[en] Whole-genome doubling (WGD) is a common yet poorly understood event associated with poor clinical outcomes. Here, we characterize mechanisms by which WGD drives tumor evolution, utilizing mouse mammary tumor models of WGD established through cell fusion. We find that WGD increases transcriptomic and epigenetic heterogeneity and identify the YM155 BIRC5 inhibitor as a compound specifically suppressing WGD+ tumors. WGD triggers immune evasion by escaping CD8+ T cell responses, rendering WGD+ tumors more sensitive to anti-PD-L1. Through single-cell profiling, we discover that WGD+ cancer cells exhibit reduced antigen presentation and response to IFNγ, attributed to the epigenetic silencing of MHCI transcriptional regulators via elevated histone H3 lysine 27 trimethylation. Further investigations reveal decreased KDM6 activity and increased succinate levels in WGD+ tumors. PRC2 inhibition preferentially suppresses WGD+ tumor growth, enhances antigen presentation, and CD8+ T cell infiltration. Our results underscore metabolic and epigenetic alterations as critical drivers of WGD-associated immune escape.
Disciplines :
Oncology
Author, co-author :
Foidart, Pierre ; Université de Liège - ULiège > Département des sciences cliniques ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'oncologie médicale ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
Li, Zheqi; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
Cai, Xinran; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
Seehawer, Marco; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
Brown, Daniel D; Institute for Precision Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA
Tawawalla, Amatullah; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Baldominos, Pilar; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA, Department of Immunology, Harvard Medical School, Boston, MA 02115, USA
Parvin, Salma; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
Nishida, Jun; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
Rojas-Jimenez, Ernesto; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
Bui, Triet M; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
Diciaccio, Benedetto; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
Kumar, Rahul; Women's Cancer Research Center, UPMC Hillman Cancer Center, Magee-Women's Research Institute, Pittsburgh, PA 15260, USA, Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA
Schlegel, Brent T; Women's Cancer Research Center, UPMC Hillman Cancer Center, Magee-Women's Research Institute, Pittsburgh, PA 15260, USA, Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA
Goyette, Marie-Anne; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
Scales, TashJae; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Yan, Pengze; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
Qiu, Xintao; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Li, Rong; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Jiang, Yijia; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Xie, Yingtian; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Aarabi, Mahmoud; Departments of Pathology, and Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA, UPMC Cytogenetics Laboratoires, UPMC Magee-Womens Hospital, Pittsburgh, PA 15213, USA
Huang, Xiao-Yun; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Stevens, Laura E; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
Cejas, Paloma; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Mangiante, Lise; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
Sotomayor Vivas, Cristina Irene; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
Houlahan, Kathleen E; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
Curtis, Christina; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
Oesterreich, Steffi; Women's Cancer Research Center, UPMC Hillman Cancer Center, Magee-Women's Research Institute, Pittsburgh, PA 15260, USA, Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA
Harris, Isaac S; University of Rochester Medical Center, Rochester, NY 14642, USA
Letai, Anthony G; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
Lee, Adrian V; Institute for Precision Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA, Women's Cancer Research Center, UPMC Hillman Cancer Center, Magee-Women's Research Institute, Pittsburgh, PA 15260, USA, Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA
Long, Henry W; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Agudo, Judith; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA, Department of Immunology, Harvard Medical School, Boston, MA 02115, USA
Polyak, Kornelia ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. Electronic address: kornelia_polyak@dfci.harvard.edu
CIHR - Canadian Institutes of Health Research BAEF - Belgian American Educational Foundation WBI - Wallonie-Bruxelles International NIH. NCI - National Institutes of Health. National Cancer Institute
Gordon, D.J., Resio, B., Pellman, D., Causes and consequences of aneuploidy in cancer. Nat. Rev. Genet. 13 (2012), 189–203, 10.1038/nrg3123.
Sansregret, L., Swanton, C., The Role of Aneuploidy in Cancer Evolution. Cold Spring Harb. Perspect. Med., 7, 2017, a028373, 10.1101/cshperspect.a028373.
