Publications by authors named "Catherine H Wilson"

15 Publications

  • Page 1 of 1

Disease risk scores for skin cancers.

Nat Commun 2021 01 8;12(1):160. Epub 2021 Jan 8.

23andMe Inc., 223N Mathilda Ave, Sunnyvale, CA, 94086, USA.

We trained and validated risk prediction models for the three major types of skin cancer- basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma-on a cross-sectional and longitudinal dataset of 210,000 consented research participants who responded to an online survey covering personal and family history of skin cancer, skin susceptibility, and UV exposure. We developed a primary disease risk score (DRS) that combined all 32 identified genetic and non-genetic risk factors. Top percentile DRS was associated with an up to 13-fold increase (odds ratio per standard deviation increase >2.5) in the risk of developing skin cancer relative to the middle DRS percentile. To derive lifetime risk trajectories for the three skin cancers, we developed a second and age independent disease score, called DRSA. Using incident cases, we demonstrated that DRSA could be used in early detection programs for identifying high risk asymptotic individuals, and predicting when they are likely to develop skin cancer. High DRSA scores were not only associated with earlier disease diagnosis (by up to 14 years), but also with more severe and recurrent forms of skin cancer.
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http://dx.doi.org/10.1038/s41467-020-20246-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794415PMC
January 2021

Direct-to-consumer genetic testing for factor V Leiden and prothrombin 20210G>A: the consumer experience.

Mol Genet Genomic Med 2020 11 16;8(11):e1468. Epub 2020 Sep 16.

23andMe, Inc, Sunnyvale, CA, USA.

Background: Clinical genetic testing for inherited predisposition to venous thromboembolism (VTE) is common among patients and their families. However, there is incomplete consensus about which individuals should receive testing, and the relative risks and benefits.

Methods: We assessed outcomes of receiving direct-to-consumer (DTC) results for the two most common genetic risk factors for VTE, factor V Leiden in the F5 gene (FVL) and prothrombin 20210G>A in the F2 gene (PT). Two thousand three hundred fifty-four customers (1244 variant-positive and 1110 variant-negative individuals) of the personal genetics company 23andMe, Inc., who had received results online for F5 and F2 variants, participated in an online survey-based study. Participants responded to questions about perception of VTE risk, discussion of results with healthcare providers (HCPs) and recommendations received, actions taken to control risk, emotional responses to receiving risk results, and perceived value of the information.

Results: Most participants (90% of variant-positive individuals, 99% of variant-negative individuals) had not previously been tested for F5 and/or F2 variants. The majority of variant-positive individuals correctly perceived that they were at higher than average risk for developing VTE. These individuals reported moderate rates of discussing results with HCPs (41%); receiving prevention advice from HCPs (31%), and making behavioral changes to control risk (e.g., exercising more, 30%). A minority (36%) of variant-positive individuals worried more after receiving VTE results. Nevertheless, most participants reported that knowing their risk had been an advantage (78% variant-positive and 58% variant-negative) and were satisfied knowing their genetic probability for VTE (81% variant-positive and 67% variant-negative).

Conclusion: Consumers reported moderate rates of behavioral change and perceived personal benefit from receiving DTC genetic results for VTE risk.
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http://dx.doi.org/10.1002/mgg3.1468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667316PMC
November 2020

Myc linked to dysregulation of cholesterol transport and storage in nonsmall cell lung cancer.

J Lipid Res 2020 11 4;61(11):1390-1399. Epub 2020 Aug 4.

Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.

Nonsmall cell lung cancer (NSCLC) is a leading cause of cancer-related deaths. While mutations in Kras and overexpression of Myc are commonly found in patients, the role of altered lipid metabolism in lung cancer and its interplay with oncogenic Myc is poorly understood. Here we use a transgenic mouse model of Kras-driven lung adenocarcinoma with reversible activation of Myc combined with surface analysis lipid profiling of lung tumors and transcriptomics to study the effect of Myc activity on cholesterol homeostasis. Our findings reveal that the activation of Myc leads to the accumulation of cholesteryl esters (CEs) stored in lipid droplets. Subsequent Myc deactivation leads to further increases in CEs, in contrast to tumors in which Myc was never activated. Gene expression analysis linked cholesterol transport and storage pathways to Myc activity. Our results suggest that increased Myc activity is associated with increased cholesterol influx, reduced efflux, and accumulation of CE-rich lipid droplets in lung tumors. Targeting cholesterol homeostasis is proposed as a promising avenue to explore for novel treatments of lung cancer, with diagnostic and stratification potential in human NSCLC.
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http://dx.doi.org/10.1194/jlr.RA120000899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604716PMC
November 2020

Reactivation of Myc transcription in the mouse heart unlocks its proliferative capacity.

