Evolutionary history of human colitis-associated colorectal cancer

Baker, Ann‐Marie; Cross, William; Curtius, Kit; Bakir, Ibrahim Al; Choi, Chang-Ho Ryan; Belnoue-Davis, Hayley L.; Temko, Daniel; Biswas, Sujata; Martinez, Pierre; Williams, Marc; Lindsay, James O.; Feakins, Roger; Vega, Roser; Hayes, Stephen; Tomlinson, Ian; McDonald, Stuart; Moorghen, Morgan; Silver, Andrew; East, James E.; Wright, Nicholas A.; Wang, Lai Mun; Rodriguez‐Justo, Manuel; Jansen, Marnix; Hart, Ailsa; Leedham, Simon J.; Graham, Trevor A.

doi:10.1136/gutjnl-2018-316191

Cited by 126 publications

(130 citation statements)

References 39 publications

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“…We observed a nominally significant enrichment in genes associated with colorectal cancer (q=0.043) and cancer of any type (q=0.043), but these were driven by the mutations in ARID1A described above. As previously stated, we did not find a single mutation in APC, KRAS or TP53, the genes most commonly mutated in both sporadic-and colitis-associated colorectal cancer 23,24 . We did observe two large-scale deletions that overlap known tumour suppressors, PIK3R1 and CUX1, and are likely drivers.…”

Section: Ibd Drives Positive Selection In Colonic Stem Cellssupporting

confidence: 71%

“…The application of dNdScv revealed three genes, ARID1A, PIGR and ZC3H12A, to be under positive selection in the IBD colon ( Figure 4A). ARID1A is a well-established tumour suppressor, both in sporadic-and colitis-associated colorectal cancer 23,24 , and also plays a role in maintaining the intestinal stem cell niche 25 . Heterozygous truncating mutations in ARID1A preceded several clonal expansions in our dataset and some patients carried distinct ARID1A mutations in different crypts ( Figure 4B).…”

Section: Ibd Drives Positive Selection In Colonic Stem Cellsmentioning

confidence: 99%

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Somatic evolution in non-neoplastic IBD-affected colon

McIntyre

Coorens

Butler

et al. 2019

Preprint

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paragraph Inflammatory bowel disease (IBD) is a chronic inflammatory disease associated with increased risk of gastrointestinal cancers 1-3 but our understanding of the effects of IBD on the mutational profile and clonal structure of the colon is limited. Here, we isolated and whole-genome sequenced 370 colonic crypts from 45 IBD patients, and compared these to 413 crypts from 41 non-IBD controls. We estimated the base substitution rate of affected colonic epithelial cells to be doubled after IBD onset. This change was primarily driven by acceleration of mutational processes ubiquitously observed in normal colon, and we did not detect an IBD-specific mutational process. In contrast to the normal colon, where clonal expansions outside the confines of the crypt are rare, we observed widespread millimeterscale clonal expansions. We also found that non-synonymous mutations in ARID1A, PIGR and ZC3H12A, and genes in the interleukin 17 and Toll-like receptor pathways, were under positive selection in colonic crypts from IBD patients. With the exception of ARID1A, these genes and pathways have not been previously associated with cancer risk. Our results provide new insights into the consequences of chronic intestinal inflammation on the 2. Adami, H.-O. et al. The continuing uncertainty about cancer risk in inflammatory bowel disease. Gut 65, 889-893 (2016). 3. Lutgens, M. W. M. D. et al. Declining risk of colorectal cancer in inflammatory bowel disease: an updated meta-analysis of population-based cohort studies. Inflamm. Bowel Dis.