Kirsch-Volders, M., Mišík, M., Fenech, M., Tetraploidy in normal tissues and diseases: mechanisms and consequences. Chromosoma, 134, 2025, 3, 10.1007/s00412-025-00829-1.
Dewhurst, S.M., McGranahan, N., Burrell, R.A., Rowan, A.J., Grönroos, E., Endesfelder, D., Joshi, T., Mouradov, D., Gibbs, P., Ward, R.L., et al. Tolerance of whole- genome doubling propagates chromosomal instability and accelerates cancer genome evolution. Cancer Discov. 4 (2014), 175–185, 10.1158/2159-8290.CD-13-0285.
Ippolito, M.R., Martis, V., Martin, S., Tijhuis, A.E., Hong, C., Wardenaar, R., Dumont, M., Zerbib, J., Spierings, D.C.J., Fachinetti, D., et al. Gene copy-number changes and chromosomal instability induced by aneuploidy confer resistance to chemotherapy. Dev. Cell 56 (2021), 2440–2454.e6, 10.1016/j.devcel.2021.07.006.
Vendramin, R., Litchfield, K., Swanton, C., Cancer evolution: Darwin and beyond. EMBO J., 40, 2021, e108389, 10.15252/embj.2021108389.
Sdeor, E., Okada, H., Saad, R., Ben-Yishay, T., Ben-David, U., Aneuploidy as a driver of human cancer. Nat. Genet. 56 (2024), 2014–2026, 10.1038/s41588-024-01916-2.
Garrido-Castro, A.C., Lin, N.U., Polyak, K., Insights into Molecular Classifications of Triple-Negative Breast Cancer: Improving Patient Selection for Treatment. Cancer Discov. 9 (2019), 176–198, 10.1158/2159-8290.CD-18-1177.
Cortes, J., Rugo, H.S., Cescon, D.W., Im, S.A., Yusof, M.M., Gallardo, C., Lipatov, O., Barrios, C.H., Perez-Garcia, J., Iwata, H., et al. Pembrolizumab plus Chemotherapy in Advanced Triple-Negative Breast Cancer. N. Engl. J. Med. 387 (2022), 217–226, 10.1056/NEJMoa2202809.
Bardia, A., Hurvitz, S.A., Tolaney, S.M., Loirat, D., Punie, K., Oliveira, M., Brufsky, A., Sardesai, S.D., Kalinsky, K., Zelnak, A.B., et al. Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer. N. Engl. J. Med. 384 (2021), 1529–1541, 10.1056/NEJMoa2028485.
Shu, S., Lin, C.Y., He, H.H., Witwicki, R.M., Tabassum, D.P., Roberts, J.M., Janiszewska, M., Huh, S.J., Liang, Y., Ryan, J., et al. Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer. Nature 529 (2016), 413–417, 10.1038/nature16508.
Alečković, M., Li, Z., Zhou, N., Qiu, X., Lulseged, B., Foidart, P., Huang, X.Y., Garza, K., Shu, S., Kesten, N., et al. Combination Therapies to Improve the Efficacy of Immunotherapy in Triple-negative Breast Cancer. Mol. Cancer Therapeut. 22 (2023), 1304–1318, 10.1158/1535-7163.MCT-23-0303.
Shu, S., Wu, H.J., Ge, J.Y., Zeid, R., Harris, I.S., Jovanović, B., Murphy, K., Wang, B., Qiu, X., Endress, J.E., et al. Synthetic Lethal and Resistance Interactions with BET Bromodomain Inhibitors in Triple-Negative Breast Cancer. Mol. Cell 78 (2020), 1096–1113.e8, 10.1016/j.molcel.2020.04.027.
