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3. Reducing Risk of Head Injury in Youth Soccer: An Extension of Behavioral Skills Training for Heading

Author

Quintero, Laura M., Moore, James W., Yeager, M. Garrett, Rowsey, Kyle, Olmi, D. Joe, Britton-Slater, Joshua, Harper, Michaela L., and Zezenski, Lauren E.

Abstract

Recently, concerns regarding sport-related concussions have increased within the research literature, the media, and popular culture. One potential source of soccer-related concussions involves the purposeful striking of the ball with one's head (i.e., heading). There is currently limited research on an effective teaching method to improve safe heading technique. In the current study, Behavior Skills Training (BST) was evaluated as a method to teach correct heading techniques to youth soccer players. BST increased the percentage of correct steps for each player based on a task analysis of heading. Based on social validity questionnaires administered to players and the coach, BST was rated as an acceptable form of training. After the final training session, experienced coaches rated each player as having improved from baseline to training.

Published
2020
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5. Polymorphisms of an innate immune gene, toll-like receptor 4, and aggressive prostate cancer risk: A systematic review and meta-analysis

Author

Witte, John, Weng, PH, Huang, YL, Page, JH, Chen, JH, Xu, J, Koutros, S, Berndt, S, Chanock, S, Yeager, M, and Witte, JS

Abstract

© 2014 Weng et al.Background: Toll-like receptor 4 (TLR4) is one of the best known TLR members expressed on the surface of several leukocytes and tissue cells and has a key function in detecting pathogen and danger-associated molecular patterns. The role o

Published
2014

6. Detectable clonal mosaicism and its relationship to aging and cancer

Author

Wiencke, John, Wrensch, Margaret, Jacobs, KB, Yeager, M, Zhou, W, Wacholder, S, Wang, Z, Rodriguez-Santiago, B, Hutchinson, A, Deng, X, Liu, C, and Horner, MJ

Abstract

In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities,

Published
2012

7. GENOME‐WIDE ASSOCIATION STUDY OF CHILDHOOD BURKITT LYMPHOMA IN EAST AFRICA IDENTIFIES A NOVEL GERMLINE SUSCEPTIBILITY LOCUS ON CHROMOSOME 21

Author

Dutta, D., primary, Gorman, B., additional, Gouveia, M., additional, Ogwang, M. D., additional, Kerchan, P., additional, Reynolds, S. J., additional, Tenge, C. N., additional, Were, P. A., additional, Kuremu, R. T., additional, Wekesa, W. N., additional, Masalu, N., additional, Kawira, E., additional, Kinyera, T., additional, Otim, I., additional, Legason, I. D., additional, Nabalende, H., additional, Dhudha, H., additional, Mumia, M., additional, Ayers, L. W., additional, Bhatia, K., additional, Goedert, J. J., additional, Manning, M., additional, Cole, N., additional, Luo, W., additional, Hutchinson, A., additional, Hicks, B., additional, Chagaluka, G., additional, Johnston, W. T., additional, Mutalima, N., additional, Borgstein, E., additional, Liomba, G. N., additional, Kamiza, S., additional, Mkandawire, N., additional, Mitambo, C., additional, Molyneux, E., additional, Newton, R., additional, Glaser, S., additional, Kretzmer, H., additional, Adeyemo, A. A., additional, Rotimi, C. N., additional, Chanock, S. J., additional, Dean, M., additional, Siebert, R., additional, Yeager, M., additional, Prokunina‐Olsson, L., additional, and Mbulaiteye, S. M., additional

Published
2023
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8. Three‐dimensional structure of the rotavirus haemagglutinin VP4 by cryo‐electron microscopy and difference map analysis.

Author

Yeager, M, Berriman, JA, Baker, TS, and Bellamy, AR

Subjects
Biochemistry and Cell Biology, Biological Sciences, Animals, Capsid, Capsid Proteins, Cell Line, Freezing, Hemagglutinins, Viral, Microscopy, Electron, Models, Structural, Protein Conformation, Rotavirus, CRYOELECTRON MICROSCOPY, IMAGE PROCESSING, HEMAGGLUTININ, ROTAVIRUS, Information and Computing Sciences, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

