Nat. Commun. 4, 1502 (2013).
Roberts, S.A. & Gordenin, D.A. Hypermutation in human cancer genomes: footprints and mechanisms. Nat. Rev. Cancer 14, 786–800 (2014).
Schuster-Böckler, B. & Lehner, B. Chromatin organization is a major influence on regional mutation rates in human cancer cells. Nature 488, 504–507 (2012).
Polak, P. et al. Cell-of-origin chromatin organization shapes the mutational landscape of cancer. Nature 518, 360–364 (2015).
Perera, D. et al. Differential DNA repair underlies mutation hotspots at active promoters in cancer genomes. Nature 532, 259–263 (2016).
Sabarinathan, R., Mularoni, L., Deu-Pons, J., Gonzalez-Perez, A. & López-Bigas, N. Nucleotide excision repair is impaired by binding of transcription factors to DNA. Nature 532, 264–267 (2016).
Smith, K.S. et al. Signatures of accelerated somatic evolution in gene promoters in multiple cancer types. Nucleic Acids Res. 43, 5307–5317 (2015).
Pedersen, B.S. & De, S. Loss of heterozygosity preferentially occurs in early replicating regions in cancer genomes. Nucleic Acids Res. 41, 7615–7624 (2013).
Watson, I.R., Takahashi, K., Futreal, P.A. & Chin, L. Emerging patterns of somatic mutations in cancer. Nat. Rev. Genet. 14, 703–718 (2013).
Alexandrov, L.B. & Stratton, M.R. Mutational signatures: the patterns of somatic mutations hidden in cancer genomes. Curr. Opin. Genet. Dev. 24, 52–60 (2014).
Lawrence, M.S. et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214–218 (2013).
De, S. & Ganesan, S. Looking beyond drivers and passengers in cancer genome sequencing data. Ann. Oncol. 28, 938–945 (2016).
Bickmore, W.A. The spatial organization of the human genome. Annu. Rev. Genomics Hum. Genet. 14, 67–84 (2013).
Gibcus, J.H. & Dekker, J. The hierarchy of the 3D genome. Mol. Cell 49, 773–782 (2013).
Cavalli, G. & Misteli, T. Functional implications of genome topology. Nat. Struct. Mol. Biol. 20, 290–299 (2013).
Guelen, L. et al. Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature 453, 948–951 (2008).
Peric-Hupkes, D. et al. Molecular maps of the reorganization of genome-nuclear lamina interactions during differentiation. Mol. Cell 38, 603–613 (2010).
Meister, P., Taddei, A. & Gasser, S.M. In and out of the replication factory. Cell 125, 1233–1235 (2006).
Ball, A.R. Jr. & Yokomori, K. Damage site chromatin: open or closed? Curr. Opin. Cell Biol. 23, 277–283 (2011).
Bell, O., Tiwari, V.K., Thomä, N.H. & Schübeler, D. Determinants and dynamics of genome accessibility. Nat. Rev. Genet. 12, 554–564 (2011).
Lemaître, C. & Bickmore, W.A. Chromatin at the nuclear periphery and the regulation of genome functions. Histochem. Cell Biol. 144, 111–122 (2015).
Lemaître, C. et al. Nuclear position dictates DNA repair pathway choice. Genes Dev. 28, 2450–2463 (2014).
Shimi, T. & Goldman, R.D. Nuclear lamins and oxidative stress in cell proliferation and longevity. Adv. Exp. Med. Biol. 773, 415–430 (2014).
Ananda, G., Chiaromonte, F. & Makova, K.D. A genome-wide view of mutation rate co-variation using multivariate analyses. Genome Biol. 12, R27 (2011).
Weischenfeldt, J. et al. Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking. Nat. Genet. 49, 65–74 (2017).
Kaiser, V.B., Taylor, M.S. & Semple, C.A. Mutational biases drive elevated rates of substitution at regulatory sites across cancer types. PLoS Genet. 12, e1006207 (2016).
Berger, M.F. et al. Melanoma genome sequencing reveals frequent PREX2 mutations. Nature 485, 502–506 (2012).
Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature 489, 519–525 (2012).
Wang, K. et al. Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. Nat. Genet. 46, 573–582 (2014).
