• Sun protection behavior after diagnosis of high-risk primary melanoma and risk of a subsequent primary

      von Schuckmann, L; Wilson, L; Hughes, M; Beesley, L; Janda, M; van der Pols, J; Smithers, B; Khosrotehrani, K; Green, Adèle C; Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia (2019)
      BACKGROUND: Melanoma survivors are at high risk of further primary melanomas. OBJECTIVE: To assess sun behavior after melanoma diagnosis and in relation to further primary melanomas. METHODS: We applied repeated measures latent class analysis to reported primary prevention behavior at time of diagnosis and every 6 months for 2 years after diagnosis in patients with clinical stage IB or II melanoma. Correlates of behavior trajectories and risk of subsequent primaries were determined by using multivariable logistic and Cox regression analyses, respectively. RESULTS: Among the 448 male and 341 female patients, sunscreen use fell into 3 trajectories: stable never-use (26% of males and 12% of females), stable sometimes-use (35% of males and 29% of females), and increased to often-use (39% of males and 59% of females). Most reduced their weekend sun exposure, but in 82% of males and 69% of females it remained increased. Males, smokers, the less educated, those who tanned, and those not self-checking their skin were more likely to have trajectories of inadequate protection. Patients with a history of melanoma before the study doubled their risk of another primary melanoma in the next 2 years if sunscreen use in that time was inadequate (hazard ratio, 2.45; 95% confidence interval, 1.00-6.06). LIMITATIONS: Patient-reported data are susceptible to recall bias. CONCLUSION: Our results may assist clinicians in identifying patients not using adequate sun protection and providing information for patient counseling.
    • Fluoromethylcyclopropylamine derivatives as potential in vivo toxicophores - a cautionary disclosure

      Acton, Ben; Small, Helen F; Smith, Kate M; McGonagle, Alison E; Stowell, Alexandra I; James, Dominic I; Hamilton, Nial M; Hamilton, Nicola S; Hitchin, James R; Hutton, Colin P; Waddell, Ian D; Ogilvie, Donald J; Jordan, Allan M; Drug Discovery Unit, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Macclesfield SK10 4TG, UK (2019)
      Fluorination of metabolic hotspots in a molecule is a common medicinal chemistry strategy to improve in vivo half-life and exposure and, generally, this strategy offers significant benefits. Here, we report the application of this strategy to a series of poly-ADP ribose glycohydrolase (PARG) inhibitors, resulting in unexpected in vivo toxicity which was attributed to this single-atom modification.
    • Survival of patients with early invasive melanoma down-staged under the new eighth edition of the American Joint Committee on Cancer staging system.

      von Schuckmann, L; Hughes, M; Lee, R; Lorigan, Paul C; Khosrotehrani, K; Smithers, M; Green, Adèle C; Population Health Department, Queensland Institute of Medical Research Berghofer Medical Research Institute, Herston, Australia (2019)
    • Multi-parametric and multi-regional histogram analysis of MRI: modality integration reveals imaging phenotypes of glioblastoma.

      Li, C; Wang, S; Serra, A; Torheim, T; Yan, JL; Boonzaier, NR; Huang, Y; Matys, T; McLean, MA; Markowetz, Florian; Price, SJ; Cambridge Brain Tumour Imaging Laboratory, Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Box 167 Cambridge Biomedical Campus, Cambridge, CB2 0QQ, (2019)
      OBJECTIVES: Integrating multiple imaging modalities is crucial for MRI data interpretation. The purpose of this study is to determine whether a previously proposed multi-view approach can effectively integrate the histogram features from multi-parametric MRI and whether the selected features can offer incremental prognostic values over clinical variables. METHODS: Eighty newly-diagnosed glioblastoma patients underwent surgery and chemoradiotherapy. Histogram features of diffusion and perfusion imaging were extracted from contrast-enhancing (CE) and non-enhancing (NE) regions independently. An unsupervised patient clustering was performed by the multi-view approach. Kaplan-Meier and Cox proportional hazards regression analyses were performed to evaluate the relevance of patient clustering to survival. The metabolic signatures of patient clusters were compared using multi-voxel spectroscopy analysis. The prognostic values of histogram features were evaluated by survival and ROC curve analyses. RESULTS: Two patient clusters were generated, consisting of 53 and 27 patients respectively. Cluster 2 demonstrated better overall survival (OS) (p?=?0.007) and progression-free survival (PFS) (p?<?0.001) than Cluster 1. Cluster 2 displayed lower N-acetylaspartate/creatine ratio in NE region (p?=?0.040). A higher mean value of anisotropic diffusion in NE region was associated with worse OS (hazard ratio [HR]?=?1.40, p?=?0.020) and PFS (HR?=?1.36, p?=?0.031). The seven features selected by this approach showed significantly incremental value in predicting 12-month OS (p?=?0.020) and PFS (p?=?0.022). CONCLUSIONS: The multi-view clustering method can provide an effective integration of multi-parametric MRI. The histogram features selected may be used as potential prognostic markers. KEY POINTS: • Multi-parametric magnetic resonance imaging captures multi-faceted tumor physiology. • Contrast-enhancing and non-enhancing tumor regions represent different tumor components with distinct clinical relevance. • Multi-view data analysis offers a method which can effectively select and integrate multi-parametric and multi-regional imaging features.
    • The effects of a multidisciplinary high-throughput skin clinic on healthcare costs of organ transplant recipients.