The three-dimensional structure of the rotavirus spike haemagglutinin viral protein 4 (VP4) has been determined to a resolution of 26 A by cryo-electron microscopy and difference analysis of intact virions and smooth (spikeless) particles. Native and spikeless virions were mixed prior to cryo-preservation so that both structures could be determined from the same micrograph, thereby minimizing systematic errors. This mixing strategy was crucial for difference map analysis since VP4 only accounts for approximately 1% of the virion mass. The VP4 spike is multi-domained and has a radial length of approximately 200 A with approximately 110 A projecting from the surface of the virus. Interactions between VP4 and cell surface receptors are facilitated by the bi-lobed head, which allows multi-site interactions, as well as the uniform distribution of the VP4 heads at maximum radius. The bi-lobed head is attached to a square-shaped body formed by two rods that have a slight left-handed helical twist. These rods merge with an angled, rod-like domain connected to a globular base approximately 85 A in diameter. The anchoring base displays pseudo 6-fold symmetry. This surprising finding may represent a novel folding motif in which a single polypeptide of VP4 contributes similar but non-equivalent domains to form the arms of the hexameric base. The VP4 spike penetrates the virion surface approximately 90 A and interacts with both outer (VP7) and inner (VP6) capsid proteins. The extensive VP4-VP7 and VP4-VP6 interactions imply a scaffolding function in which VP4 may participate in maintaining precise geometric register between the inner and outer capsids.(ABSTRACT TRUNCATED AT 250 WORDS)

Published
1994

9. TET2 binds the androgen receptor and loss is associated with prostate cancer

Author

Nickerson, M L, Das, S, Im, K M, Turan, S, Berndt, S I, Li, H, Lou, H, Brodie, S A, Billaud, J N, Zhang, T, Bouk, A J, Butcher, D, Wang, Z, Sun, L, Misner, K, Tan, W, Esnakula, A, Esposito, D, Huang, W Y, Hoover, R N, Tucker, M A, Keller, J R, Boland, J, Brown, K, Anderson, S K, Moore, L E, Isaacs, W B, Chanock, S J, Yeager, M, Dean, M, and Andresson, T

Published
2017
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10. Early steps in reovirus infection are associated with dramatic changes in supramolecular structure and protein conformation: analysis of virions and subviral particles by cryoelectron microscopy and image reconstruction

Author

Dryden, KA, Wang, G, Yeager, M, Nibert, ML, Coombs, KM, Furlong, DB, Fields, BN, and Baker, TS

Subjects
Biochemistry and Cell Biology, Biological Sciences, Infectious Diseases, Genetics, Animals, Capsid, Cells, Cultured, Cold Temperature, DNA, Viral, Fibroblasts, Image Processing, Computer-Assisted, Macromolecular Substances, Mice, Microscopy, Electron, Protein Conformation, RNA, Double-Stranded, RNA, Messenger, RNA, Viral, Reoviridae, Reoviridae Infections, Transcription, Genetic, Viral Core Proteins, Virion, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Three structural forms of type 1 Lang reovirus (virions, intermediate subviral particles [ISVPs], and cores) have been examined by cryoelectron microscopy (cryoEM) and image reconstruction at 27 to 32-A resolution. Analysis of the three-dimensional maps and known biochemical composition allows determination of capsid protein location, globular shape, stoichiometry, quaternary organization, and interactions with adjacent capsid proteins. Comparisons of the virion, ISVP and core structures and examination of difference maps reveal dramatic changes in supra-molecular structure and protein conformation that are related to the early steps of reovirus infection. The intact virion (approximately 850-A diam) is designed for environmental stability in which the dsRNA genome is protected not only by tight sigma 3-mu 1, lambda 2-sigma 3, and lambda 2-mu 1 interactions in the outer capsid but also by a densely packed core shell formed primarily by lambda 1 and sigma 2. The segmented genome appears to be packed in a liquid crystalline fashion at radii < 240 A. Depending on viral growth conditions, virions undergo cleavage by enteric or endosomal/lysosomal proteases, to generate the activated ISVP (approximately 800-A diam). This transition involves the release of an outer capsid layer spanning radii from 360 to 427 A that is formed by 60 tetrameric and 60 hexameric clusters of ellipsoidal subunits of sigma 3. The vertex-associated cell attachment protein, sigma 1, also undergoes a striking change from a poorly visualized, more compact form, to an extended, flexible fiber. This conformational change may maximize interactions of sigma 1 with cell surface receptors. Transcription of viral mRNAs is mediated by the core particle (approximately 600-A diam), generated from the ISVP after penetration and uncoating. The transition from ISVP to core involves release of the 12 sigma 1 fibers and the remaining outer capsid layer formed by 200 trimers of rod-shaped mu 1 subunits that span radii from 306 to 395 A. In the virion and ISVP, flower-shaped pentamers of the lambda 2 protein are centered at the vertices. In the ISVP-to-core transition, domains of the lambda 2 subunits rotate and swing upward and outward to form a turret-like structure extending from radii 305 to 400 A, with a diameter of 184 A, and a central channel 84 A wide. This novel conformational change allows the potential diffusion of substrates for transcription and exit of newly synthesized mRNA segments.(ABSTRACT TRUNCATED AT 400 WORDS)

Published
1993

11. Three-dimensional structure of rhesus rotavirus by cryoelectron microscopy and image reconstruction.

Author

Yeager, M, Dryden, KA, Olson, NH, Greenberg, HB, and Baker, TS

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Bioengineering, Infectious Diseases, Animals, Cryopreservation, Image Processing, Computer-Assisted, Macaca, Macaca mulatta, Microscopy, Electron, Rotavirus, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