Morin, R.D. et al. Mutational and structural analysis of diffuse large B-cell lymphoma using whole-genome sequencing. Blood 122, 1256–1265 (2013).
Puente, X.S. et al. Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature 526, 519–524 (2015).
Abeshouse, A. et al. The molecular taxonomy of primary prostate cancer. Cell 163, 1011–1025 (2015).
Berger, M.F. et al. The genomic complexity of primary human prostate cancer. Nature 470, 214–220 (2011).
Alexandrov, L.B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).
Bolzer, A. et al. Three-dimensional maps of all chromosomes in human male fibroblast nuclei and prometaphase rosettes. PLoS Biol. 3, e157 (2005).
Németh, A. et al. Initial genomics of the human nucleolus. PLoS Genet. 6, e1000889 (2010).
Gehring, J.S., Fischer, B., Lawrence, M. & Huber, W. SomaticSignatures: inferring mutational signatures from single-nucleotide variants. Bioinformatics 31, 3673–3675 (2015).
Kazanov, M.D. et al. APOBEC-induced cancer mutations are uniquely enriched in early-replicating, gene-dense, and active chromatin regions. Cell Rep. 13, 1103–1109 (2015).
Morganella, S. et al. The topography of mutational processes in breast cancer genomes. Nat. Commun. 7, 11383 (2016).
Woo, Y.H. & Li, W.H. DNA replication timing and selection shape the landscape of nucleotide variation in cancer genomes. Nat. Commun. 3, 1004 (2012).
Butin-Israeli, V., Adam, S.A. & Goldman, R.D. Regulation of nucleotide excision repair by nuclear lamin b1. PLoS One 8, e69169 (2013).
Di Noia, J.M. & Neuberger, M.S. Molecular mechanisms of antibody somatic hypermutation. Annu. Rev. Biochem. 76, 1–22 (2007).
Puente, X.S. et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature 475, 101–105 (2011).
Hu, Y. et al. Activation-induced cytidine deaminase (AID) is localized to subnuclear domains enriched in splicing factors. Exp. Cell Res. 322, 178–192 (2014).
Misteli, T. & Soutoglou, E. The emerging role of nuclear architecture in DNA repair and genome maintenance. Nat. Rev. Mol. Cell Biol. 10, 243–254 (2009).
Liang, Y., Franks, T.M., Marchetto, M.C., Gage, F.H. & Hetzer, M.W. Dynamic association of NUP98 with the human genome. PLoS Genet. 9, e1003308 (2013).
Nagai, S. et al. Functional targeting of DNA damage to a nuclear pore-associated SUMO-dependent ubiquitin ligase. Science 322, 597–602 (2008).
Hsu, T.C. A possible function of constitutive heterochromatin: the bodyguard hypothesis. Genetics 79 (Suppl.), 137–150 (1975).
Malhas, A.N., Lee, C.F. & Vaux, D.J. Lamin B1 controls oxidative stress responses via Oct-1. J. Cell Biol. 184, 45–55 (2009).
Lange, S.S., Takata, K. & Wood, R.D. DNA polymerases and cancer. Nat. Rev. Cancer 11, 96–110 (2011).
Solimando, L. et al. Spatial organization of nucleotide excision repair proteins after UV-induced DNA damage in the human cell nucleus. J. Cell Sci. 122, 83–91 (2009).
Hanahan, D. & Weinberg, R.A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Stratton, M.R., Campbell, P.J. & Futreal, P.A. The cancer genome. Nature 458, 719–724 (2009).
Mardis, E.R. et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N. Engl. J. Med. 361, 1058–1066 (2009).
Ohta, T. The nearly neutral theory of molecular evolution. Annu. Rev. Ecol. Syst. 23, 263–286 (1992).
Meuleman, W. et al. Constitutive nuclear lamina-genome interactions are highly conserved and associated with A/T-rich sequence. Genome Res. 23, 270–280 (2013).
Hansen, R.S. et al. Sequencing newly replicated DNA reveals widespread plasticity in human replication timing. Proc. Natl. Acad. Sci. USA 107, 139–144 (2010).
Supek, F. & Lehner, B. Differential DNA mismatch repair underlies mutation rate variation across the human genome. Nature 521, 81–84 (2015).