      Gordon, LG; Rodriguez-Acevedo, AJ; Papier, K; Khosrotehrani, K; Isbel, N; Campbell, S; Griffin, A; Green, Adele C; QIMR Berghofer Medical Research Institute, Population Health Department, Brisbane, Queensland, Australia (2019)
      BACKGROUND: A long-term complication among organ transplant recipients (OTRs) is skin malignancies which are associated with level and duration of immunosuppressive treatment, sun exposure and age. Dermatological surveillance is recommended for OTRs at high risk of skin malignancies, but evidence is lacking on the benefits of such services. OBJECTIVE: To examine the economic impact on patients and on the hospital service of a multidisciplinary high-throughput skin cancer Clinic in Brisbane, Australia, dedicated to dermatological and surgical care of high-risk OTRs. METHODS: In a pre-post design, hospital admission and cost data were obtained for 101 consecutively-enrolled study participants from 12 months prior to the introduction of the Clinic (to February 2016), the 3-month 'run-in' period (March to May 2016), and 12 months subsequent (to June 2017). Differences between pre- and post-Clinic hospital costs were tested using non-parametric bootstrapping and interrupted time series analysis. A survey of patient out-of-pocket costs and perceived financial burden was also undertaken during the Clinic. RESULTS: Overall hospital costs were higher after the Clinic but 3-monthly hospital costs for skin procedures trended downwards. Despite 3-monthly mean hospital visits increasing from 85 to 314, mean 3-monthly costs reduced by AU$1,491 (p<0.001) indicating greater cost-efficiency. Total patient out-of-pocket costs were AU$18,377 over 3 months. CONCLUSION: Clinical costing data revealed higher, more rapid throughput, and significantly lower per patient costs pre- and post- establishment of a multidisciplinary skin cancer Clinic for OTRs.
    • Shared heritability and functional enrichment across six solid cancers.