The structure of rhesus rotavirus was examined by cryoelectron microscopy and image analysis. Three-dimensional reconstructions of infectious virions were computed at 26- and 37-A resolution from electron micrographs recorded at two different levels of defocus. The major features revealed by the reconstructions are (a) both outer and inner capsids are constructed with T = 13l icosahedral lattice symmetry; (b) 60 spikelike projections, attributed to VP4, extend at least 100 A from the outer capsid surface; (c) the outer capsid, attributed primarily to VP7, has a smoothly rippled surface at a mean radius of 377 A and is perforated by 132 aqueous holes ranging from 40-65 A in diameter; (d) the inner capsid has a "bristled" outer surface composed of 260 trimeric-shaped columns of density, attributed to VP6, which merge with a smooth, spherical shell of density at a lower, mean radius of 299 A, and which is perforated by holes in register with those in the outer capsid; (e) a "core" region contains a third, nonspherical shell of density at a mean radius of 225 A that encapsidates the double-stranded RNA genome; and (f) the space between the outer and inner capsids forms an open aqueous network that may provide pathways for the diffusion of ions and small regulatory molecules as well as the extrusion of RNA. The assignment of different viral structural proteins to specific features of the reconstruction has been tentatively made on the basis of excluded volume estimates and previous biochemical characterizations of rotavirus.

Published
1990

19. Tuberculosis infection and lung adenocarcinoma: Mendelian randomization and pathway analysis of genome-wide association study data from never-smoking Asian women

Author

Wong, J.Y.Y., Hsiung, C.A., Matsuo, K., Wong, M.P., Seow, W.J., Song, M., Chang, I.-S., Chatterjee, N., Hu, W., Wu, C., Mitsudomi, T., Zheng, W., Kim, J.H., Seow, A., Caporaso, N.E., Shin, M.-H., Chung, L.P., An, S.-J., Zheng, H., Yatabe, Y., Kim, Y.T., Cai, Q., Kim, Y.-C., Bassig, B.A., Ho, J.C.M., Ji, B.-T., Daigo, Y., Ito, H., Momozawa, Y., Ashikawa, K., Kamatani, Y., Honda, T., Hosgood, H.D., Sakamoto, H., Kunitoh, H., Tsuta, K., Watanabe, S.-I., Kubo, M., Miyagi, Y., Nakayama, H., Matsumoto, S., Tsuboi, M., Goto, K., Song, L., Hua, X., Takahashi, A., Goto, A., Minamiya, Y., Shimizu, K., Tanaka, K., Wei, F., Matsuda, F., Kim, Y.H., Oh, I.-J., Song, F., Su, W.-C., Chang, G.-C., Chen, K.-Y., Chien, L.-H., Xiang, Y.-B., Kweon, S.-S., Lee, K.-M., Blechter, B., Qian, B., Lu, D., Jeon, H.-S., Hsiao, C.-F., Sung, J.S., Tsai, Y.-H., Jung, Y.J., Chung, C.C., Burdett, L., Yeager, M., Hutchinson, A., Berndt, S.I., Pang, H., Choi, J.E., Park, K.H., Sung, S.W., Zhu, M., Guan, P., Tan, W., Hsin, M., Sit, K.-Y., Ho, J., Choi, Y.Y., Kim, J.S., Yoon, H.I., Park, I.K., Xu, P., He, Q., Perng, R.-P., Vermeulen, R., Lim, W.-Y., Chen, K.-C., Jin, L., Jiang, S.-S., Yamaji, T., Hicks, B., Wyatt, K., Dai, J., Jin, G., Song, B., Cheng, S., Cui, P., Iwasaki, M., Shimazu, T., Tsugane, S., Fei, K., Wu, G., Lin, H.-C., Fang, Y.-H., Tsai, F.-Y., Hsieh, W.-S., Yu, J., Stevens, V.L., Laird-Offringa, I.A., Marconett, C.N., Rieswijk, L., Chao, A., Shu, X.-O., Lin, D., Chen, K., Zhou, B., Kohno, T., Shen, H., Chanock, S.J., Rothman, N., Lan, Q., IRAS OH Epidemiology Chemical Agents, and dIRAS RA-2

Subjects
Lung adenocarcinoma, Pathway analysis, Mendelian randomization, Tuberculosis, Lung cancer
Abstract

We investigated whether genetic susceptibility to tuberculosis (TB) influences lung adenocarcinoma development among never-smokers using TB genome-wide association study (GWAS) results within the Female Lung Cancer Consortium in Asia. Pathway analysis with the adaptive rank truncated product method was used to assess the association between a TB-related gene-set and lung adenocarcinoma using GWAS data from 5512 lung adenocarcinoma cases and 6277 controls. The gene-set consisted of 31 genes containing known/suggestive associations with genetic variants from previous TB-GWAS. Subsequently, we followed-up with Mendelian Randomization to evaluate the association between TB and lung adenocarcinoma using three genome-wide significant variants from previous TB-GWAS in East Asians. The TB-related gene-set was associated with lung adenocarcinoma (p = 0.016). Additionally, the Mendelian Randomization showed an association between TB and lung adenocarcinoma (OR = 1.31, 95% CI: 1.03, 1.66, p = 0.027). Our findings support TB as a causal risk factor for lung cancer development among never-smoking Asian women.