Nat Commun 2020 04 14;11(1):1827. Epub 2020 Apr 14.

Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, UK.

It is unclear why some tissues are refractory to the mitogenic effects of the oncogene Myc. Here we show that Myc activation induces rapid transcriptional responses followed by proliferation in some, but not all, organs. Despite such disparities in proliferative response, Myc is bound to DNA at open elements in responsive (liver) and non-responsive (heart) tissues, but fails to induce a robust transcriptional and proliferative response in the heart. Using heart as an exemplar of a non-responsive tissue, we show that Myc-driven transcription is re-engaged in mature cardiomyocytes by elevating levels of the positive transcription elongation factor (P-TEFb), instating a large proliferative response. Hence, P-TEFb activity is a key limiting determinant of whether the heart is permissive for Myc transcriptional activation. These data provide a greater understanding of how Myc transcriptional activity is determined and indicate modification of P-TEFb levels could be utilised to drive regeneration of adult cardiomyocytes for the treatment of heart myopathies.
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http://dx.doi.org/10.1038/s41467-020-15552-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156407PMC
April 2020

Heterogeneity of Myc expression in breast cancer exposes pharmacological vulnerabilities revealed through executable mechanistic modeling.

Proc Natl Acad Sci U S A 2019 10 14;116(44):22399-22408. Epub 2019 Oct 14.

Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom;

Cells with higher levels of Myc proliferate more rapidly and supercompetitively eliminate neighboring cells. Nonetheless, tumor cells in aggressive breast cancers typically exhibit significant and stable heterogeneity in their Myc levels, which correlates with refractoriness to therapy and poor prognosis. This suggests that Myc heterogeneity confers some selective advantage on breast tumor growth and progression. To investigate this, we created a traceable -driven in vivo chimeric mammary tumor model comprising an admixture of low-Myc- and reversibly switchable high-Myc-expressing clones. We show that such tumors exhibit interclonal mutualism wherein cells with high-Myc expression facilitate tumor growth by promoting protumorigenic stroma yet concomitantly suppress Wnt expression, which renders them dependent for survival on paracrine Wnt provided by low-Myc-expressing clones. To identify any therapeutic vulnerabilities arising from such interdependency, we modeled Myc/Ras/p53/Wnt signaling cross talk as an executable network for low-Myc, for high-Myc clones, and for the 2 together. This executable mechanistic model replicated the observed interdependence of high-Myc and low-Myc clones and predicted a pharmacological vulnerability to coinhibition of COX2 and MEK. This was confirmed experimentally. Our study illustrates the power of executable models in elucidating mechanisms driving tumor heterogeneity and offers an innovative strategy for identifying combination therapies tailored to the oligoclonal landscape of heterogenous tumors.
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http://dx.doi.org/10.1073/pnas.1903485116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825310PMC
October 2019

Myc Cooperates with Ras by Programming Inflammation and Immune Suppression.

Cell 2017 Nov;171(6):1301-1315.e14

Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK; Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address:

The two oncogenes KRas and Myc cooperate to drive tumorigenesis, but the mechanism underlying this remains unclear. In a mouse lung model of KRas-driven adenomas, we find that co-activation of Myc drives the immediate transition to highly proliferative and invasive adenocarcinomas marked by highly inflammatory, angiogenic, and immune-suppressed stroma. We identify epithelial-derived signaling molecules CCL9 and IL-23 as the principal instructing signals for stromal reprogramming. CCL9 mediates recruitment of macrophages, angiogenesis, and PD-L1-dependent expulsion of T and B cells. IL-23 orchestrates exclusion of adaptive T and B cells and innate immune NK cells. Co-blockade of both CCL9 and IL-23 abrogates Myc-induced tumor progression. Subsequent deactivation of Myc in established adenocarcinomas triggers immediate reversal of all stromal changes and tumor regression, which are independent of CD4CD8 T cells but substantially dependent on returning NK cells. We show that Myc extensively programs an immune suppressive stroma that is obligatory for tumor progression.
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http://dx.doi.org/10.1016/j.cell.2017.11.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5720393PMC
November 2017

Determination of the physiological and pathological roles of E2F3 in adult tissues.

