Honors & Awards
The Innovative Genomics Initiative Fellow, The Innovative Genomics Initiative (2016 - 2018)
UCAS-BHP Billiton Scholarship, University of Chinese Academy of Sciences & BHP Billiton (2013)
Presidential Award (Excellent) of Chinese Academy of Sciences, Chinese Academy of Sciences (2013)
Excellent Student Award of Beijing Institute of Genomics, Beijing Institute of Genomics (2014)
Doctor of Philosophy, Chinese Academy Of Sciences (2015)
Bachelor of Engineering, Huazhong University Of Science & Technology (2010)
Christina Curtis, Postdoctoral Faculty Sponsor
Current Research and Scholarly Interests
My interest is applying population genetics approaches to the study of tumor evolution and dynamics with focus on the principles of intratumour heterogeneity, tumor progression, origin of metastasis and drug resistance etc.
Quantitative evidence for early metastatic seeding in colorectal cancer.
Both the timing and molecular determinants of metastasis are unknown, hindering treatment and prevention efforts. Here we characterize the evolutionary dynamics of this lethal process by analyzing exome-sequencing data from 118biopsies from 23patients with colorectal cancer with metastases to the liver or brain. The data show that the genomic divergence between the primary tumor and metastasis is low and that canonical driver genes were acquired early. Analysis within a spatial tumor growth model and statistical inference framework indicates that early disseminated cells commonly (81%, 17 out of 21evaluable patients) seed metastases while the carcinoma is clinically undetectable (typically, less than 0.01cm3). We validated the association between early drivers and metastasis in an independent cohort of 2,751colorectal cancers, demonstrating their utility as biomarkers of metastasis. This conceptual and analytical framework provides quantitative in vivo evidence that systemic spread can occur early in colorectal cancer and illuminates strategies for patient stratification and therapeutic targeting of the canonical drivers of tumorigenesis.
View details for DOI 10.1038/s41588-019-0423-x
View details for PubMedID 31209394
Clonal replacement and heterogeneity in breast tumors treated with neoadjuvant HER2-targeted therapy.
2019; 10 (1): 657
Genomic changes observed across treatment may result from either clonal evolution or geographically disparate sampling of heterogeneous tumors. Here we use computational modeling based on analysis of fifteen primary breast tumors and find that apparent clonal change between two tumor samples can frequently be explained by pre-treatment heterogeneity, such that at least two regions are necessary to detect treatment-induced clonal shifts. To assess for clonal replacement, we devise a summary statistic based on whole-exome sequencing of a pre-treatment biopsy and multi-region sampling of the post-treatment surgical specimen and apply this measure to five breast tumors treated with neoadjuvant HER2-targeted therapy. Two tumors underwent clonal replacement with treatment, and mathematical modeling indicates these two tumors had resistant subclones prior to treatment and rates of resistance-related genomic changes that were substantially larger than previous estimates. Our results provide a needed framework to incorporate primary tumor heterogeneity in investigating the evolution of resistance.
View details for PubMedID 30737380
Big Bang Tumor Growth and Clonal Evolution.
Cold Spring Harbor perspectives in medicine
2018; 8 (5)
The advent and application of next-generation sequencing (NGS) technologies to tumor genomes has reinvigorated efforts to understand clonal evolution. Although tumor progression has traditionally been viewed as a gradual stepwise process, recent studies suggest that evolutionary rates in tumors can be variable with periods of punctuated mutational bursts and relative stasis. For example, Big Bang dynamics have been reported, wherein after transformation, growth occurs in the absence of stringent selection, consistent with effectively neutral evolution. Although first noted in colorectal tumors, effective neutrality may be relatively common. Additionally, punctuated evolution resulting from mutational bursts and cataclysmic genomic alterations have been described. In this review, we contrast these findings with the conventional gradualist view of clonal evolution and describe potential clinical and therapeutic implications of different evolutionary modes and tempos.
View details for PubMedID 28710260
- Is the evolution in tumors Darwinian or non-Darwinian? NATIONAL SCIENCE REVIEW 2018; 5 (1): 15–17
Between-region genetic divergence reflects the mode and tempo of tumor evolution.
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. By simulating spatial tumor growth under different evolutionary modes and examining patterns of between-region subclonal genetic divergence from multiregion sequencing (MRS) data, we demonstrate that it is feasible to distinguish tumors driven by strong positive subclonal selection from those evolving neutrally or under weak selection, as the latter fail to dramatically alter subclonal composition. We developed a classifier based on measures of between-region subclonal genetic divergence and projected patient data into model space, finding different modes of evolution both within and between solid tumor types. Our findings have broad implications for how human tumors progress, how they accumulate intratumoral heterogeneity, and ultimately how they may be more effectively treated.
View details for DOI 10.1038/ng.3891
View details for PubMedID 28581503
A population genetics perspective on the determinants of intra-tumor heterogeneity.
