Order Matters: The Order of Somatic Mutations Influences Cancer Evolution

Kent, David G.; Green, Anthony

doi:10.1101/cshperspect.a027060

Cited by 57 publications

(53 citation statements)

References 64 publications

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“…These "driver" mutations are often tissue-specific, suggesting context-dependency as in the case of APC mutations in gastrointestinal tumors (Fearon and Vogelstein 1990;Horii et al 1992;Nakatsuru et al 1992) and DNMT3 in leukemias (Shlush et al 2014). Nonetheless, multiple driver mutations (and clonal expansions) are typically required to initiate a cancer (Vogelstein and Kinzler 2015) and several studies have suggested that the order of mutations influences the phenotype of tumor initiating cells and may be associated with different clinical outcomes (Weaver et al 2014;Ortmann et al 2015; see also Kent and Green 2017).…”

Section: Pretumor Progression and Factors Influencing Clonal Expansionsmentioning

confidence: 99%

Big Bang Tumor Growth and Clonal Evolution

Sun

Curtis

2017

Cold Spring Harb Perspect Med

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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.

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Section: Pretumor Progression and Factors Influencing Clonal Expansionsmentioning

confidence: 99%

Big Bang Tumor Growth and Clonal Evolution

Sun

Curtis

2017

Cold Spring Harb Perspect Med

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“…Here, again, a number of different truncal or initiating mutations could promote clonal expansion of stem or progenitor cells, but two genes, TP53 and NOTCH1, were the most common truncal mutations.A rather dramatic impact upon clinical features, the responses to therapy, the biology of stem and progenitor cells, and even clonal evolution, has also been observed in myeloproliferative neoplasms, depending on whether a mutation in TET2 occurs before a mutation in JAK2 or vice versa. Rather clearly, the order in which these two mutations occur influences the evolution and even the optimal treatment of these tumors (Ortmann et al, 2015;Kent and Green, 2017). When the genetic (JAK2) or the epigenetic (TET2) mutation is the initial truncal mutation, they each have very different impacts upon the gene expression of the progenitor cell, so that the second mutation results in quite different properties of the cancer.…”

mentioning

confidence: 99%

The Roles of Initiating Truncal Mutations in Human Cancers: The Order of Mutations and Tumor Cell Type Matters

2019

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We propose that initiating truncal mutations plays a special role in tumor formation by both enhancing the survival of the initiating cancer cell and by selecting for secondary mutations that contribute to tumor progression, and that these mutations often act in a tissue-preferred fashion. Here, we explain why inherited mutations often have different tissue specificities compared with spontaneous mutations in the same gene. Initiating truncal mutations make excellent neo-antigens for immunotherapy, and understanding why one mutation selects for a second mutation in a particular tissue type could one day aid in the design of genetargeted combination therapies. PerspectiveMost cancers develop over time, accumulating a series of mutations that combine to produce a malignant tumor. As a consequence, most cancers in humans occur later in life, with a steep increase in their frequencies approximated by the binomial equation I(t) = kt rÀ1 , where I is the incidence as a function of time, k is a constant that depends upon the lifespan of the species, t is time, and r is a function of the number of mutations it takes to form the cancer (Armitage and Doll, 1954). If the first mutation in the series is inherited, the curve giving the age of the onset of tumors in a population shifts to the left or younger ages, indicating the critical role of r or mutation number. As mutations accumulate, they frequently occur in different functional pathways that regulate genomic stability, metabolic processes, cell-cycle regulation, epigenetic stability, immunological detection, etc., in a list that has come to be recognized as the hallmarks of cancer Weinberg, 2000, 2011).The first recognition that the order of mutations occurring in a cancerous precursor cell was an important variable and even determined the nature of the subsequent mutations that gave rise to the cancer was appreciated by Bert Vogelstein and colleagues in a series of papers studying colorectal cancer (CRC) in humans. Vogelstein's laboratory took advantage of the fact that this cancer develops in stages over time, starting with benign small-sized polyps, which, with further time, develop into larger benign polyps and eventually malignant colorectal carcinomas (Nigro et al., 1989;Baker et al., 1990aBaker et al., , 1990b. By taking samples from these different stages using colonoscopy and sequencing the DNA, they appreciated that CRC develops through the stepwise selection of genetic changes. The initiating or gatekeeping mutation was primarily biallelic loss of APC, which occurs in >80% of cases, or at a lower frequency the b-catenin gene (CTNNB1) in the same WNT signaling pathway. Subsequent activating mutations in KRAS were identified in early-to-intermediate adenoma-stage tumors, while loss-offunction mutations in SMAD4 were identified in large adenomas. Finally, the loss of p53 functions resulted in a malignant adeno-carcinoma. Large-scale CRC genome-sequencing studies also identified numerous infrequently mutated genes in CRC, in addition to the commonly mutated AP...

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“…As explained in Methods section, we note that a total of 1000 initial-states were randomly generated to compute the mutation-sensitivity and the orderspecificity values in Eqs. (1) and (2) in all simulations. In addition, we constructed a set of ordered gene pairs to be investigated, Ω, for tractable simulation.…”

Section: Resultsmentioning

confidence: 89%

“…For example, the double mutation in the order of TP53 and NOTCH, which are representative tumorsuppressor and oncogenes, respectively, was frequently observed in early stage of esophageal carcinoma patients [53], whereas the reverse-ordered mutation is likely to lead to a metastasis progression in mouse experiments [63,64]. It was also shown that alteration of RAS, which is another oncogene, before loss of P53 formed a malignant tumor with metastatic behavior, but the reverseordered mutation resulted in benign tumors [2,65].…”

Section: Analysis Of Tumor Suppressor and Oncogenes With Respect To Omentioning

confidence: 99%

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Effects of ordered mutations on dynamics in signaling networks

2020

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Background: Many previous clinical studies have found that accumulated sequential mutations are statistically related to tumorigenesis. However, they are limited in fully elucidating the significance of the ordered-mutation because they did not focus on the network dynamics. Therefore, there is a pressing need to investigate the dynamics characteristics induced by ordered-mutations.Methods: To quantify the ordered-mutation-inducing dynamics, we defined the mutation-sensitivity and the orderspecificity that represent if the network is sensitive against a double knockout mutation and if mutation-sensitivity is specific to the mutation order, respectively, using a Boolean network model.Results: Through intensive investigations, we found that a signaling network is more sensitive when a doublemutation occurs in the direction order inducing a longer path and a smaller number of paths than in the reverse order. In addition, feedback loops involving a gene pair decreased both the mutation-sensitivity and the orderspecificity. Next, we investigated relationships of functionally important genes with ordered-mutation-inducing dynamics. The network is more sensitive to mutations subject to drug-targets, whereas it is less specific to the mutation order. Both the sensitivity and specificity are increased when different-drug-targeted genes are mutated. Further, we found that tumor suppressors can efficiently suppress the amplification of oncogenes when the former are mutated earlier than the latter.Conclusion: Taken together, our results help to understand the importance of the order of mutations with respect to the dynamical effects in complex biological systems.

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Order Matters: The Order of Somatic Mutations Influences Cancer Evolution

Cited by 57 publications

References 64 publications

Big Bang Tumor Growth and Clonal Evolution

Big Bang Tumor Growth and Clonal Evolution

The Roles of Initiating Truncal Mutations in Human Cancers: The Order of Mutations and Tumor Cell Type Matters

Effects of ordered mutations on dynamics in signaling networks

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