Sci Rep 2017 08 30;7(1):9932. Epub 2017 Aug 30.

Department of Biochemistry, University of Cambridge, Cambridge, UK.

While genetically engineered mice have made an enormous contribution towards the elucidation of human disease, it has hitherto not been possible to tune up or down the level of expression of any endogenous gene. Here we describe compound genetically modified mice in which expression of the endogenous E2f3 gene may be either reversibly elevated or repressed in adult animals by oral administration of tetracycline. This technology is, in principle, applicable to any endogenous gene, allowing direct determination of both elevated and reduced gene expression in physiological and pathological processes. Applying this switchable technology to the key cell cycle transcription factor E2F3, we demonstrate that elevated levels of E2F3 drive ectopic proliferation in multiple tissues. By contrast, E2F3 repression has minimal impact on tissue proliferation or homeostasis in the majority of contexts due to redundancy of adult function with E2F1 and E2F2. In the absence of E2F1 and E2F2, however, repression of E2F3 elicits profound reduction of proliferation in the hematopoietic compartments that is rapidly lethal in adult animals.
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http://dx.doi.org/10.1038/s41598-017-09494-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577339PMC
August 2017

Myc Expression Drives Aberrant Lipid Metabolism in Lung Cancer.

Cancer Res 2016 08 22;76(16):4608-18. Epub 2016 Jun 22.

Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom. MRC Human Nutrition Research, Cambridge, United Kingdom.

MYC-mediated pathogenesis in lung cancer continues to attract interest for new therapeutic strategies. In this study, we describe a transgenic mouse model of KRAS-driven lung adenocarcinoma that affords reversible activation of MYC, used here as a tool for lipidomic profiling of MYC-dependent lung tumors formed in this model. Advanced mass spectrometric imaging and surface analysis techniques were used to characterize the spatial and temporal changes in lipid composition in lung tissue. We found that normal lung tissue was characterized predominantly by saturated phosphatidylcholines and phosphatidylglycerols, which are major lipid components of pulmonary surfactant. In contrast, tumor tissues displayed an increase in phosphatidylinositols and arachidonate-containing phospholipids that can serve as signaling precursors. Deactivating MYC resulted in a rapid and dramatic decrease in arachidonic acid and its eicosanoid metabolites. In tumors with high levels of MYC, we found an increase in cytosolic phospholipase A2 (cPLA2) activity with a preferential release of membrane-bound arachidonic acid, stimulating the lipoxygenase (LOX) and COX pathways also amplified by MYC at the level of gene expression. Deactivating MYC lowered cPLA2 activity along with COX2 and 5-LOX mRNA levels. Notably, inhibiting the COX/5-LOX pathways in vivo reduced tumor burden in a manner associated with reduced cell proliferation. Taken together, our results show how MYC drives the production of specific eicosanoids critical for lung cancer cell survival and proliferation, with possible implications for the use of COX and LOX pathway inhibitors for lung cancer therapy. Cancer Res; 76(16); 4608-18. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-3403DOI Listing
August 2016

Nuclear receptor-binding protein 1: a novel tumour suppressor and pseudokinase.

Biochem Soc Trans 2013 Aug;41(4):1055-60

School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK.

Pseudokinases are a class of kinases which are structurally designated as lacking kinase activity. Despite the lack of kinase domain sequence conservation, there is increasing evidence that a number of pseudokinases retain kinase activity and/or have critical cellular functions, casting aside previous notions that pseudokinases simply exist as redundant kinases. Moreover, a number of recent studies have implicated pseudokinases as critical components in cancer formation and progression. The present review discusses the interactions and potential functions that nuclear receptor-binding protein 1, a pseudokinase recently described to have a tumour-suppressive role in cancer, may play in cellular homoeostasis and protein regulation. The recent findings highlighted in the present review emphasize the requirement to fully determine the function of pseudokinases in vitro and in vivo, the understanding of which may ultimately uncover new directions for drug discovery.
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http://dx.doi.org/10.1042/BST20130069DOI Listing
August 2013

Nuclear receptor binding protein 1 regulates intestinal progenitor cell homeostasis and tumour formation.