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Section: Ibd Drives Positive Selection In Colonic Stem Cellssupporting

confidence: 71%

Section: Ibd Drives Positive Selection In Colonic Stem Cellsmentioning

confidence: 99%

Somatic evolution in non-neoplastic IBD-affected colon

McIntyre

Coorens

Butler

et al. 2019

Preprint

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“…These observations are especially relevant for cancer screening approaches. As the latency between the emergence of the invasive clone and metastatic spread can be short the window for early detection could be very limited 117 . Many questions about evolutionary trajectories remain including the environmental conditions which favour gradual evolution (gradual accumulation of driver mutations), or punctuated evolution (large-scale rearrangements of the genome leading to many drivers acquired at once) and how these may be altered for therapeutic benefit.…”

Section: Cin and Clinical Outcomesmentioning

confidence: 99%

Resolving genetic heterogeneity in cancer

et al. 2019

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To a large extent cancer conforms to evolutionary rules defined by the rates at which clones mutate, adapt and grow. Compared to species evolution however, cancer is a particular case, due to the vast population size, chromosomal instability, and the potential for phenotypic plasticity. Nevertheless, an evolutionary framework is a powerful aid in our understanding of cancer progression and therapy failure, and could be applied to predict individual tumour behaviour and aid treatment strategies. Introduction Tumours are composed of subpopulations of cells (subclones) that may be distinguished by a variety of features impacting their phenotype, including genetic alterations. Genetic intratumour heterogeneity (ITH) has been documented across most cancers (reviewed in 1) and acts as a substrate for clonal evolution. The fundamental biological mechanisms underlying clonal evolution [G] in cancer are similar to those that underpin the evolution of asexually-reproducing species: replication, heritable variation, genetic drift [G], selection [G] and environmental changes. Central to the neo-Darwinian synthesis of evolutionary biology is the paradigm of molecular evolution [G], which links Mendelian genetics to Darwinian adaptation. Molecular evolution is relevant to cancer because the use of genomic sequencing is a key technology to understand temporal and spatial patterns of somatic evolution [G]. At the core of molecular evolution, in turn, is theoretical population genetics, which has been the fundamental mathematical formalism to describe evolution for the past 90 years 2,3 The same theoretical framework has been used to understand clonal evolution in cancer 4 5 6 7 8 9 10 11. The study of the evolutionary dynamics of cancer clones is fundamentally concerned with the relative frequencies of cancer subpopulations over space

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“…Following sustained inflammatory injury in the presence of genetic alterations (e.g., APC mutation), precancerous conditions are often able to take hold in the tissue niche [17]. Examples of this include Barrett's esophagus, intestinal adenomas, pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasia (IPMN), and others [17][18][19][20][21]. Although inflammatory conditions may progress to precancer which ultimately gives rise to cancer, current knowledge suggests that the majority of patients with acute or chronic inflammatory conditions will not experience progression to cancer.…”

Section: Clinical Relevance Of Gi Inflammation On the Transition Tomentioning

confidence: 99%

Implications for Tumor Microenvironment and Epithelial Crosstalk in the Management of Gastrointestinal Cancers

Westphalen

Wee

et al. 2019

Journal of Oncology

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Rapid advances in technology are revealing previously unknown organization, cooperation, and limitations within the population of nontumor cells surrounding the tumor epithelium known as the tumor microenvironment (TME). Nowhere are these findings more pertinent than in the gastrointestinal (GI) tract where exquisite cell specialization supports a complex microenvironmental niche characterized by rapid stemness-associated cell turnover, pathogen sensing, epithelial orchestration of immune signaling, and other facets that maintain the complex balance between homeostasis, inflammation, and disease. Here, we summarize and discuss select emerging concepts in the precancerous microenvironment, TME, and tumor epithelial-TME crosstalk as well as their implications for the management of GI cancers.

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Evolutionary history of human colitis-associated colorectal cancer

Cited by 126 publications

References 39 publications

Somatic evolution in non-neoplastic IBD-affected colon

Somatic evolution in non-neoplastic IBD-affected colon

Resolving genetic heterogeneity in cancer

Implications for Tumor Microenvironment and Epithelial Crosstalk in the Management of Gastrointestinal Cancers

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