Bernstein, B.E. et al. The NIH Roadmap Epigenomics Mapping Consortium. Nat. Biotechnol. 28, 1045–1048 (2010).
Speir, M.L. et al. The UCSC Genome Browser database: 2016 update. Nucleic Acids Res. 44 D1, D717–D725 (2016).
Freedman, D.A. On the so-called 'Huber sandwich estimator' and 'robust standarderrors'. Am. Stat. 60, 299–302 (2006).
Strobl, C., Boulesteix, A.-L., Kneib, T., Augustin, T. & Zeileis, A. Conditional variable importance for random forests. BMC Bioinformatics 9, 307 (2008).
Acknowledgements
The authors acknowledge financial support from T15LM009451 (K.S.S.), U54CA193461 (F.M.), P30CA072720, the American Cancer Society, and the Boettcher Foundation (S.D.). The authors thank other members of the laboratories of F.M. and S.D. for helpful discussions. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Author information
Authors and Affiliations
Contributions
S.D. conceived the project with F.M.; K.S.S., L.L.L., F.M., and S.D. designed the experiments. K.S.S., L.L.L., and S.D. performed the experiments. K.S.S., L.L.L., S.G., F.M., and S.D. interpreted the results. F.M. and S.D. wrote the manuscript with input from other authors.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Integrated supplementary information
Supplementary Figure 1 Summary of the samples analyzed for the six cancer cohorts.
A) Mutation frequencies for the cohorts were comparable to those published elsewhere (Lawrence et al. Nature, 499, 214-218, 2013. Whiskers in the boxplot indicate upper and lower quartiles. B) Mutation callers used for the different cohorts are listed.
Supplementary Figure 2 Chromosome-level differences in patterns of genomic alterations.
(A) There was no significant difference in the chromosome average copy number log2 ratios between chr18 and chr19 in the LUSC cohort (p-value >0.1; Mann Whitney test), indicating that lower AMR in chr19 was not due to recurrent copy number loss of segments of this chromosome. (B) Chromosome-wise AMR and copy number log2 ratios for cLAD and iLADs in the LUSC cohort, shown after grouping according to chromosomes show that difference in AMR between cLADs and iLADs was not due to systematic difference in copy number gain or loss. Copy number log2 ratios were obtained from the cBio portal, and were reported as segment means. Whiskers in the boxplot indicate upper and lower quartiles.
Supplementary Figure 3 Effects of nuclear localization on somatic mutation patterns after refinement of the list of cLAD and iLAD regions.
A) After excluding regions that overlap with nucleolus-associated domains (NAD), filtered constant nuclear periphery (cLAD-NAD) regions tend to have a significantly higher adjusted mutation rate compared to filtered constant nuclear core (iLAD-NAD) regions (Mann Whitney U test p-value <0.05 in all cohorts). Whiskers in the boxplot indicate upper and lower quartiles. B) Constant periphery regions that are also conserved between human and mouse in their nuclear localization (cLADc) tend to have a significantly higher adjusted mutation rate (AMR) compared to constant core regions with equivalent evolutionary conservation in nuclear localization (iLADc; Mann Whitney U test p-value <0.05 in all cohorts). Whiskers in the boxplot indicate upper and lower quartiles.
Supplementary Figure 4 Mutation-signature analysis for genomic regions in the nuclear core and periphery.
(A) Substitution patterns and (B) contribution of those substitution classes to the major somatic mutation signatures in the six cancer types – melanoma (SKCA), lung cancer (LUSC), gastric cancer (STAD), lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), and prostate cancer (PRAD). Mutation signatures were generated based on non-negative matrix factorization using the somaticSignature R package. (C) AMR for cLAD and iLAD considering only C:G>A:T mutations was calculated, and AMR(cLAD)/AMR(iLAD) was plotted against the number of pack years smoked (Spearman correlation coefficient: 0.29; p-value >0.05), suggesting that the relative strength of signature of oxidative damage cause by smoking in the nuclear periphery was proportionally higher for heavy smokers compared to light smokers.
Supplementary Figure 5 Multivariate analysis to determine the effects of nuclear localization on mutation frequencies.