      Jiang, X; Finucane, HK; Schumacher, FR; Schmit, SL; Tyrer, JP; Han, Y; Michailidou, K; Lesseur, C; Kuchenbaecker, KB; Dennis, J; Conti, DV; Casey, G; Gaudet, MM; Huyghe, JR; Albanes, D; Aldrich, MC; Andrew, AS; Andrulis, IL; Anton-Culver, H; Antoniou, AC; Antonenkova, NN; Arnold, SM; Aronson, KJ; Arun, BK; Bandera, EV; Barkardottir, RB; Barnes, DR; Batra, J; Beckmann, MW; Benitez, J; Benlloch, S; Berchuck, A; Berndt, SI; Bickeboller, H; Bien, SA; Blomqvist, C; Boccia, S; Bogdanova, NV; Bojesen, SE; Bolla, MK; Brauch, H; Brenner, H; Brenton, JD; Brook, MN; Brunet, J; Brunnstrom, H; Buchanan, DD; Burwinkel, B; Butzow, R; Cadoni, G; Caldes, T; Caligo, MA; Campbell, I; Campbell, PT; Cancel-Tassin, G; Cannon-Albright, L; Campa, D; Caporaso, N; Carvalho, AL; Chan, AT; Chang-Claude, J; Chanock, SJ; Chen, C; Christiani, DC; Claes, KBM; Claessens, F; Clements, J; Collee, JM; Correa, MC; Couch, FJ; Cox, A; Cunningham, JM; Cybulski, C; Czene, K; Daly, MB; deFazio, A; Devilee, P; Diez, O; Gago-Dominguez, M; Donovan, JL; Dork, T; Duell, EJ; Dunning, AM; Dwek, M; Eccles, DM; Edlund, CK; Edwards, DRV; Ellberg, C; Evans, DG; Fasching, PA; Ferris, RL; Liloglou, T; Figueiredo, JC; Fletcher, O; Fortner, RT; Fostira, F; Franceschi, S; Friedman, E; Gallinger, SJ; Ganz, PA; Garber, J; Garcia-Saenz, JA; Gayther, SA; Giles, GG; Godwin, AK; Goldberg, MS; Goldgar, DE; Goode, EL; Goodman, MT; Goodman, G; Grankvist, K; Greene, MH; Gronberg, H; Gronwald, J; Guenel, P; Hakansson, N; Hall, P; Hamann, U; Hamdy, FC; Hamilton, RJ; Hampe, J; Haugen, A; Heitz, F; Herrero, R; Hillemanns, P; Hoffmeister, M; Hogdall, E; Hong, YC; Hopper, JL; Houlston, R; Hulick, PJ; Hunter, DJ; Huntsman, DG; Idos, G; Imyanitov, EN; Ingles, SA; Isaacs, C; Jakubowska, A; James, P; Jenkins, MA; Johansson, M; Johansson, M; John, EM; Joshi, AD; Kaneva, R; Karlan, BY; Kelemen, LE; Kuhl, T; Khaw, KT; Khusnutdinova, E; Kibel, AS; Kiemeney, LA; Kim, J; Kjaer, SK; Knight, JA; Kogevinas, M; Kote-Jarai, Z; Koutros, S; Kristensen, VN; Kupryjanczyk, J; Lacko, M; Lam, S; Lambrechts, D; Landi, MT; Lazarus, P; Le, ND; Lee, E; Lejbkowicz, F; Lenz, HJ; Leslie, G; Lessel, D; Lester, J; Levine, DA; Li, L; Li, CI; Lindblom, A; Lindor, NM; Liu, G; Loupakis, F; Lubinski, J; Maehle, L; Maier, C; Mannermaa, A; Marchand, LL; Margolin, S; May, T; McGuffog, L; Meindl, A; Middha, P; Miller, A; Milne, RL; MacInnis, RJ; Modugno, F; Montagna, M; Moreno, V; Moysich, KB; Mucci, L; Muir, K; Mulligan, AM; Nathanson, KL; Neal, DE; Ness, AR; Neuhausen, SL; Nevanlinna, H; Newcomb, PA; Newcomb, LF; Nielsen, FC; Nikitina-Zake, L; Nordestgaard, BG; Nussbaum, RL; Offit, K; Olah, E; Olama, AAA; Olopade, OI; Olshan, AF; Olsson, H; Osorio, A; Pandha, H; Park, JY; Pashayan, N; Parsons, MT; Pejovic, T; Penney, KL; Peters, WHM; Phelan, CM; Phipps, AI; Plaseska-Karanfilska, D; Pring, M; Prokofyeva, D; Radice, P; Stefansson, K; Ramus, SJ; Raskin, L; Rennert, G; Rennert, HS; van, Rensburg, EJ; Riggan, MJ; Risch, HA; Risch, A; Roobol, MJ; Rosenstein, BS; Rossing, MA; De, RK; Saloustros, E; Sandler, DP; Sawyer, EJ; Schabath, MB; Schleutker, J; Schmidt, MK; Setiawan, VW; Shen, H; Siegel, EM; Sieh, W; Singer, CF; Slattery, ML; West, Catharine, ML; Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, 677 Huntington Ave, Boston, MA, 02115, USA (2019)
      Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg?=?0.57, p?=?4.6?×?10-8), breast and ovarian cancer (rg?=?0.24, p?=?7?×?10-5), breast and lung cancer (rg?=?0.18, p =1.5?×?10-6) and breast and colorectal cancer (rg?=?0.15, p?=?1.1?×?10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.
    • Author correction: Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.