Biochimica et biophysica acta
2017; 1867 (2): 109-126
Cancer results from the acquisition of somatic alterations in a microevolutionary process that typically occurs over many years, much of which is occult. Understanding the evolutionary dynamics that are operative at different stages of progression in individual tumors might inform the earlier detection, diagnosis, and treatment of cancer. Although these processes cannot be directly observed, the resultant spatiotemporal patterns of genetic variation amongst tumor cells encode their evolutionary histories. Such intra-tumor heterogeneity is pervasive not only at the genomic level, but also at the transcriptomic, phenotypic, and cellular levels. Given the implications for precision medicine, the accurate quantification of heterogeneity within and between tumors has become a major focus of current research. In this review, we provide a population genetics perspective on the determinants of intra-tumor heterogeneity and approaches to quantify genetic diversity. We summarize evidence for different modes of evolution based on recent cancer genome sequencing studies and discuss emerging evolutionary strategies to therapeutically exploit tumor heterogeneity. This article is part of a Special Issue entitled: Evolutionary principles - heterogeneity in cancer?, edited by Dr. Robert A. Gatenby.
View details for DOI 10.1016/j.bbcan.2017.03.001
View details for PubMedID 28274726
- Inferring Tumor Phylogenies from Multi-region Sequencing. Cell systems 2016; 3 (1): 12-14
Further genetic diversification in multiple tumors and an evolutionary perspective on therapeutics
View details for DOI 10.1101/025429
Extremely high genetic diversity in a single tumor points to prevalence of non-Darwinian cell evolution
Proc Natl Acad Sci U S A
View details for DOI 10.1073/pnas.1519556112
Age-Dependent Transition from Cell-Level to Population-Level Control in Murine Intestinal Homeostasis Revealed by Coalescence Analysis
2013; 9 (2)
In multi-cellular organisms, tissue homeostasis is maintained by an exquisite balance between stem cell proliferation and differentiation. This equilibrium can be achieved either at the single cell level (a.k.a. cell asymmetry), where stem cells follow strict asymmetric divisions, or the population level (a.k.a. population asymmetry), where gains and losses in individual stem cell lineages are randomly distributed, but the net effect is homeostasis. In the mature mouse intestinal crypt, previous evidence has revealed a pattern of population asymmetry through predominantly symmetric divisions of stem cells. In this work, using population genetic theory together with previously published crypt single-cell data obtained at different mouse life stages, we reveal a strikingly dynamic pattern of stem cell homeostatic control. We find that single-cell asymmetric divisions are gradually replaced by stochastic population-level asymmetry as the mouse matures to adulthood. This lifelong process has important developmental and evolutionary implications in understanding how adult tissues maintain their homeostasis integrating the trade-off between intrinsic and extrinsic regulations.
View details for DOI 10.1371/journal.pgen.1003326
View details for Web of Science ID 000315638300068
View details for PubMedID 23468655
Putative EPHX1 Enzyme Activity Is Related with Risk of Lung and Upper Aerodigestive Tract Cancers: A Comprehensive Meta-Analysis
2011; 6 (3)
EPHX1 is a key enzyme in metabolizing some exogenous carcinogens such as products of cigarette-smoking. Two functional polymorphisms in the EPHX1 gene, Tyr113His and His139Arg can alter the enzyme activity, suggesting their possible association with carcinogenesis risk, particularly of some tobacco-related cancers.A comprehensive systematic review and meta-analysis was performed of available studies on these two polymorphisms and cancer risk published up to November 2010, consisting of 84 studies (31144 cases and 42439 controls) for Tyr113His and 77 studies (28496 cases and 38506 controls) for His139Arg primarily focused on lung cancer, upper aerodigestive tract (UADT) cancers (including oral, pharynx, larynx and esophagus cancers), colorectal cancer or adenoma, bladder cancer and breast cancer. Results showed that Y113H low activity allele (H) was significantly associated with decreased risk of lung cancer (OR = 0.88, 95%CI = 0.80-0.96) and UADT cancers (OR = 0.86, 95%CI = 0.77-0.97) and H139R high activity allele (R) with increased risk of lung cancer (OR = 1.18, 95%CI = 1.04-1.33) but not of UADT cancers (OR = 1.05, 95%CI = 0.93-1.17). Pooled analysis of lung and UADT cancers revealed that low EPHX1 enzyme activity, predicted by the combination of Y113H and H139R showed decreased risk of these cancers (OR = 0.83, 95%CI = 0.75-0.93) whereas high EPHX1 activity increased risk of the cancers (OR = 1.20, 95%CI = 0.98-1.46). Furthermore, modest difference for the risk of lung and UADT cancers was found between cigarette smokers and nonsmokers both in single SNP analyses (low activity allele H: OR = 0.77/0.85 for smokers/nonsmokers; high activity allele R: OR = 1.20/1.09 for smokers/nonsmokers) and in combined double SNP analyses (putative low activity: OR = 0.73/0.88 for smokers/nonsmokers; putative high activity: OR = 1.02/0.93 for smokers/ nonsmokers).Putative low EPHX1 enzyme activity may have a potential protective effect on tobacco-related carcinogenesis of lung and UADT cancers, whereas putative high EPHX1 activity may have a harmful effect. Moreover, cigarette-smoking status may influence the association of EPHX1 enzyme activity and the related cancer risk.
View details for DOI 10.1371/journal.pone.0014749
View details for Web of Science ID 000288545100001
View details for PubMedID 21445251