Overview of the simulation framework and the genomic data analysis pipeline.

Given the implications of tumor dynamics for precision medicine, there is a need to systematically characterize the mode of evolution across diverse solid tumor types. In particular, methods to infer the role of natural selection within established human tumors are lacking. read more...

Figure 1. The Big Bang model of tumor growth.

(a) After initiation, a tumor grows predominantly as a single expansion populated by numerous heterogeneous subclones. ITH results from private alterations (colored arrowheads) that continuously accumulate owing to replication errors. In addition to public alterations present in the first transformed cell, private alterations acquired early persist and become pervasive in the final tumor although remaining non-dominant (colored segments). Late-arising alterations are only present in small regions of the tumor.

(b) In the Big Bang model, the pervasiveness of private alterations depends on when the alteration occurs during growth, rather than on selection for that alteration. The schematic illustrates how early private alterations, despite remaining non-dominant, are pervasive within the tumor (for example, red and yellow) and can be found in distant regions, thus appearing variegated (for example, red). This is owing to aberrant subclone mixing in the primordial tumor, followed by scattering during expansion. Late alterations are restricted to small regions (for example, black, pink, gray) and are essentially undetectable by conventional bulk genomic profiling. Distance from the dashed vertical axis corresponds to increasingly late onset for alterations. Dashed boxes represent sampled regions.

(c) We sampled an average of 23 individual tumor glands (<10,000 cells) from distant regions (~0.5 cm3 in size) and bulk (left and right) samples. Samples were profiled using several genomic techniques, including copy number analysis, whole-exome and targeted sequencing, neutral methylation tag sequencing and FISH, providing a panoramic view of genomic alterations throughout the tumor on multiple spatial scales.


Bhatt AS, Curtis C. AGBT meeting reportGenome Biol. 2018 May 21;19(1):60. doi: 10.1186/s13059-018-1447-8.

Pogrebniak K & Curtis C. Harnessing tumor evolution to circumvent resistance. Trends In Genetics, in press

Calvin Kuo & Curtis C. Organoids reveal cancer dynamics. Nature, News & Views doi:10.1038/d41586-018-03841-x, 2018

Afghahi A, Purington N, Han S, Desai M, Pierson E, Mathur M, Seto T, Thompson C, Rigdon J, Telli M, Badve S, Curtis C, West R, Horst K, Gomez G, Ford J, Sledge G & Kurian A. Higher Absolute Lymphocyte Counts Predict Lower Mortality from Early-Stage Triple-Negative Breast Cancer. Clinical Cancer Research, pii: clincanres.1323.2017. doi: 10.1158/1078-0432.CCR-17-1323, 2018

Rogers ZN, McFarland CD, Winters IP, Seoane JA, Brady JJ, Curtis C, Petrov D & Winslow MM. The fitness landscape of tumor suppression in lung adenocarcinoma in vivo. Nature Genetics 2018 doi:10.1038/s41588-018-0083-2

Williams MK, Werner B, Curtis C, Barnes CP, Sottoriva S & Graham TA. Quantification of subclonal selection in cancer from bulk sequencing data. In press, Nature Genetics, 50(6):895-903. doi: 10.1038/s41588-018-0128-6, 2018

Cho S, Xu J, Sun R, Mumbach M, Carter AC, Chen YG, Yost KE, Kim J, Nevins S, Chin SF, Carlos Caldas C, Liu JS, Horbeck M, Lim DA, Weissman JS, Curtis C & Chang HY. Promoter of lncRNA gene PVT1 is a tumor suppressor DNA boundary element. In press, Cell, 31;173(6):1398-1412.e22, 2018


Mello SS, Valente LJ, Raj N, Seoane JA, ... , Curtis C, Attardi LD. A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic CancerCancer Cell. 32(4):460-473.e6 2017

Sun R, Hu Z, Curtis, CBig Bang tumor dynamics and clonal evolution. In Cancer Evolution. Cold Spring Harbor Perspect Med, Cold Spring Harbor Press. pii: a028381 2017. doi: 10.1101, 2017.

Yan KS, Gevaert O, Zheng GX, Anchang B, Probert CS, ... , Curtis C, Ji HP, Li L, Henning SK, Wong MH & Kuo CJ. Mature enteroendocrine cells possess injury-inducible reserve stem cell function. Cell Stem Cell, 6;21(1):78-90.e6, 2017 

Sun R, Hu Z, Sottoriva A, Graham TA, Harpak A, Ma Z, Shibata D & Curtis C. Between-region genetic divergence reflects the mode and tempo of tumor evolution. Nature Genetics, 2017 doi: 10.1038/ng.3891 

Hu Z, Sun R & Curtis, C. A Population Genetic Perspective on Tumor Evolution. Evolutionary principles – heterogeneity in cancerBiochimica et Biophysica Acta - Reviews on Cancer, pii: S0304-419X(17)30046-X. doi: 10.1016/j.bbcan.2017.03.001, 2017.

Zhao J, Salomon MP, Shibata D, Curtis C, Siegmund K & Marjoram P. Early mutation bursts and cancer stem cell division asymmetry in colorectal tumors. PLoS One, 12(3):e0172516, 2017

TCGA Research Atlas Network, Seoane JA…Curtis, C...  Integrated genomic characterization of oesophageal carcinoma. Nature Jan, 2017 doi: 10.1038/nature20805

Gendelman R, Xing H, Mirzoeva OK, Sarde P, Curtis C, Feiler HS, McDonagh P, Gray JW, Khalil I, & Korn MW.. Bayesian network inference modeling identifies TRIB1 as a novel regulator of cell cycle progression and survival in cancer cells. Cancer Research, 2017.