      Schumacher, FR; Olama, AAA; Berndt, SI; Benlloch, S; Ahmed, M; Saunders, EJ; Dadaev, T; Leongamornlert, D; Anokian, E; Cieza-Borrella, C; Goh, C; Brook, MN; Sheng, X; Fachal, L; Dennis, J; Tyrer, J; Muir, K; Lophatananon, A; Stevens, VL; Gapstur, SM; Carter, BD; Tangen, CM; Goodman, PJ; Thompson, IM; Batra, J; Chambers, S; Moya, L; Clements, J; Horvath, L; Tilley, W; Risbridger, GP; Gronberg, H; Aly, M; Nordstrom, T; Pharoah, P; Pashayan, N; Schleutker, J; Tammela, TLJ; Sipeky, C; Auvinen, A; Albanes, D; Weinstein, S; Wolk, A; Hakansson, N; West, Catharine, ML; Dunning, AM; Burnet, N; Mucci, LA; Giovannucci, E; Andriole, GL; Cussenot, O; Cancel-Tassin, G; Koutros, S; Beane Freeman, LE; Sorensen, KD; Orntoft, TF; Borre, M; Maehle, L; Grindedal, EM; Neal, DE; Donovan, JL; Hamdy, FC; Martin, RM; Travis, RC; Key, TJ; Hamilton, RJ; Fleshner, NE; Finelli, A; Ingles, SA; Stern, MC; Rosenstein, BS; Kerns, SL; Ostrer, H; Lu, YJ; Zhang, HW; Feng, N; Mao, X; Guo, X; Wang, G; Sun, Z; Giles, GG; Southey, MC; MacInnis, RJ; FitzGerald, LM; Kibel, AS; Drake, BF; Vega, A; Gomez-Caamano, A; Szulkin, R; Eklund, M; Kogevinas, M; Llorca, J; Castano-Vinyals, G; Penney, KL; Stampfer, M; Park, JY; Sellers, TA; Lin, HY; Stanford, JL; Cybulski, C; Wokolorczyk, D; Lubinski, J; Ostrander, EA; Geybels, MS; Nordestgaard, BG; Nielsen, SF; Weischer, M; Bisbjerg, R; Roder, MA; Iversen, P; Brenner, H; Cuk, K; Holleczek, B; Maier, C; Luedeke, M; Schnoeller, T; Kim, J; Logothetis, CJ; John, EM; Teixeira, MR; Paulo, P; Cardoso, M; Neuhausen, SL; Steele, L; Ding, YC; De, RK; De, MG; Ost, P; Razack, A; Lim, J; Teo, SH; Lin, DW; Newcomb, LF; Lessel, D; Gamulin, M; Kulis, T; Kaneva, R; Usmani, N; Singhal, S; Slavov, C; Mitev, V; Parliament, M; Claessens, F; Joniau, S; Van den Broeck, T; Larkin, S; Townsend, Paul A; Aukim-Hastie, C; Gago-Dominguez, M; Castelao, JE; Martinez, ME; Roobol, MJ; Jenster, G; van Schaik, RHN; Menegaux, F; Truong, T; Koudou, YA; Xu, J; Khaw, KT; Cannon-Albright, L; Pandha, H; Michael, A; Thibodeau, SN; McDonnell, SK; Schaid, DJ; Lindstrom, S; Turman, C; Ma, J; Hunter, DJ; Riboli, E; Siddiq, A; Canzian, F; Kolonel, LN; Le, ML; Hoover, RN; Machiela, MJ; Cui, Z; Kraft, P; Amos, CI; Conti, DV; Easton, DF; Wiklund, F; Chanock, SJ; Henderson, BE; Kote-Jarai, Z; Haiman, CA; Eeles, RA; Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA (2019)
      In the version of this article initially published, the name of author Manuela Gago-Dominguez was misspelled as Manuela Gago Dominguez. The error has been corrected in the HTML and PDF version of the article.
    • Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways.

      Duffy, DL; Zhu, G; Li, X; Sanna, M; Iles, MM; Jacobs, LC; Evans, DM; Yazar, S; Beesley, J; Law, MH; Kraft, P; Visconti, A; Taylor, JC; Liu, F; Wright, MJ; Henders, AK; Bowdler, L; Glass, D; Ikram, MA; Uitterlinden, AG; Madden, PA; Heath, AC; Nelson, EC; Green, Adele C; Chanock, S; Barrett, JH; Brown, MA; Hayward, NK; MacGregor, S; Sturm, RA; Hewitt, AW; Kayser, M; Hunter, DJ; Bishop, JAN; Spector, TD; Montgomery, GW; Mackey, DA; Smith, GD; Nijsten, TE; Bishop, DT; Bataille, V; Falchi, M; Han, J; Martin, NG; Lee, JE; Brossard, M; Moses, EK; Song, F; Kumar, R; Easton, DF; Pharoah, PDP; Swerdlow, AJ; Kypreou, KP; Harland, M; Randerson-Moor, J; Akslen, LA; Andresen, PA; Avril, MF; Azizi, E; Scarra, GB; Brown, KM; Debniak, T; Elder, DE; Fang, SY; Friedman, E; Galan, P; Ghiorzo, P; Gillanders, EM; Goldstein, AM; Gruis, NA; Hansson, J; Helsing, P; Hocevar, M; Hoiom, V; Ingvar, C; Kanetsky, PA; Chen, WV; Landi, MT; Lang, J; Lathrop, GM; Lubinski, J; Mackie, RM; Mann, GJ; Molven, A; Novakovic, S; Olsson, H; Puig, S; Puig-Butille, JA; Radford-Smith, GL; van der Stoep, N; van Doorn, R; Whiteman, DC; Craig, JE; Schadendorf, D; Simms, LA; Burdon, KP; Nyholt, DR; Pooley, KA; Orr, N; Stratigos, AJ; Cust, AE; Ward, SV; Schulze, HJ; Dunning, AM; Demenais, F; Amos, CI; QIMR Berghofer Medical Research Institute, Brisbane, Australia (2019)
      The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, UK, and USA comprising 52,506 individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B, DOCK8, and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis.
    • A phase I pilot study of pre-operative radiotherapy for prostate cancer: long-term toxicity and oncologic outcomes.