Ge, J.Y., Shu, S., Kwon, M., Jovanović, B., Murphy, K., Gulvady, A., Fassl, A., Trinh, A., Kuang, Y., Heavey, G.A., et al. Acquired resistance to combined BET and CDK4/6 inhibition in triple-negative breast cancer. Nat. Commun., 11, 2020, 2350, 10.1038/s41467-020-16170-3.
Pfau, S.J., Silberman, R.E., Knouse, K.A., Amon, A., Aneuploidy impairs hematopoietic stem cell fitness and is selected against in regenerating tissues in vivo. Genes Dev. 30 (2016), 1395–1408, 10.1101/gad.278820.116.
Santaguida, S., Richardson, A., Iyer, D.R., M'Saad, O., Zasadil, L., Knouse, K.A., Wong, Y.L., Rhind, N., Desai, A., Amon, A., Chromosome Mis-segregation Generates Cell-Cycle-Arrested Cells with Complex Karyotypes that Are Eliminated by the Immune System. Dev. Cell 41 (2017), 638–651.e5, 10.1016/j.devcel.2017.05.022.
Bakhoum, S.F., Cantley, L.C., The Multifaceted Role of Chromosomal Instability in Cancer and Its Microenvironment. Cell 174 (2018), 1347–1360, 10.1016/j.cell.2018.08.027.
Mackenzie, K.J., Carroll, P., Martin, C.A., Murina, O., Fluteau, A., Simpson, D.J., Olova, N., Sutcliffe, H., Rainger, J.K., Leitch, A., et al. cGAS surveillance of micronuclei links genome instability to innate immunity. Nature 548 (2017), 461–465, 10.1038/nature23449.
Taylor, A.M., Shih, J., Ha, G., Gao, G.F., Zhang, X., Berger, A.C., Schumacher, S.E., Wang, C., Hu, H., Liu, J., et al. Genomic and Functional Approaches to Understanding Cancer Aneuploidy. Cancer Cell 33 (2018), 676–689.e3, 10.1016/j.ccell.2018.03.007.
Davoli, T., Uno, H., Wooten, E.C., Elledge, S.J., Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy. Science, 355, 2017, eaaf8399, 10.1126/science.aaf8399.
Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 490 (2012), 61–70, 10.1038/nature11412.
Quinton, R.J., DiDomizio, A., Vittoria, M.A., Kotýnková, K., Ticas, C.J., Patel, S., Koga, Y., Vakhshoorzadeh, J., Hermance, N., Kuroda, T.S., et al. Whole-genome doubling confers unique genetic vulnerabilities on tumour cells. Nature 590 (2021), 492–497, 10.1038/s41586-020-03133-3.
Senovilla, L., Vitale, I., Martins, I., Tailler, M., Pailleret, C., Michaud, M., Galluzzi, L., Adjemian, S., Kepp, O., Niso-Santano, M., et al. An immunosurveillance mechanism controls cancer cell ploidy. Science 337 (2012), 1678–1684, 10.1126/science.1224922.
Wang, R.W., Viganò, S., Ben-David, U., Amon, A., Santaguida, S., Aneuploid senescent cells activate NF-kappaB to promote their immune clearance by NK cells. EMBO Rep., 22, 2021, e52032, 10.15252/embr.202052032.
Bielski, C.M., Zehir, A., Penson, A.V., Donoghue, M.T.A., Chatila, W., Armenia, J., Chang, M.T., Schram, A.M., Jonsson, P., Bandlamudi, C., et al. Genome doubling shapes the evolution and prognosis of advanced cancers. Nat. Genet. 50 (2018), 1189–1195, 10.1038/s41588-018-0165-1.
Carter, S.L., Cibulskis, K., Helman, E., McKenna, A., Shen, H., Zack, T., Laird, P.W., Onofrio, R.C., Winckler, W., Weir, B.A., et al. Absolute quantification of somatic DNA alterations in human cancer. Nat. Biotechnol. 30 (2012), 413–421, 10.1038/nbt.2203.