Published
2020

20. Tuberculosis infection and lung adenocarcinoma: Mendelian randomization and pathway analysis of genome-wide association study data from never-smoking Asian women

Author

IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Wong, J.Y.Y., Hsiung, C.A., Matsuo, K., Wong, M.P., Seow, W.J., Song, M., Chang, I.-S., Chatterjee, N., Hu, W., Wu, C., Mitsudomi, T., Zheng, W., Kim, J.H., Seow, A., Caporaso, N.E., Shin, M.-H., Chung, L.P., An, S.-J., Zheng, H., Yatabe, Y., Kim, Y.T., Cai, Q., Kim, Y.-C., Bassig, B.A., Ho, J.C.M., Ji, B.-T., Daigo, Y., Ito, H., Momozawa, Y., Ashikawa, K., Kamatani, Y., Honda, T., Hosgood, H.D., Sakamoto, H., Kunitoh, H., Tsuta, K., Watanabe, S.-I., Kubo, M., Miyagi, Y., Nakayama, H., Matsumoto, S., Tsuboi, M., Goto, K., Song, L., Hua, X., Takahashi, A., Goto, A., Minamiya, Y., Shimizu, K., Tanaka, K., Wei, F., Matsuda, F., Kim, Y.H., Oh, I.-J., Song, F., Su, W.-C., Chang, G.-C., Chen, K.-Y., Chien, L.-H., Xiang, Y.-B., Kweon, S.-S., Lee, K.-M., Blechter, B., Qian, B., Lu, D., Jeon, H.-S., Hsiao, C.-F., Sung, J.S., Tsai, Y.-H., Jung, Y.J., Chung, C.C., Burdett, L., Yeager, M., Hutchinson, A., Berndt, S.I., Pang, H., Choi, J.E., Park, K.H., Sung, S.W., Zhu, M., Guan, P., Tan, W., Hsin, M., Sit, K.-Y., Ho, J., Choi, Y.Y., Kim, J.S., Yoon, H.I., Park, I.K., Xu, P., He, Q., Perng, R.-P., Vermeulen, R., Lim, W.-Y., Chen, K.-C., Jin, L., Jiang, S.-S., Yamaji, T., Hicks, B., Wyatt, K., Dai, J., Jin, G., Song, B., Cheng, S., Cui, P., Iwasaki, M., Shimazu, T., Tsugane, S., Fei, K., Wu, G., Lin, H.-C., Fang, Y.-H., Tsai, F.-Y., Hsieh, W.-S., Yu, J., Stevens, V.L., Laird-Offringa, I.A., Marconett, C.N., Rieswijk, L., Chao, A., Shu, X.-O., Lin, D., Chen, K., Zhou, B., Kohno, T., Shen, H., Chanock, S.J., Rothman, N., Lan, Q., IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Wong, J.Y.Y., Hsiung, C.A., Matsuo, K., Wong, M.P., Seow, W.J., Song, M., Chang, I.-S., Chatterjee, N., Hu, W., Wu, C., Mitsudomi, T., Zheng, W., Kim, J.H., Seow, A., Caporaso, N.E., Shin, M.-H., Chung, L.P., An, S.-J., Zheng, H., Yatabe, Y., Kim, Y.T., Cai, Q., Kim, Y.-C., Bassig, B.A., Ho, J.C.M., Ji, B.-T., Daigo, Y., Ito, H., Momozawa, Y., Ashikawa, K., Kamatani, Y., Honda, T., Hosgood, H.D., Sakamoto, H., Kunitoh, H., Tsuta, K., Watanabe, S.-I., Kubo, M., Miyagi, Y., Nakayama, H., Matsumoto, S., Tsuboi, M., Goto, K., Song, L., Hua, X., Takahashi, A., Goto, A., Minamiya, Y., Shimizu, K., Tanaka, K., Wei, F., Matsuda, F., Kim, Y.H., Oh, I.-J., Song, F., Su, W.-C., Chang, G.-C., Chen, K.-Y., Chien, L.-H., Xiang, Y.-B., Kweon, S.-S., Lee, K.-M., Blechter, B., Qian, B., Lu, D., Jeon, H.-S., Hsiao, C.-F., Sung, J.S., Tsai, Y.-H., Jung, Y.J., Chung, C.C., Burdett, L., Yeager, M., Hutchinson, A., Berndt, S.I., Pang, H., Choi, J.E., Park, K.H., Sung, S.W., Zhu, M., Guan, P., Tan, W., Hsin, M., Sit, K.-Y., Ho, J., Choi, Y.Y., Kim, J.S., Yoon, H.I., Park, I.K., Xu, P., He, Q., Perng, R.-P., Vermeulen, R., Lim, W.-Y., Chen, K.-C., Jin, L., Jiang, S.-S., Yamaji, T., Hicks, B., Wyatt, K., Dai, J., Jin, G., Song, B., Cheng, S., Cui, P., Iwasaki, M., Shimazu, T., Tsugane, S., Fei, K., Wu, G., Lin, H.-C., Fang, Y.-H., Tsai, F.-Y., Hsieh, W.-S., Yu, J., Stevens, V.L., Laird-Offringa, I.A., Marconett, C.N., Rieswijk, L., Chao, A., Shu, X.-O., Lin, D., Chen, K., Zhou, B., Kohno, T., Shen, H., Chanock, S.J., Rothman, N., and Lan, Q.