      Glicksman, R; Sanmamed, N; Thoms, J; Zlotta, AR; Finelli, A; van der Kwast, T; Sweet, J; Jewett, M; Klotz, LH; Rosewall, T; Fleshner, NE; Bristow, Robert G; Warde, P; Berlin, A; Department of Radiation Oncology, University of Toronto, Toronto, Canada (2019)
      PURPOSE: Neoadjuvant radiation therapy (RT) improves disease control in various cancers and has become an established oncologic treatment strategy. During 2001 to 2004, we conducted a phase 1 pilot study assessing the role of short-course preoperative RT (PreORT) for men with unfavorable intermediate- and high-risk localized prostate cancer. Herein, we present long-term follow-up toxicity and oncologic outcomes. METHODS AND MATERIALS: Eligible patients had histologically proven prostate cancer, cT1-T2N0M0 disease, prostate-specific antigen >15 to 35 ng/mL regardless of Gleason score, or prostate-specific antigen 10 to 15 ng/mL with Gleason score ?7. Patients received 25 Gy in 5 consecutive daily fractions (5 Gy per fraction) to the prostate only, followed by radical prostatectomy within 14 days after RT completion. Primary outcomes were intraoperative morbidity and late genitourinary (GU) and gastrointestinal toxicities. RESULTS: In total, 15 patients were enrolled; 14 patients completed PreORT followed by radical prostatectomy, which also included bilateral lymph node dissections in 13 cases. Median follow-up was 12.2 years (range, 6.7-16.3). Late GU toxicity was common, with 2 patients (13.3%) experiencing G2 toxicity and 6 patients (40%) G3 toxicity. There were no patients with G4 to G5 late GU toxicity. Late gastrointestinal toxicity was infrequent, with only 1 patient (6.7%) experiencing transient G2 proctitis. At last follow-up, 8 (53.3%) and 6 (40%) patients experienced biochemical and metastatic disease recurrence, respectively. CONCLUSIONS: The use of PreORT in men with high-risk prostate cancer is associated with unexpected high rates of late GU toxicity. Future studies examining the role of RT preradical prostatectomy must cautiously select RT technique and dose schedule. Importantly, long-term follow-up data are essential to fully determine the therapeutic index of PreORT in the management of localized disease.
    • Cancer stem cell mobilization and therapeutic targeting of the 5T4 oncofetal antigen.

      Harrop, R; O'Neill, E; Stern, Peter L; Oxford BioMedica plc, Windrush Court, Transport Way, Oxford, OX4 6LT, UK (2019)
      Cancer stem cells (CSCs) can act as the cellular drivers of tumors harnessing stem cell properties that contribute to tumorigenesis either as founder elements or by the gain of stem cell traits by the malignant cells. Thus, CSCs can self-renew and generate the cellular heterogeneity of tumors including a hierarchical organization similar to the normal tissue. While the principle tumor growth contribution is often from the non-CSC components, it is the ability of small numbers of CSCs to avoid the effects of therapeutic strategies that can contribute to recurrence after treatment. However, identifying and characterizing CSCs for therapeutic targeting is made more challenging by their cellular potency being influenced by a particular tissue niche or by the capacity of more committed cells to regain stem cell functions. This review discusses the properties of CSCs including the limitations of the available cell surface markers, the assays that document tumor initiation and clonogenicity, the roles of epithelial mesenchymal transition and molecular pathways such as Notch, Wnt, Hippo and Hedgehog. The ability to target and eliminate CSCs is thought to be critical in the search for curative cancer treatments. The oncofetal tumor-associated antigen 5T4 (TBGP) has been linked with CSC properties in several different malignancies. 5T4 has functional attributes that are relevant to the spread of tumors including through EMT, CXCR4/CXCL12, Wnt, and Hippo pathways which may all contribute through the mobilization of CSCs. There are several different immunotherapies targeting 5T4 in development including antibody-drug conjugates, antibody-targeted bacterial super-antigens, a Modified Vaccinia Ankara-basedvaccine and 5T4-directed chimeric antigen receptor T-cells. These immune therapies would have the advantage of targeting both the bulk tumor as well as mobilized CSC populations.
    • Molecular landmarks of tumor hypoxia across cancer types.