Curtis, C., Shah, S.P., Chin, S.-F., Turashvili, G., Rueda, O.M., Dunning, M.J., Speed, D., Lynch, A.G., Samarajiwa, S., Yuan, Y., et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486 (2012), 346–352.
Martínez-Jiménez, F., Movasati, A., Brunner, S.R., Nguyen, L., Priestley, P., Cuppen, E., Van Hoeck, A., Pan-cancer whole-genome comparison of primary and metastatic solid tumours. Nature 618 (2023), 333–341, 10.1038/s41586-023-06054-z.
Rees, M.G., Seashore-Ludlow, B., Cheah, J.H., Adams, D.J., Price, E.V., Gill, S., Javaid, S., Coletti, M.E., Jones, V.L., Bodycombe, N.E., et al. Correlating chemical sensitivity and basal gene expression reveals mechanism of action. Nat. Chem. Biol. 12 (2016), 109–116, 10.1038/nchembio.1986.
Barretina, J., Caponigro, G., Stransky, N., Venkatesan, K., Margolin, A.A., Kim, S., Wilson, C.J., Lehár, J., Kryukov, G.V., Sonkin, D., et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483 (2012), 603–607, 10.1038/nature11003.
Nakahara, T., Kita, A., Yamanaka, K., Mori, M., Amino, N., Takeuchi, M., Tominaga, F., Hatakeyama, S., Kinoyama, I., Matsuhisa, A., et al. YM155, a novel small-molecule survivin suppressant, induces regression of established human hormone-refractory prostate tumor xenografts. Cancer Res. 67 (2007), 8014–8021, 10.1158/0008-5472.CAN-07-1343.
Ryan, J., Letai, A., BH3 profiling in whole cells by fluorimeter or FACS. Methods 61 (2013), 156–164, 10.1016/j.ymeth.2013.04.006.
Reschke, R., Gajewski, T.F., CXCL9 and CXCL10 bring the heat to tumors. Sci. Immunol., 7, 2022, eabq6509, 10.1126/sciimmunol.abq6509.
Chen, Q., Liu, Y., Gao, Y., Zhang, R., Hou, W., Cao, Z., Jiang, Y.Z., Zheng, Y., Shi, L., Ma, D., et al. A comprehensive genomic and transcriptomic dataset of triple-negative breast cancers. Sci. Data, 9, 2022, 587, 10.1038/s41597-022-01681-z.
Alshetaiwi, H., Pervolarakis, N., McIntyre, L.L., Ma, D., Nguyen, Q., Rath, J.A., Nee, K., Hernandez, G., Evans, K., Torosian, L., et al. Defining the emergence of myeloid-derived suppressor cells in breast cancer using single-cell transcriptomics. Sci. Immunol., 5, 2020, eaay6017, 10.1126/sciimmunol.aay6017.
Jin, S., Guerrero-Juarez, C.F., Zhang, L., Chang, I., Ramos, R., Kuan, C.H., Myung, P., Plikus, M.V., Nie, Q., Inference and analysis of cell-cell communication using CellChat. Nat. Commun., 12, 2021, 1088, 10.1038/s41467-021-21246-9.
Ding, K., Chen, F., Priedigkeit, N., Brown, D.D., Weiss, K., Watters, R., Levine, K.M., Heim, T., Li, W., Hooda, J., et al. Single cell heterogeneity and evolution of breast cancer bone metastasis and organoids reveals therapeutic targets for precision medicine. Ann. Oncol. 33 (2022), 1085–1088, 10.1016/j.annonc.2022.06.005.
Andreatta, M., Corria-Osorio, J., Müller, S., Cubas, R., Coukos, G., Carmona, S.J., Interpretation of T cell states from single-cell transcriptomics data using reference atlases. Nat. Commun., 12, 2021, 2965, 10.1038/s41467-021-23324-4.
Wang, S., Sun, H., Ma, J., Zang, C., Wang, C., Wang, J., Tang, Q., Meyer, C.A., Zhang, Y., Liu, X.S., Target analysis by integration of transcriptome and ChIP-seq data with BETA. Nat. Protoc. 8 (2013), 2502–2515, 10.1038/nprot.2013.150.
