Genetic architecture of mouse skin inflammation and tumour susceptibility

Quigley, David A.; To, Minh D.; Pérez-Losada, Jesús; Pelorosso, Facundo Germán; Mao, Jian‐Hua; Nagase, Hiroki; Ginzinger, David G.; Balmain, Allan

doi:10.1038/nature07683

Cited by 121 publications

(148 citation statements)

References 28 publications

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“…It has previously been suggested that genetic polymorphisms can influence the levels of gene expression in the context of phenotypic modifiers of complex traits (16,17). We therefore asked whether any of the genes located within the minimal chromosome 17 region might be differentially expressed between the parental strains and therefore contribute to the observed differences in the invasion phenotypes.…”

Section: Anaplastic Lymphoma Kinase Resides In the Chromosome 17 Minimalmentioning

confidence: 99%

Polymorphic genetic control of tumor invasion in a mouse model of pancreatic neuroendocrine carcinogenesis

Chun

Mao

Chiu

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Cancer is a disease subject to both genetic and environmental influences. In this study, we used the RIP1-Tag2 (RT2) mouse model of islet cell carcinogenesis to identify a genetic locus that influences tumor progression to an invasive growth state. RT2 mice inbred into the C57BL/6 (B6) background develop both noninvasive pancreatic neuroendocrine tumors (PNET) and invasive carcinomas with varying degrees of aggressiveness. In contrast, RT2 mice inbred into the C3HeB/Fe (C3H) background are comparatively resistant to the development of invasive tumors, as are RT2 C3HB6(F1) hybrid mice. Using linkage analysis, we identified a 13-Mb locus on mouse chromosome 17 with significant linkage to the development of highly invasive PNETs. A gene residing in this locus, the anaplastic lymphoma kinase (Alk), was expressed at significantly lower levels in PNETs from invasion-resistant C3H mice compared with invasion-susceptible B6 mice, and pharmacological inhibition of Alk led to reduced tumor invasiveness in RT2 B6 mice. Collectively, our results demonstrate that tumor invasion is subject to polymorphic genetic control and identify Alk as a genetic modifier of invasive tumor growth.anaplastic lymphoma kinase | cancer modifier genes | malignant progression | pancreas cancer | transgenic mouse C ancer is a complex disease governed by environmental and genetic factors, including genetic mutations and polymorphisms that modulate cancer susceptibility (1). Although many investigations have focused on identifying factors that affect initial tumor development (2, 3), data from both human and mouse studies have demonstrated that genetic polymorphisms can modulate multiple aspects of tumorigenesis, such as tumor progression (4-6) and response to therapy (7).In this study, we investigated the effects of genetic background on tumor progression to an invasive growth state, motivated by a provocative observation that mice carrying the same oncogenic transgene but differing in genetic background developed tumors that were markedly distinctive in their invasiveness. This model, the RIP1-Tag2 (RT2) mouse model of islet cell carcinogenesis, develops multiple pancreatic neuroendocrine tumors (PNET) in a relatively synchronous and predictable multistage progression pattern by 12-14 wk of age owing to the expression of the SV40 T antigen oncoprotein (Tag) in the pancreatic β cells (8). The tumorigenesis pathway has predominantly been studied in RT2 mice inbred into the C57BL/6 (B6) background, and the PNETs that arise in this genetic context display a spectrum of invasive phenotypes and can be classified as noninvasive islet tumors (IT), focally invasive type-1 carcinomas (IC1), and broadly invasive type-2 carcinomas (IC2) (9). Surprisingly, we observed that when RT2 mice were inbred into a second strain, C3HeB/Fe (C3H), the tumors that arose were predominantly noninvasive, despite being otherwise similar in their tumorigenesis phenotype. The implication that the invasive phenotype was influenced by genetic background prompted our investigation...