      Bhandari, V; Hoey, C; Liu, LY; Lalonde, E; Ray, J; Livingstone, J; Lesurf, R; Shiah, YJ; Vujcic, T; Huang, X; Espiritu, SMG; Heisler, LE; Yousif, F; Huang, V; Yamaguchi, TN; Yao, CQ; Sabelnykova, VY; Fraser, M; Chua, MLK; van der Kwast, T; Liu, SK; Boutros, PC; Bristow, Robert G; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada (2019)
      Many primary-tumor subregions have low levels of molecular oxygen, termed hypoxia. Hypoxic tumors are at elevated risk for local failure and distant metastasis, but the molecular hallmarks of tumor hypoxia remain poorly defined. To fill this gap, we quantified hypoxia in 8,006 tumors across 19 tumor types. In ten tumor types, hypoxia was associated with elevated genomic instability. In all 19 tumor types, hypoxic tumors exhibited characteristic driver-mutation signatures. We observed widespread hypoxia-associated dysregulation of microRNAs (miRNAs) across cancers and functionally validated miR-133a-3p as a hypoxia-modulated miRNA. In localized prostate cancer, hypoxia was associated with elevated rates of chromothripsis, allelic loss of PTEN and shorter telomeres. These associations are particularly enriched in polyclonal tumors, representing a constellation of features resembling tumor nimbosus, an aggressive cellular phenotype. Overall, this work establishes that tumor hypoxia may drive aggressive molecular features across cancers and shape the clinical trajectory of individual tumors.
    • Publisher correction: Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways.

      Duffy, DL; Zhu, G; Li, X; Sanna, M; Iles, MM; Jacobs, LC; Evans, DM; Yazar, S; Beesley, J; Law, MH; Kraft, P; Visconti, A; Taylor, JC; Liu, F; Wright, MJ; Henders, AK; Bowdler, L; Glass, D; Ikram, MA; Uitterlinden, AG; Madden, PA; Heath, AC; Nelson, EC; Green, Adele C; Chanock, S; Barrett, JH; Brown, MA; Hayward, NK; MacGregor, S; Sturm, RA; Hewitt, AW; Kayser, M; Hunter, DJ; Newton Bishop, JA; Spector, TD; Montgomery, GW; Mackey, DA; Smith, GD; Nijsten, TE; Bishop, DT; Bataille, V; Falchi, M; Han, J; Martin, NG; QIMR Berghofer Medical Research Institute, Brisbane, Australia (2019)
      The original version of this Article contained errors in the spelling of the authors Fan Liu and M. Arfan Ikram, which were incorrectly given as Fan Lui and Arfan M. Ikram. In addition, the original version of this Article also contained errors in the author affiliations which are detailed in the associated Publisher Correction.
    • Runx/Cbfbeta complexes protect group 2 innate lymphoid cells from exhausted-like hyporesponsiveness during allergic airway inflammation.

      Miyamoto, C; Kojo, S; Yamashita, M; Moro, K; Lacaud, Georges; Shiroguchi, K; Taniuchi, I; Ebihara, T; Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, 230-0045, Japan (2019)
      Group 2 innate lymphoid cells (ILC2s) have tissue-resident competence and contribute to the pathogenesis of allergic diseases. However, the mechanisms regulating prolonged ILC2-mediated TH2 cytokine production under chronic inflammatory conditions are unclear. Here we show that, at homeostasis, Runx deficiency induces excessive ILC2 activation due to overly active GATA-3 functions. By contrast, during allergic inflammation, the absence of Runx impairs the ability of ILC2s to proliferate and produce effector TH2 cytokines and chemokines. Instead, functional deletion of Runx induces the expression of exhaustion markers, such as IL-10 and TIGIT, on ILC2s. Finally, these 'exhausted-like' ILC2s are unable to induce type 2 immune responses to repeated allergen exposures. Thus, Runx confers competence for sustained ILC2 activity at the mucosa, and contributes to allergic pathogenesis
    • Clonal haematopoiesis - a source of biological noise in cell-free DNA analyses.

      Abbosh, Christopher; Swanton, Charles; Birkbak, NJ; Cancer Research UK Lung Cancer Centre of Excellence London and Manchester, University College London (2019)
    • DNA methylation of immune checkpoints in the peripheral blood of breast and colorectal cancer patients.

      Elashi, AA; Sasidharan, N; Taha, RZ; Shaath, H; Elkord, Eyad; Cancer Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar (2019)
      Aberrant expression of immune checkpoints (ICs) in cancer creates an immunosuppressive microenvironment, which supports immune evasion of tumor cells. We have recently reported that epigenetic modifications are critical for ICs expression in the tumor microenvironment (TME) of primary breast cancer (PBC) and colorectal cancer (CRC). Herein, we investigated transcriptomic expression of ICs (PD-1, CTLA-4, LAG-3, TIM-3, TIGIT) and PD-L1 in peripheral blood of PBC and CRC patients, compared to healthy donors (HD). We found that expressions of TIM-3, TIGIT, PD-L1 were significantly upregulated, while LAG-3 expression was downregulated in peripheral blood of PBC and CRC patients. Demethylation enzymes TET2 and TET3 were also upregulated. In addition, promoter DNA methylation status of PD-1 was significantly hypermethylated, while PD-L1 was hypomethylated in PBC and CRC patients. Furthermore, TIGIT was significantly hypomethylated only in CRC patients. Remarkably, promoter methylation status of LAG-3, TIGIT and PD-L1 was in concordance with transcriptomic expression in CRC: the more the hypomethylation, the higher the expression. In comparison, we found that CTLA-4, TIM-3, TIGIT and PD-L1 in PBC, and CTLA-4 in CRC patients were significantly upregulated in peripheral blood, compared with tumor tissues of the same patients. However, demethylation status of all ICs was higher in TT, except for TIGIT in PBC, and CTLA-4 in CRC patients. These data indicate that the underlying mechanisms behind peripheral upregulation of PD-L1 and TIGIT in cancer patients could be due to aberrant promoter methylation profile. Moreover, demethylation inhibitors together with anti-PD-L1/anti-TIGIT could be a more efficient therapeutic strategy in cancer patients.
    • Clinical intensity-modulated proton therapy for Hodgkin lymphoma: which patients benefit the most?