Sundaram, L., Kumar, A., Zatzman, M., Salcedo, A., Ravindra, N., Shams, S., Louie, B.H., Bagdatli, S.T., Myers, M.A., Sarmashghi, S., et al. Single-cell chromatin accessibility reveals malignant regulatory programs in primary human cancers. Science, 385, 2024, eadk9217, 10.1126/science.adk9217.
Qi, W., Zhao, K., Gu, J., Huang, Y., Wang, Y., Zhang, H., Zhang, M., Zhang, J., Yu, Z., Li, L., et al. An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED. Nat. Chem. Biol. 13 (2017), 381–388, 10.1038/nchembio.2304.
Baksh, S.C., Finley, L.W.S., Metabolic Coordination of Cell Fate by alpha-Ketoglutarate-Dependent Dioxygenases. Trends Cell Biol. 31 (2021), 24–36, 10.1016/j.tcb.2020.09.010.
Vittoria, M.A., Quinton, R.J., Ganem, N.J., Whole-genome doubling in tissues and tumors. Trends Genet. 39 (2023), 954–967, 10.1016/j.tig.2023.08.004.
Frankell, A.M., Dietzen, M., Al Bakir, M., Lim, E.L., Karasaki, T., Ward, S., Veeriah, S., Colliver, E., Huebner, A., Bunkum, A., et al. The evolution of lung cancer and impact of subclonal selection in TRACERx. Nature 616 (2023), 525–533, 10.1038/s41586-023-05783-5.
Storchová, Z., Breneman, A., Cande, J., Dunn, J., Burbank, K., O'Toole, E., Pellman, D., Genome-wide genetic analysis of polyploidy in yeast. Nature 443 (2006), 541–547, 10.1038/nature05178.
Govindan, R., Townsend, A.R., Miller, K.D., Mehmi, I., Kuboki, Y., Dumbrava, E.E., Hamilton, E.P., Vuu, I., Rasmussen, E., Mileshkin, L.R., et al. Trial in progress: A phase 1, multicenter, open-label, dose-exploration and dose-expansion study evaluating the safety, tolerability, pharmacokinetics, and efficacy of AMG650 in subjects with advanced solid tumors. J. Clin. Oncol., 39, 2021, TPS5600, 10.1200/JCO.2021.39.15_suppl.TPS5600.
Ippolito, M.R., Zerbib, J., Eliezer, Y., Reuveni, E., Viganò, S., De Feudis, G., Shulman, E.D., Savir Kadmon, A., Slutsky, R., Chang, T., et al. Increased RNA and Protein Degradation Is Required for Counteracting Transcriptional Burden and Proteotoxic Stress in Human Aneuploid Cells. Cancer Discov. 14 (2024), 2532–2553, 10.1158/2159-8290.CD-23-0309.
Veneti, Z., Gkouskou, K.K., Eliopoulos, A.G., Polycomb Repressor Complex 2 in Genomic Instability and Cancer. Int. J. Mol. Sci., 18, 2017, 1657, 10.3390/ijms18081657.
Tang, M., Gong, M., Liu, X., Zhang, T., Liu, Z., Song, D., Recent update on the development of EZH2 inhibitors and degraders for cancer therapy. Eur. J. Med. Chem., 299, 2025, 118106, 10.1016/j.ejmech.2025.118106.
McPherson, A., Vázquez-García, I., Myers, M.A., Al-Rawi, D.H., Zatzman, M., Weiner, A.C., Freeman, S., Mohibullah, N., Satas, G., Williams, M.J., et al. Ongoing genome doubling shapes evolvability and immunity in ovarian cancer. Nature 644 (2025), 1078–1087, 10.1038/s41586-025-09240-3.