EMBO J 2012 May 17;31(11):2486-97. Epub 2012 Apr 17.

Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

Genetic screens in simple model organisms have identified many of the key components of the conserved signal transduction pathways that are oncogenic when misregulated. Here, we identify H37N21.1 as a gene that regulates vulval induction in let-60(n1046gf), a strain with a gain-of-function mutation in the Caenorhabditis elegans Ras orthologue, and show that somatic deletion of Nrbp1, the mouse orthologue of this gene, results in an intestinal progenitor cell phenotype that leads to profound changes in the proliferation and differentiation of all intestinal cell lineages. We show that Nrbp1 interacts with key components of the ubiquitination machinery and that loss of Nrbp1 in the intestine results in the accumulation of Sall4, a key mediator of stem cell fate, and of Tsc22d2. We also reveal that somatic loss of Nrbp1 results in tumourigenesis, with haematological and intestinal tumours predominating, and that nuclear receptor binding protein 1 (NRBP1) is downregulated in a range of human tumours, where low expression correlates with a poor prognosis. Thus NRBP1 is a conserved regulator of cell fate, that plays an important role in tumour suppression.
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http://dx.doi.org/10.1038/emboj.2012.91DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3365428PMC
May 2012

Activation of K-RAS by co-mutation of codons 19 and 20 is transforming.

J Mol Signal 2011 Mar 3;6. Epub 2011 Mar 3.

Department of Pathology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK, CB2 0QQ, UK.

The K-RAS oncogene is widely mutated in human cancers. Activating mutations in K-RAS give rise to constitutive signalling through the MAPK/ERK and PI3K/AKT pathways promoting increased cell division, reduced apoptosis and transformation. The majority of activating mutations in K-RAS are located in codons 12 and 13. In a human colorectal cancer we identified a novel K-RAS co-mutation that altered codons 19 and 20 resulting in transitions at both codons (L19F/T20A) in the same allele. Using focus forming transformation assays in vitro , we showed that co-mutation of L19F/T20A in K-RAS demonstrated intermediate transforming ability that was greater than that of individual L19F and T20A mutants, but less than that of G12D and G12V K-RAS mutants. This demonstrated the synergistic effects of co-mutation of codons 19 and 20 and illustrated that co-mutation of these codons is functionally significant.
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http://dx.doi.org/10.1186/1750-2187-6-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3056876PMC
March 2011

PARK2 deletions occur frequently in sporadic colorectal cancer and accelerate adenoma development in Apc mutant mice.

Proc Natl Acad Sci U S A 2010 Aug 9;107(34):15145-50. Epub 2010 Aug 9.

Department of Pathology, University of Cambridge, Cambridge CB2 0QQ, United Kingdom.

In 100 primary colorectal carcinomas, we demonstrate by array comparative genomic hybridization (aCGH) that 33% show DNA copy number (DCN) loss involving PARK2, the gene encoding PARKIN, the E3 ubiquitin ligase whose deficiency is responsible for a form of autosomal recessive juvenile parkinsonism. PARK2 is located on chromosome 6 (at 6q25-27), a chromosome with one of the lowest overall frequencies of DNA copy number alterations recorded in colorectal cancers. The PARK2 deletions are mostly focal (31% approximately 0.5 Mb on average), heterozygous, and show maximum incidence in exons 3 and 4. As PARK2 lies within FRA6E, a large common fragile site, it has been argued that the observed DCN losses in PARK2 in cancer may represent merely the result of enforced replication of locally vulnerable DNA. However, we show that deficiency in expression of PARK2 is significantly associated with adenomatous polyposis coli (APC) deficiency in human colorectal cancer. Evidence of some PARK2 mutations and promoter hypermethylation is described. PARK2 overexpression inhibits cell proliferation in vitro. Moreover, interbreeding of Park2 heterozygous knockout mice with Apc(Min) mice resulted in a dramatic acceleration of intestinal adenoma development and increased polyp multiplicity. We conclude that PARK2 is a tumor suppressor gene whose haploinsufficiency cooperates with mutant APC in colorectal carcinogenesis.
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http://dx.doi.org/10.1073/pnas.1009941107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2930574PMC
August 2010

Novel candidate cancer genes identified by a large-scale cross-species comparative oncogenomics approach.