Hu Z, Curtis C. Inferring tumor phylogenies from multi-region sequencing. Cell Syst. 3(1):12-4, 2016. 

Hu Z*, Mao JH*, Curtis C*, Huang G*, Kuo WL, Lenburg ME, Gu S, Korkola JE, Ziyad S, Bayani N, Samarajiwa S, Seoane JA, Dan M, Esch A, Feiler HS, Wang NJ, Hardwicke MA, Laquerre S, Jackson J, Wood K, Weber B, Spellman PT, Aparicio S, Wooster R, Caldas C, & Gray JW. Genomic co-amplification up-regulates a mitotic gene network whose activity predicts outcome and response to mitotic protein inhibitors in breast cancer. Breast Cancer Research, 18(1):70, 2016. 


Kang H, Salomon MP, Sottoriva A, Zhao J, Toy M, Press MF, Curtis C, Marjoram P, Siegmund K, Shibata D. Many private mutations originate from the first few divisions of a human colorectal adenoma. J Pathology, 2015.    

Sottoriva A, Kang H, Ma Z, Graham TA, Salomon M, Zhao J, Marjoram P, Siegmund K, Press MF, Shibata D & Curtis C. A Big Bang Model of human colorectal tumor growthNature Genetics, 2015.

** Recommended by Faculty of 1000 Prime

Nature Genetics News and Views Commentary: Big Bang and Context Driven Collapse

Nature Reviews Cancer Research Highlight: Explosive Beginnings 

Curtis C. Genomic Profiling of breast cancersCurr Opin Obstet Gynecol, 27(1), 2015.

Piccirillo SGM, Spiteri I, Sottoriva A, Touloumis A, Ber S, Price SJ, Heywood R, Francis NJ, Collins VP, Venkitaraman AR,Curtis C, Marioni JC, Tavaré S & Watts C. Contributions to drug resistance in glioblastoma derived from malignant cells in the sub-ependymal zoneCancer Res 75(1), 2015. 

Moen Vollan HK, Rueda OM, Chin SF, Curtis C, Turashvili G, Shah SP, Lingjaerde OC, Yuan Y, Ng CK, Dunning MJ, Dicks E, Provenzano E, Sammut S, McKinney S, Ellis IO, Pinder S, Purushotham A, Murphy LC, METABRIC Group, Tavaré S, Brenton JD, Pharoah PD, Børrensen-Dale AL, Aparicio S & Caldas C. A tumor DNA complex-arm aberration index is an independent predictor of survival in breast and ovarian cancerMolecular Oncology9(1), 2015. 


Ali HR, Rueda OM, Chin SF, Curtis C, Dunning M, Aparicio S and Caldas C. Genome-driven integrated classification of breast cancer validated in over 7,500 samplesGenome Biology 15(8), 2014. 



    Yuan, Y, Failmezger H, Rueda OM, Ali R, Gräf S, Schwarz R, Chin SF, Curtis C, Bardwell H, Provenzano E, Aparicio S, Caldas C & Markowetz F. Quantitative image analysis of cellular heterogeneity in breast tumorsScience Translational Medicine, 4(157):157ra143, 2012. 

    Lynch AG, Chin SF, Dunning MJ, Caldas C, Tavaré S & Curtis C. Calling sample mixups in cancer population studiesPLoS One, 7(8): e41815, 2012. 

    Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, Speed D, Lynch AG, Samarajiwa S, Yuan Y, Gräf S, Ha G, Haffari G, Bashashati A, Russell R, McKinney S, METABRIC Group, Langerød A, Green A, Provenzano E, Wishart G, Pinder S, Børrensen-Dale, Brenton JD, Tavaré, Caldas C & Aparicio S. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroupsNature, 486(7403):346-52, 2012. 

    Shah SP, Roth A, Goya R, Oloumi A, Ha G, Zhao Y, Turashvili G, Ding J, Tse K, Haffari G, Bashashati A, Prentice LM, Khattra J, Burleigh A, Yap D, Bernard V, McPherson A, Shumansky K, Crisan A, Giuliany R, Heravi-Moussavi A, Rosner J, Lai D, Birol I, Varhol R, Tam A, Dhalla N, Zeng T, Ma K, Chan SK, Griffith M, Moradian A, Cheng SW, Morin GB, Watson P, Gelmon K, Chia S, Chin SF, Curtis C, Rueda OM, Pharoah PD, Damaraju S, Mackey J, Hoon K, Harkins T,Tadigotla V, Sigaroudinia M, Gascard P, Tlsty T, Costello JF, Meyer IM, Eaves CJ, Wasserman WW, Jones S, Huntsman D, Hirst M, Caldas C, Marra MA, Aparicio S. The clonal and mutational evolution spectrum of primary triple-negative breast cancersNature, 486(7403):395-9, 2012. 

    Maia AT, Antoniou AC, O'Reilly M, Samarajiwa S, Dunning M, Kartsonaki C, Chin SF, Curtis C, McGuffog L, Domchek SM, Embrace E, Easton DF, Peock S, Frost D, Evans DG, Eeles R, Izatt L, Adlard J, Eccles D, Gemo G, Sinilnikova OM, Mazoyer S, Stoppa-Lyonnet D, Gauthier-Villars M, Faivre L, Venat-Bouvet L, Delnatte C, Nevanlinna H, Couch FJ, Godwin AK, Caligo MA, Swe-Brca SB, Barkardottir RB, Kconfab K, Chen X, Beesley J, Healey S, Caldas C, Chenevix-Trench G, Ponder BA. Effects of BRCA2 cis-regulation in normal breast and cancer risk amongst BRCA2 mutation carriersBreast Cancer Res, 18;14(2):R63, 2012. 

2011 & Earlier