Published
2020

24. Comprehensive Analysis of Hormone and Genetic Variation in 36 Genes Related to Steroid Hormone Metabolism in Pre- and Postmenopausal Women from the Breast and Prostate Cancer Cohort Consortium (BPC3)

Author

Beckmann, L., Hüsing, A., Setiawan, V. W., Amiano, P., Clavel-Chapelon, F., Chanock, S. J., Cox, D. G., Diver, R., Dossus, L., Feigelson, H. S., Haiman, C., Hallmans, G., Hayes, R. B., Henderson, B. E., Hoover, R. N., Hunter, D. J., Khaw, K., Kolonel, L. N., Kraft, P., Lund, E., Le Marchand, L., Peeters, P. H. M., Riboli, E., Stram, D., Thomas, G., Thun, M. J., Tumino, R., Trichopoulos, D., Vogel, U., Willett, W. C., Yeager, M., Ziegler, R., Hankinson, S. E., and Kaaks, R.

Published
2011

32. Three-dimensional organization of a human water channel

Author

Cheng, Anchi, van Hoek, A.N., Yeager, M., Verkman, A.S., and Mitra, A.K.

Subjects
Molecules -- Models, Membrane proteins -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

The three-dimensional structure of deglycosylated, human erythrocyte aquaporin AQP1 presents a number of interesting features. It has an in-plane, intramolecular 2-fold axis of symmetry located in the hydrophobic core of the bilayer. Six membrane-spanning, tilted alpha-helices make up the AQP1 monomer. It can be established that there is intramolecular symmetry within the AQP1 molecule. This presents a new representation of the topology and design of membrane protein channels.

Published
1997

35. Projection structure of the CHIP28 water channel in lipid bilayer membranes at 12-angstrom resolution

Author

Mitra, A.K., Yeager, M., Hoek, A.N. van, Wiener, M.C., and Verkman, A.S.

Subjects
Bilayer lipid membranes -- Analysis, Erythrocytes -- Research, Biological transport -- Research, Biological sciences, Chemistry
Abstract

A study of the structure of a membrane channel protein that has specificity for water, CHIP28, in membranes through Fourier transforms of low-dose electron micrographs of large two-dimensional crystals of purified and deglycosylated erythrocyte CHIP28, stored in negative stain, reveals a tetragonal crystal lattice, with p4g plane group symmetry. Tetrameric structures are formed around the 4-fold axes normal to the membrane plane where the negative stain is excluded. The molecular boundary and distribution of the CHIP28 monomers in the membrane plane are determined by a projection density map at 12-angstrom resolution. Two opposingly oriented oblong-shaped (37 X 25 angstroms) monomers constitute the CHIP28 dimers, with each unit cell having four of them.

Published
1994

36. Factors associated with oxidative stress and cancer risk in the Breast and Prostate Cancer Cohort Consortium

Author

Blein, S, Berndt, S, Joshi, Ad, Campa, D, Ziegler, Rg, Riboli, E, Cox, Dg, Gaudet, Mm, Stevens, Vl, Diver, Wr, Gapstur, Sm, Chanock, Sj, Hoover, Rn, Yeager, M, Albanes, D, Virtamo, J, Crawford, Ed, Isaacs, C, Berg, C, Trichopoulos, D, Peeters, Ph, Johansson, M, Khaw, Kt, Kraft, P, Hunter, Dj, Lindström, S, Ma, J, Stampfer, M, Gaziano, Jm, Giovannucci, E, Willett, Wh, Hankinson, Se, Lee, Im, Buring, J, Henderson, B, Marchand, Ll, Kolonel, L, Haiman, C.j., PANICO, SALVATORE, Blein, S, Berndt, S, Joshi, Ad, Campa, D, Ziegler, Rg, Riboli, E, Cox, Dg, Gaudet, Mm, Stevens, Vl, Diver, Wr, Gapstur, Sm, Chanock, Sj, Hoover, Rn, Yeager, M, Albanes, D, Virtamo, J, Crawford, Ed, Isaacs, C, Berg, C, Trichopoulos, D, Panico, Salvatore, Peeters, Ph, Johansson, M, Khaw, Kt, Kraft, P, Hunter, Dj, Lindström, S, Ma, J, Stampfer, M, Gaziano, Jm, Giovannucci, E, Willett, Wh, Hankinson, Se, Lee, Im, Buring, J, Henderson, B, Marchand, Ll, Kolonel, L, and Haiman, C. j.