Prip, F., Lamy, P., Lindskrog, S.V., Strandgaard, T., Nordentoft, I., Birkenkamp-Demtröder, K., Birkbak, N.J., Kristjánsdóttir, N., Kjær, A., Andreasen, T.G., et al. Comprehensive genomic characterization of early-stage bladder cancer. Nat. Genet. 57 (2025), 115–125, 10.1038/s41588-024-02030-z.
Schreiber, R.D., Old, L.J., Smyth, M.J., Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 331 (2011), 1565–1570, 10.1126/science.1203486.
Jiang, Y.Z., Ma, D., Suo, C., Shi, J., Xue, M., Hu, X., Xiao, Y., Yu, K.D., Liu, Y.R., Yu, Y., et al. Genomic and Transcriptomic Landscape of Triple-Negative Breast Cancers: Subtypes and Treatment Strategies. Cancer Cell 35 (2019), 428–440.e5, 10.1016/j.ccell.2019.02.001.
Tsherniak, A., Vazquez, F., Montgomery, P.G., Weir, B.A., Kryukov, G., Cowley, G.S., Gill, S., Harrington, W.F., Pantel, S., Krill-Burger, J.M., et al. Defining a Cancer Dependency Map. Cell 170 (2017), 564–576.e16, 10.1016/j.cell.2017.06.010.
Bankhead, P., Loughrey, M.B., Fernández, J.A., Dombrowski, Y., McArt, D.G., Dunne, P.D., McQuaid, S., Gray, R.T., Murray, L.J., Coleman, H.G., et al. QuPath: Open source software for digital pathology image analysis. Sci. Rep., 7, 2017, 16878, 10.1038/s41598-017-17204-5.
Hao, Y., Hao, S., Andersen-Nissen, E., Mauck, W.M. 3rd, Zheng, S., Butler, A., Lee, M.J., Wilk, A.J., Darby, C., Zager, M., et al. Integrated analysis of multimodal single-cell data. Cell 184 (2021), 3573–3587.e29, 10.1016/j.cell.2021.04.048.
Villanueva, R.A.M., Chen, Z.J., ggplot2: Elegant Graphics for Data Analysis. Measurement: Interdisciplinary Research and Perspectives 17 (2019), 160–167, 10.1080/15366367.2019.1565254.
Stuart, T., Srivastava, A., Madad, S., Lareau, C.A., Satija, R., Single-cell chromatin state analysis with Signac. Nat. Methods 18 (2021), 1333–1341, 10.1038/s41592-021-01282-5.
Love, M.I., Huber, W., Anders, S., Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol., 15, 2014, 550, 10.1186/s13059-014-0550-8.
Gu, Z., Eils, R., Schlesner, M., Complex heatmaps reveal patterns and correlations in multidimensional genomic data. Bioinformatics 32 (2016), 2847–2849, 10.1093/bioinformatics/btw313.
Hänzelmann, S., Castelo, R., Guinney, J., GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinf., 14, 2013, 7, 10.1186/1471-2105-14-7.
Dann, E., Henderson, N.C., Teichmann, S.A., Morgan, M.D., Marioni, J.C., Differential abundance testing on single-cell data using k-nearest neighbor graphs. Nat. Biotechnol. 40 (2022), 245–253, 10.1038/s41587-021-01033-z.
Cornwell, M., Vangala, M., Taing, L., Herbert, Z., Köster, J., Li, B., Sun, H., Li, T., Zhang, J., Qiu, X., et al. VIPER: Visualization Pipeline for RNA-seq, a Snakemake workflow for efficient and complete RNA-seq analysis. BMC Bioinformatics, 19, 2018, 135, 10.1186/s12859-018-2139-9.
Robinson, M.D., McCarthy, D.J., Smyth, G.K., edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26 (2010), 139–140, 10.1093/bioinformatics/btp616.
Yu, G., Wang, L.G., He, Q.Y., ChIPseeker: an R/Bioconductor package for ChIP peak annotation, comparison and visualization. Bioinformatics 31 (2015), 2382–2383, 10.1093/bioinformatics/btv145.