Cancer Res 2010 Feb 26;70(3):883-95. Epub 2010 Jan 26.

The Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom.

Comparative genomic hybridization (CGH) can reveal important disease genes but the large regions identified could sometimes contain hundreds of genes. Here we combine high-resolution CGH analysis of 598 human cancer cell lines with insertion sites isolated from 1,005 mouse tumors induced with the murine leukemia virus (MuLV). This cross-species oncogenomic analysis revealed candidate tumor suppressor genes and oncogenes mutated in both human and mouse tumors, making them strong candidates for novel cancer genes. A significant number of these genes contained binding sites for the stem cell transcription factors Oct4 and Nanog. Notably, mice carrying tumors with insertions in or near stem cell module genes, which are thought to participate in cell self-renewal, died significantly faster than mice without these insertions. A comparison of the profile we identified to that induced with the Sleeping Beauty (SB) transposon system revealed significant differences in the profile of recurrently mutated genes. Collectively, this work provides a rich catalogue of new candidate cancer genes for functional analysis.
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http://dx.doi.org/10.1158/0008-5472.CAN-09-1737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880710PMC
February 2010

A high-throughput splinkerette-PCR method for the isolation and sequencing of retroviral insertion sites.

Nat Protoc 2009 30;4(5):789-98. Epub 2009 Apr 30.

Division of Molecular Genetics, Cancer Genomics Centre, Netherlands Cancer Institute, Plesmanlaan, Amsterdam, The Netherlands.

Insertional mutagens such as viruses and transposons are a useful tool for performing forward genetic screens in mice to discover cancer genes. These screens are most effective when performed using hundreds of mice; however, until recently, the cost-effective isolation and sequencing of insertion sites has been a major limitation to performing screens on this scale. Here we present a method for the high-throughput isolation of insertion sites using a highly efficient splinkerette-PCR method coupled with capillary or 454 sequencing. This protocol includes a description of the procedure for DNA isolation, DNA digestion, linker or splinkerette ligation, primary and secondary PCR amplification, and sequencing. This method, which takes about 1 week to perform, has allowed us to isolate hundreds of thousands of insertion sites from mouse tumors and, unlike other methods, has been specifically optimized for the murine leukemia virus (MuLV), and can easily be performed in a 96-well plate format for the efficient multiplex isolation of insertion sites.
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http://dx.doi.org/10.1038/nprot.2009.64DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3627465PMC
September 2009

Numerous keratinocyte subtypes involved in wound re-epithelialization.

J Invest Dermatol 2006 Feb;126(2):497-502

Department of Dermatology, School of Medicine,Cardiff University, Cardiff, UK.

The expression of different keratin intermediate filaments has been used to define keratinocyte maturation and different phenotypic subtypes involved in acute wound (AW) healing. Immunohistochemistry with specific anti-keratin monoclonal and polyclonal antibodies was used to examine AW in normal healthy volunteers (n = 16). In all wounds examined, basal keratinocytes and cells at the leading edge of the wound expressed keratins K5 and K14. However, suprabasal cells had a more complex pattern of keratin expression, which was dependent on their position relative to the wound and location within the suprabasal compartment of the epidermis. In general, K10 was expressed in suprabasal keratinocytes at the wound edge, but not in keratinocytes covering the wound center, which expressed K6, K16, and K17 in a complex fashion. Ki67 expression, a marker of cell proliferation, was restricted to basal and immediate suprabasal layers at the wound edge. Keratinocytes populated the wound bed below the scab by migration, which was supported by keratinocyte proliferation in the surrounding epidermis both at and adjacent to the wound edge.
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http://dx.doi.org/10.1038/sj.jid.5700101DOI Listing
February 2006