Subjects
MnSOD, Male, Oncology, medicine.medical_specialty, Genotype, Biology, medicine.disease_cause, Polymorphism, Single Nucleotide, Biochemistry, Prostate cancer, Breast cancer, Prostate, Internal medicine, Epidemiology, medicine, Genetic Predisposition to Disease, Breast, Survival analysis, Gynecology, Medicine (all), Oxidative Stre, General Medicine, medicine.disease, Mitochondria, medicine.anatomical_structure, Alcohol, GPX-1, Prostatic Neoplasm, Cohort, Female, Survival Analysi, Reactive Oxygen Specie, Breast Neoplasm, Oxidative stress, Human
Abstract

Both endogenous factors (genomic variations) and exogenous factors (environmental exposures, lifestyle) impact the balance of reactive oxygen species (ROS). Variants of the ND3 (rs2853826; G10398A) gene of the mitochondrial genome, manganese superoxide dismutase (MnSOD; rs4880 Val16Ala) and glutathione peroxidase (GPX-1; rs1050450 Pro198Leu), are purported to have functional effects on regulation of ROS balance. In this study, we examined associations of breast and prostate cancer risks and survival with these variants, and interactions between rs4880-rs1050450, and alcohol consumption-rs2853826. Nested case-control studies were conducted in the Breast and Prostate Cancer Cohort Consortium (BPC3), consisting of nine cohorts. The analyses included over 10726 post-menopausal breast and 7532 prostate cancer cases with matched controls. Logistic regression models were used to evaluate associations with risk, and proportional hazard models were used for survival outcomes. We did not observe significant interactions between polymorphisms in MnSOD and GPX-1, or between mitochondrial polymorphisms and alcohol intake and risk of either breast (p-interaction of 0.34 and 0.98, respectively) or prostate cancer (p-interaction of 0.49 and 0.50, respectively). We observed a weak inverse association between prostate cancer risk and GPX-1 Leu198Leu carriers (OR 0.87, 95% CI 0.79-0.97, p = 0.01). Overall survival among women with breast cancer was inversely associated with G10398 carriers who consumed alcohol (HR 0.66 95% CI 0.49-0.88). Given the high power in our study, it is unlikely that interactions tested have more than moderate effects on breast or prostate cancer risk. Observed associations need both further epidemiological and biological confirmation.

Published
2014

37. Whole exome sequencing reveals a C-terminal germline variant in CEBPA-associated acute myeloid leukemia: 45-year follow up of a large family

Author

Pathak A Seipel K Pemov A Dewan R Brown C Ravichandran S Luke BT Malasky M Suman S Yeager M

Abstract

Familial acute myeloid leukemia is rare and linked to germline mutations in RUNX1 GATA2 or CCAAT/enhancer binding protein a (CEBPA). We re evaluated a large family with acute myeloid leukemia originally seen at NIH in 1969. We used whole exome sequencing to study this family and conducted in silico bioinformatics analysis protein structural modeling and laboratory experiments to assess the impact of the identified CEBPA Q311P mutation. Unlike most previously identified germline mutations in CEBPA which were N terminal frameshift mutations we identified a novel Q311P variant that was located in the C terminal bZip domain of C/EBPa. Protein structural modeling suggested that the Q311P mutation alters the ability of the CEBPA dimer to bind DNA. Electrophoretic mobility shift assays showed that the Q311P mu tant had attenuated binding to DNA as predicted by the protein modeling. Consistent with these findings we found that the Q311P mutation has reduced transactivation consistent with a loss of function mutation. From 45 years of follow up we observed incomplete penetrance (46) of CEBPA Q311P. This study of a large multi generational pedigree reveals that a germline mutation in the C terminal bZip domain can alter the ability of C/EBP a to bind DNA and reduces transactivation leading to acute myeloid leukemia.