McKenna, A., Hanna, M., Banks, E., Sivachenko, A., Cibulskis, K., Kernytsky, A., Garimella, K., Altshuler, D., Gabriel, S., Daly, M., DePristo, M.A., The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20 (2010), 1297–1303, 10.1101/gr.107524.110.
Li, H., Durbin, R., Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics 26 (2010), 589–595, 10.1093/bioinformatics/btp698.
Li, H., Handsaker, B., Wysoker, A., Fennell, T., Ruan, J., Homer, N., Marth, G., Abecasis, G., Durbin, R., 1000 Genome Project Data Processing Subgroup. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25 (2009), 2078–2079, 10.1093/bioinformatics/btp352.
Shen, R., Seshan, V.E., FACETS: allele-specific copy number and clonal heterogeneity analysis tool for high-throughput DNA sequencing. Nucleic Acids Res., 44, 2016, e131, 10.1093/nar/gkw520.
McLaren, W., Gil, L., Hunt, S.E., Riat, H.S., Ritchie, G.R.S., Thormann, A., Flicek, P., Cunningham, F., The Ensembl Variant Effect Predictor. Genome Biol., 17, 2016, 122, 10.1186/s13059-016-0974-4.
Sachs, N., de Ligt, J., Kopper, O., Gogola, E., Bounova, G., Weeber, F., Balgobind, A.V., Wind, K., Gracanin, A., Begthel, H., et al. A Living Biobank of Breast Cancer Organoids Captures Disease Heterogeneity. Cell 172 (2018), 373–386.e10, 10.1016/j.cell.2017.11.010.
Su, Y., Subedee, A., Bloushtain-Qimron, N., Savova, V., Krzystanek, M., Li, L., Marusyk, A., Tabassum, D.P., Zak, A., Flacker, M.J., et al. Somatic Cell Fusions Reveal Extensive Heterogeneity in Basal-like Breast Cancer. Cell Rep. 11 (2015), 1549–1563, 10.1016/j.celrep.2015.05.011.
Ewels, P., Magnusson, M., Lundin, S., Käller, M., MultiQC: summarize analysis results for multiple tools and samples in a single report. Bioinformatics 32 (2016), 3047–3048, 10.1093/bioinformatics/btw354.
Cornwell, M., Vangala, M., Taing, L., Herbert, Z., Köster, J., Li, B., Sun, H., Li, T., Zhang, J., Qiu, X., et al. VIPER: Visualization Pipeline for RNA-seq, a Snakemake workflow for efficient and complete RNA-seq analysis. BMC Bioinf., 19, 2018, 135, 10.1186/s12859-018-2139-9.
Pereira, B., Chin, S.F., Rueda, O.M., Vollan, H.K.M., Provenzano, E., Bardwell, H.A., Pugh, M., Jones, L., Russell, R., Sammut, S.J., et al. The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes. Nat. Commun., 7, 2016, 11479, 10.1038/ncomms11479.
Patro, R., Duggal, G., Love, M.I., Irizarry, R.A., Kingsford, C., Salmon provides fast and bias-aware quantification of transcript expression. Nat. Methods 14 (2017), 417–419, 10.1038/nmeth.4197.
Li, Z., McGinn, O., Wu, Y., Bahreini, A., Priedigkeit, N.M., Ding, K., Onkar, S., Lampenfeld, C., Sartorius, C.A., Miller, L., et al. ESR1 mutant breast cancers show elevated basal cytokeratins and immune activation. Nat. Commun., 13, 2022, 2011, 10.1038/s41467-022-29498-9.
DePristo, M.A., Banks, E., Poplin, R., Garimella, K.V., Maguire, J.R., Hartl, C., Philippakis, A.A., del Angel, G., Rivas, M.A., Hanna, M., et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat. Genet. 43 (2011), 491–498, 10.1038/ng.806.