A) Effect of LAD on average mutation frequencies across tumors for different cancer types after adjusting for conservation, GC%, gene density, replication timing, and heterochromatin mark H3K9me3 signals using multiple linear regression. B) Effect sizes of different features on mutation rates, including phastCons score, GC%, gene density, H3K9me3, LAD density, and replication timing based on multivariate linear regression. C) cLAD regions tend to have a significantly higher adjusted mutation rate compared to iLAD regions after analyzing the effects separately for euchromatic and heterochromatic genomic regions (Mann Whitney U test p-value <0.05 for pairwise iLAD/cLAD comparisons for all cohorts). Euchromatin and heterochromatin regions were identified using Giemsa staining data (Cheung et al., Nature, 409,953-8, 2001) such that heterochromatic cLADp and iLADp regions had ≥75% Giemsa-positive staining and were deemed predominantly heterochromatic, while cLADn and iLADn had ≤25% Giemsa-positive staining and were considered predominantly euchromatic. Whiskers in the boxplot indicate upper and lower quartiles. D) cLAD regions tend to have a significantly higher adjusted mutation rate compared to iLAD regions after analyzing the effects separately for constant early replicating and constant late replicating genomic regions (Hansen et al., PNAS, 107, 139-44, 2010). cLADe and iLADe regions had early replication timing in a cell type-invariant manner. cLADl and iLADl regions had late replication timing in a cell type-invariant manner. Whiskers in the boxplot indicate upper and lower quartiles.
Supplementary Figure 6 Comparison of mutation patterns between the nuclear core and periphery in benign human cell types.
A) Data for somatic mutations detected in benign fibroblasts were obtained from Abyzov et al. Genome Res. 27, 512-523, 2017. Mutations were called based on human induced pluripotent stem cell (hiPSC) lines generated from reprogrammed skin fibroblast cells from families of donors. The SNV data was processes and analyzed in a manner similar to that described in Figure 2 and 3. B) Adjusted mutation rate (AMR) for cLAD was higher than that for iLADs, showing a trend consistent with that observed in the cancer genomes (Figure 2). But the the number of somatic mutations in each category per donor was small, and the difference was not statistically significant (Mann Whitney U test, p-value >0.05) or in the multivariate analysis similar to that presented in Figure 3. Whiskers in the boxplot indicate upper and lower quartiles.
Supplementary Figure 7 Residual plot for multivariate analysis to determine effects of nuclear localization on mutation frequencies.
A) Residual plot of multiple linear regression ‘Mutation rates ~ LAD + replication timing + GC% + gene density + H3K9me3 + phastCons’. Red lines: smoothers between residuals and fitted values from linear model. B) Residual plot of random forest regression ‘Mutation rates ~ LAD + replication timing + GC% + gene density + H3K9me3 + phastCons’. Red lines: smoothers between residuals and fitted values from the nonparametric random forest regression.
Supplementary Figure 8 Conditional variable importance analysis for nuclear localization.
A) Conditional variable importance computed by sub-dividing 1MB windows into 10 groups. Whiskers in the boxplot indicate upper and lower quartiles. B) Subsampling lymphoma cohort to test the robustness of the variable importance rankings to different sample sizes.
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–8, Supplementary Tables 1–3 and Supplementary Note (PDF 4506 kb)
Rights and permissions
About this article
Cite this article
Smith, K., Liu, L., Ganesan, S. et al. Nuclear topology modulates the mutational landscapes of cancer genomes. Nat Struct Mol Biol 24, 1000–1006 (2017). https://doi.org/10.1038/nsmb.3474
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nsmb.3474
This article is cited by
-
Integrative pan cancer analysis reveals epigenomic variation in cancer type and cell specific chromatin domains
Nature Communications (2021)
-
Convergent evolution of a genomic rearrangement may explain cancer resistance in hystrico- and sciuromorpha rodents
npj Aging and Mechanisms of Disease (2021)
-
Functional mechanisms and abnormalities of the nuclear lamina
Nature Cell Biology (2021)
-
Mutational signature SBS8 predominantly arises due to late replication errors in cancer
Communications Biology (2020)
-
Somatic mutation distributions in cancer genomes vary with three-dimensional chromatin structure
Nature Genetics (2020)