Published
2016

39. Genome-wide association study identifies the GLDC/IL33 locus associated with survival of osteosarcoma patients

Author

Koster, R. (Roelof), Panagiotou, O.A. (Orestis A.), Wheeler, W. (William), Karlins, E. (Eric), Gastier-Foster, J.M. (Julie M.), Caminada-de-Toledo, S.R. (Silvia Regina), Petrilli, A.S. (Antonio S.), Flanagan, A.M. (Adrienne M.), Tirabosco, R. (Roberto), Andrulis, I.L. (Irene L.), Wunder, J.S. (Jay S.), Gokgoz, N. (Nalan), Patiño-García, A. (Ana), Lecanda, F. (Fernando), Serra, M. (Massimo), Hattinger, C. (Claudia), Picci, P. (Piero), Scotlandi, K. (Katia), Thomas, D.M. (David M.), Ballinger, M.L. (Mandy L.), Gorlick, R.G. (Richard G.), Barkauskas, D.A. (Donald A.), Spector, L. (Logan), Tucker, M. (Margaret), Hicks, B. (Belynda), Yeager, M. (Meredith), Hoover, R.N. (Robert N.), Wacholder, S. (Sholom), Chanock, S.J. (Stephen J.), Savage, S.A. (Sharon A.), and Mirabello, L. (Lisa)

Subjects
Osteosarcoma, Genome-wide association study, Overall survival, Osteosarcoma-specific survival
Abstract

Survival rates for osteosarcoma, the most common primary bone cancer, have changed little over the past three decades and are particularly low for patients with metastatic disease. We conducted a multi-institutional genome-wide association study (GWAS) to identify germline genetic variants associated with overall survival in 632 patients with osteosarcoma, including 523 patients of European ancestry and 109 from Brazil. We conducted a time-to-event analysis and estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards models, with and without adjustment for metastatic disease.

Published
2018

40. Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility

Author

Machiela, M.J. (Mitchell J.), Grünewald, T.G.P. (Thomas G. P.), Surdez, D. (Didier), Reynaud, S. (Stephanie), Mirabeau, O. (Olivier), Karlins, E. (Eric), Rubio, R.A. (Rebeca Alba), Zaidi, S. (Sakina), Grossetete-Lalami, S. (Sandrine), Ballet, S. (Stelly), Lapouble, E. (Eve), Laurence, V. (Valérie), Michon, J. (Jean), Pierron, G. (Gaelle), Kovar, H. (Heinrich), Gaspar, N. (Nathalie), Kontny, U. (Udo), Gonzalez-Neira, A. (Anna), Picci, P. (Piero), Alonso, J. (Javier), Patiño-García, A. (Ana), Corradini, N. (Nadege), Bérard, P.M. (Perrine Marec), Freedman, N.D. (Neal D.), Rothman, N. (Nathaniel), Dagnall, C. (Casey), Burdett, L. (Laurie), Jones, K. (Krisitine), Manning, M. (Michelle), Wyatt, K. (Kathleen), Zhou, W. (Weiyin), Yeager, M. (Meredith), Cox, D.G. (David G.), Hoover, R.N. (Robert N.), Khan, J. (Javed), Armstrong, G.T. (Gregory T.), Leisenring, W.M. (Wendy M.), Bhatia, S. (Smita), Robison, L.L. (Leslie L.), Kulozik, A. (Andreas E.), Kriebel, J. (Jennifer), Meitinger, T. (Thomas), Metzler, M. (Markus), Hartmann, W. (Wolfgang), Strauch, K. (Konstantin), Kirchner, T. (Thomas), Dirksen, U. (Uta), Morton, L.M. (Lindsay M.), Mirabello, L. (Lisa), Tucker, M. (Margaret), Tirode, F. (Franck), Chanock, S.J. (Stephen J.), and Delattre, O. (Olivier)

Subjects
Genome-wide association study, Ewing sarcoma (EWS), Pediatric cancer
Abstract

Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk.

Published
2018

43. Variability and Inflammation for Sepsis Trajectory Analysis

Author

Yeager, M., primary, Jacono, F., additional, Al-Aghil, A., additional, Tackett, S., additional, Solanki, N., additional, Bonfield, T.L., additional, Guo, F., additional, Kaffashi, F., additional, Fletcher, D.R., additional, Nethery, D.E., additional, Loparo, K.A., additional, and Dick, T.E., additional

Published
2019
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45. Sex-specific glioma genome-wide association study identifies new risk locus at 3p21.31 in females, and finds sex-differences in risk at 8q24.21.

Author

Ostrom, QT, Kinnersley, B, Wrensch, MR, Eckel-Passow, JE, Armstrong, G, Rice, T, Chen, Y, Wiencke, JK, McCoy, LS, Hansen, HM, Amos, CI, Bernstein, JL, Claus, EB, Il'yasova, D, Johansen, C, Lachance, DH, Lai, RK, Merrell, RT, Olson, SH, Sadetzki, S, Schildkraut, JM, Shete, S, Rubin, JB, Lathia, JD, Berens, ME, Andersson, U, Rajaraman, P, Chanock, SJ, Linet, MS, Wang, Z, Yeager, M, GliomaScan consortium, Houlston, RS, Jenkins, RB, Melin, B, Bondy, ML, Barnholtz-Sloan, JS, Ostrom, QT, Kinnersley, B, Wrensch, MR, Eckel-Passow, JE, Armstrong, G, Rice, T, Chen, Y, Wiencke, JK, McCoy, LS, Hansen, HM, Amos, CI, Bernstein, JL, Claus, EB, Il'yasova, D, Johansen, C, Lachance, DH, Lai, RK, Merrell, RT, Olson, SH, Sadetzki, S, Schildkraut, JM, Shete, S, Rubin, JB, Lathia, JD, Berens, ME, Andersson, U, Rajaraman, P, Chanock, SJ, Linet, MS, Wang, Z, Yeager, M, GliomaScan consortium, Houlston, RS, Jenkins, RB, Melin, B, Bondy, ML, and Barnholtz-Sloan, JS