      Ntentas, G; Dedeckova, K; Andrlik, M; Aznar, Marianne Camille; George, B; Kubes, J; Darby, SC; Cutter, DJ; Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford (2019)
      PURPOSE: Radiotherapy (RT) improves control of Hodgkin lymphoma (HL), but patients undergoing RT are at risk of late effects, including cardiovascular disease and second cancers, due to radiation dose to organs at risk (OAR). Proton therapy (PT) can reduce OAR dose compared to conventional photon RT. However, access to PT is currently limited so referral must be appropriately selective. We aim to identify subgroups of HL patients who could benefit most dosimetrically from RT with PT based on their pre-chemotherapy disease characteristics. METHODS AND MATERIALS: Normal tissue radiation doses were calculated for 21 HL patients treated with deep inspiration breath-hold pencil-beam scanning (PBS) PT and compared to doses from 3D-conformal and partial-arc volumetric modulated (PartArc) photon RT. Pre-chemotherapy disease characteristics associated with significant dosimetric benefits from PBS compared to photon RT were identified. RESULTS: Treatment with PBS was well tolerated and provided with good local control. PBS provided dosimetric advantages for patients whose clinical treatment volume extended below the 7th thoracic level and for female patients with axillary disease. Additionally, an increasing dosimetric benefit for some OAR was observed for increasing target volume. PBS significantly reduced the mean dose to the heart, breast, lungs, spinal cord and esophagus. Dose homogeneity and conformity within the target volume were also superior with PBS but some high dose measures and hot spots were increased with PBS compared to PartArc. CONCLUSIONS: PBS gives good target coverage and local control whilst providing reductions in radiation dose to OAR for individuals receiving RT for HL compared to advanced photon RT. Our findings highlight certain groups of patients who would be expected to gain more dosimetric benefit from PBS. These findings facilitate the selection of patients who should be considered a priority for PT.
    • Effect of pembrolizumab on CD4(+) CD25(+) , CD4(+) LAP(+) and CD4(+) TIM-3(+) T cell subsets.

      Toor, SM; Sasidharan, N; Pfister, G; Elkord, Eyad; Cancer Research Center, Qatar, Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar (2019)
      Tumor immune evasion involves the expansion of avidly proliferating immunosuppressive cells and inhibition of effector T cell proliferation. Immune checkpoints (IC) block the activation pathways of tumor-reactive T cells. IC pathways are often exploited by tumor cells to evade immune destruction, and blocking these pathways through IC inhibitors (ICI) has shown promising results in multiple malignancies. In this study, we investigated the effects of an ICI, pembrolizumab, on various T cell subsets in vitro. We compared the suppressive activity of CD4+ CD25+ regulatory T cells (conventional Treg ) with T cells expressing T cell immunoglobulin-3+ (TIM-3+ ) and latency-associated peptide (LAP)+ T cells. We found that LAP-expressing T cells were more suppressive than conventional Treg , but TIM-3-expressing T cells were not suppressive. Our results show that pembrolizumab does not modulate functions of Treg and mediates its immunostimulatory effects via the release of effector T cells from suppression. These findings may assist in the development of agents designed to intervene in IC pathways to overcome Treg resistance to ICI.
    • Defective NOTCH signalling drives smooth muscle cell death and differentiation in bicuspid aortic valve aortopathy.