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Section: Anaplastic Lymphoma Kinase Resides In the Chromosome 17 Minimalmentioning

confidence: 99%

Polymorphic genetic control of tumor invasion in a mouse model of pancreatic neuroendocrine carcinogenesis

Chun

Mao

Chiu

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Instead of protecting from chemical carcinogens, the N21 allele seems to be slightly weaker than the wild-type allele. Because N12 and N21 were created in B6 embryonic stem cell lines, this difference was not attributable to strain contributions (Quigley et al, 2009). Combined, this report and the results in Fig.…”

Section: Outbred N12 and N21 Homozygous Mice Display No Overt Phenotypementioning

confidence: 99%

The intracellular domains of Notch1 and 2 are functionally equivalent during development and carcinogenesis

et al. 2015

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Although Notch1 and Notch2 are closely related paralogs and function through the same canonical signaling pathway, they contribute to different outcomes in some cell and disease contexts. To understand the basis for these differences, we examined in detail mice in which the Notch intracellular domains (N1ICD and N2ICD) were swapped. Our data indicate that strength (defined here as the ultimate number of intracellular domain molecules reaching the nucleus, integrating ligand-mediated release and nuclear translocation) and duration (half-life of NICD-RBPjk-MAML-DNA complexes, integrating cooperativity and stability dependent on shared sequence elements) are the factors that underlie many of the differences between Notch1 and Notch2 in all the contexts we examined, including T-cell development, skin differentiation and carcinogenesis, the inner ear, the lung and the retina. We were able to show that phenotypes in the heart, endothelium, and marginal zone B cells are attributed to haploinsufficiency but not to intracellular domain composition. Tissue-specific differences in NICD stability were most likely caused by alternative scissile bond choices by tissue-specific γ-secretase complexes following the intracellular domain swap. Reinterpretation of clinical findings based on our analyses suggests that differences in outcome segregating with Notch1 or Notch2 are likely to reflect outcomes dependent on the overall strength of Notch signals.

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“…These methods have been successfully applied to animal models of neoplastic disease to identify both individual genes and cellular processes associated with cancer susceptibility (6). These results suggest that the rich public data available for human breast cancer might be used for similar analysis to identify critical biological processes and functions associated with breast cancer progression.…”

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confidence: 94%

Integrated cross-species transcriptional network analysis of metastatic susceptibility

Rusch

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Metastatic disease is the proximal cause of mortality for most cancers and remains a significant problem for the clinical management of neoplastic disease. Recent advances in global transcriptional analysis have enabled better prediction of individuals likely to progress to metastatic disease. However, minimal overlap between predictive signatures has precluded easy identification of key biological processes contributing to the prometastatic transcriptional state. To overcome this limitation, we have applied network analysis to two independent human breast cancer datasets and three different mouse populations developed for quantitative analysis of metastasis. Analysis of these datasets revealed that the gene membership of the networks is highly conserved within and between species, and that these networks predicted distant metastasis free survival. Furthermore these results suggest that susceptibility to metastatic disease is cell-autonomous in estrogen receptor-positive tumors and associated with the mitotic spindle checkpoint. In contrast, nontumor genetics and pathway activities-associated stromal biology are significant modifiers of the rate of metastatic spread of estrogen receptor-negative tumors. These results suggest that the application of network analysis across species may provide a robust method to identify key biological programs associated with human cancer progression.gene expression | mouse models R ecent advances in global transcriptome analysis has enabled better understanding of the different subtypes of breast cancer (1), as well as tumor prognosis and treatment (2). Gene signatures derived from these analyses have provided new opportunities for better tailoring of treatment options based on individual tumor biology. However, although these signatures are potentially important clinical tools, for the most part they do not provide novel insight regarding the underlying mechanisms. This lack of insight is in part because they were developed as prognostic classifiers, based on a minimum set of genes rather than to interrogate the mechanisms underlying tumor biology. The ability of these clinical classifiers to investigate molecular mechanism is further complicated by the minimal overlap between independent signatures derived from different studies. The lack of overlap is thought to be because of the fact that there are likely thousands of genes that correlate with tumor progression (3). Membership of the individual genes in each signature is therefore dictated by the transcriptional patterns derived from the specific patient populations. Subtle variations in those populations result in different gene sets meeting the statistical thresholds to be included in the final signature. Using conventional methods, it has been estimated that thousands of samples would be required to develop a robust, stable signature (4). Thus, although these signatures have important potential for clinical applications, comparisons of the signatures have not provided similar benefit for the elucidation of mechanisms of m...

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Genetic architecture of mouse skin inflammation and tumour susceptibility

Cited by 121 publications

References 28 publications

Polymorphic genetic control of tumor invasion in a mouse model of pancreatic neuroendocrine carcinogenesis

Polymorphic genetic control of tumor invasion in a mouse model of pancreatic neuroendocrine carcinogenesis

The intracellular domains of Notch1 and 2 are functionally equivalent during development and carcinogenesis

Integrated cross-species transcriptional network analysis of metastatic susceptibility

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