      Harrison, OJ; Torrens, C; Salhiyyah, K; Modi, A; Moorjani, N; Townsend, Paul A; Ohri, SK; Cagampang, F; Institute of Developmental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK (2019)
      OBJECTIVES: Bicuspid aortic valve disease is common and is associated with ascending aortic aneurysms. Vascular smooth muscle cell (VSMC) apoptosis is characteristic of the ascending aorta of bicuspid patients, and NOTCH1 gene mutations have also been linked to the disease. NOTCH signalling is a fundamental cell signalling pathway, which dictates cell fate decisions including apoptosis. Our objective was to elucidate the role of NOTCH signalling in VSMC apoptosis and differentiation in bicuspid aortopathy. METHODS: Ascending aortic biopsies were obtained from 19 bicuspid and 12 tricuspid aortic valve patients and were sub-classified into 4 groups according to the maximum ascending aortic diameter (aneurysmal ??45?mm). Apoptotic VSMCs were counted by light microscopy using a TUNEL assay. Gene expression of key regulators of NOTCH signalling (NOTCH1 and HES1), apoptosis (BAX and BCL-2) and VSMC differentiation (MYH11, CNN1 and MYH10) were quantified using quantitative real-time PCR. Primary VSMCs were cultured from 2 tricuspid aortic valve and 2 bicuspid aortic valve patients, NOTCH signalling was inhibited with N-[N-(3,5-Difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester, and the gene expression was again quantified. RESULTS: The apoptotic cell count was significantly higher in bicuspid aortic valve patients (3.2 cells/50 000??m2 vs 1.1 cells/50 000??m2; P?=?0.033). There was a trend towards lower apoptotic cell count in the aneurysmal versus non-aneurysmal tricuspid and bicuspid groups and an increased ratio of proapoptotic gene expression, which was not statistically significant. This was associated with a 2.8-fold increase in contractile gene expression (P?=?0.026) and a 2.0-fold increase in NOTCH signalling gene expression in bicuspid versus tricuspid aortic valve patients (P?=?0.022). NOTCH inhibition in cultured VSMCs induced a similar pattern of increased proapoptotic and procontractile gene expressions. CONCLUSIONS: This preliminary study suggests that NOTCH activation in the non-aneurysmal bicuspid aortas may underlie aortopathy by influencing VSMC apoptosis and differentiation. NOTCH signalling manipulation may provide a therapeutic target for preventing aneurysms in bicuspid patients. Further studies with larger sample sizes are needed to substantiate the present findings.
    • On the mechanism of hyperthermia-induced BRCA2 protein degradation.

      van den Tempel, N; Zelensky, AN; Odijk, H; Laffeber, C; Schmidt, Christine K; Brandsma, I; Demmers, J; Krawczyk, PM; Kanaar, R; Department of Molecular Genetics, Oncode Institute, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands (2019)
      The DNA damage response (DDR) is a designation for a number of pathways that protects our DNA from various damaging agents. In normal cells, the DDR is extremely important for maintaining genome integrity, but in cancer cells these mechanisms counteract therapy-induced DNA damage. Inhibition of the DDR could therefore be used to increase the efficacy of anti-cancer treatments. Hyperthermia is an example of such a treatment-it inhibits a sub-pathway of the DDR, called homologous recombination (HR). It does so by inducing proteasomal degradation of BRCA2 -one of the key HR factors. Understanding the precise mechanism that mediates this degradation is important for our understanding of how hyperthermia affects therapy and how homologous recombination and BRCA2 itself function. In addition, mechanistic insight into the process of hyperthermia-induced BRCA2 degradation can yield new therapeutic strategies to enhance the effects of local hyperthermia or to inhibit HR. Here, we investigate the mechanisms driving hyperthermia-induced BRCA2 degradation. We find that BRCA2 degradation is evolutionarily conserved, that BRCA2 stability is dependent on HSP90, that ubiquitin might not be involved in directly targeting BRCA2 for protein degradation via the proteasome, and that BRCA2 degradation might be modulated by oxidative stress and radical scavengers.
    • Curvature-sensitive kinesin binding can explain microtubule ring formation and reveals chaotic dynamics in a mathematical model.

      Pearce, Simon P; Heil, M; Jensen, O; Jones, G; Prokop, A; School of Mathematics, University of Manchester, Manchester, UK (2018-11)
      Microtubules are filamentous tubular protein polymers which are essential for a range of cellular behaviour, and are generally straight over micron length scales. However, in some gliding assays, where microtubules move over a carpet of molecular motors, individual microtubules can also form tight arcs or rings, even in the absence of crosslinking proteins. Understanding this phenomenon may provide important explanations for similar highly curved microtubules which can be found in nerve cells undergoing neurodegeneration. We propose a model for gliding assays where the kinesins moving the microtubules over the surface induce ring formation through differential binding, substantiated by recent findings that a mutant version of the motor protein kinesin applied in solution is able to lock-in microtubule curvature. For certain parameter regimes, our model predicts that both straight and curved microtubules can exist simultaneously as stable steady states, as has been seen experimentally. Additionally, unsteady solutions are found, where a wave of differential binding propagates down the microtubule as it glides across the surface, which can lead to chaotic motion. Whilst this model explains two-dimensional microtubule behaviour in an experimental gliding assay, it has the potential to be adapted to explain pathological curling in nerve cells.