Abstract

Incidence of glioma is approximately 50% higher in males. Previous analyses have examined exposures related to sex hormones in women as potential protective factors for these tumors, with inconsistent results. Previous glioma genome-wide association studies (GWAS) have not stratified by sex. Potential sex-specific genetic effects were assessed in autosomal SNPs and sex chromosome variants for all glioma, GBM and non-GBM patients using data from four previous glioma GWAS. Datasets were analyzed using sex-stratified logistic regression models and combined using meta-analysis. There were 4,831 male cases, 5,216 male controls, 3,206 female cases and 5,470 female controls. A significant association was detected at rs11979158 (7p11.2) in males only. Association at rs55705857 (8q24.21) was stronger in females than in males. A large region on 3p21.31 was identified with significant association in females only. The identified differences in effect of risk variants do not fully explain the observed incidence difference in glioma by sex.

Published
2018

46. Genome-wide association study identifies multiple risk loci for renal cell carcinoma

Author

Scelo, G, Purdue, MP, Brown, KM, Johansson, M, Wang, Z, Eckel-Passow, JE, Ye, Y, Hoffman, JN, Choi, J, Foll, M, Gaborieau, V, Machiela, MJ, Colli, LM, Li, P, Sampson, JN, Abedi-Ardekani, B, Besse, C, Blanche, H, Boland, A, Burdette, L, Charbrier, A, Durand, G, Le Calvez-Kelm, F, Prokhortchouk, E, Robinot, N, Skyrabin, KG, Wozniak, MB, Yeager, M, Basta-Jovanovich, G, Dzamic, Z, Foretova, L, Holcatova, I, Janout, V, Mates, D, Mukeriya, A, Rascu, S, Zaridze, D, Bencko, V, Cybulski, C, Fabianova, E, Jinga, V, Lissowska, J, Lubinski, J, Navratilova, M, Rudnai, P, Szeszenia-Dabrowska, N, Benhamou, S, Cancel-Tassin, G, Cussenot, O, Baglietto, L, Boeing, H, Khaw, K-T, Weiderpass, E, Ljungberg, B, Sitaram, RT, Bruinsma, F, Jordan, SJ, Severi, G, Winship, I, Hveem, K, Vatten, LJ, Fletcher, T, Koppova, K, Larsson, SC, Wolk, A, Banks, RE, Selby, PJ, Easton, DF, Pharoah, P, Andreotti, G, Beane Freeman, LE, Koutros, S, Albanes, D, Mannisto, S, Weinstein, S, Clark, PE, Edwards, TL, Lipworth, L, Gapstur, SM, Stevens, VL, Carol, H, Freedman, ML, Pomerantz, MM, Cho, E, Kraft, P, Preston, MA, Wilson, KM, Gaziano, JM, Sesso, HD, Black, A, Freedman, ND, Huang, WY, Anema, JG, Kahnoski, RJ, Lane, BR, Noyes, SL, Petillo, D, Teh, BT, Peters, U, White, E, Anderson, GL, Johnson, L, Luo, J, Buring, J, Lee, I-M, Chow, W-H, Moore, LE, Wood, C, Eisen, T, Henrion, M, Larkin, J, Barman, P, Leibovich, BC, Choueiri, TK, Lathrop, GM, Rothman, N, Deleuze, J-F, McKay, JD, Parker, AS, Wu, X, Houlston, RS, Brennan, P, and Chanock, SJ

Abstract

Previous genome-wide association studies (GWAS) have identified six risk loci for renal cell carcinoma (RCC). We conducted a meta-analysis of two new scans of 5,198 cases and 7,331 controls together with four existing scans, totalling 10,784 cases and 20,406 controls of European ancestry. Twenty-four loci were tested in an additional 3,182 cases and 6,301 controls. We confirm the six known RCC risk loci and identify seven new loci at 1p32.3 (rs4381241, P=3.1 × 10−10), 3p22.1 (rs67311347, P=2.5 × 10−8), 3q26.2 (rs10936602, P=8.8 × 10−9), 8p21.3 (rs2241261, P=5.8 × 10−9), 10q24.33-q25.1 (rs11813268, P=3.9 × 10−8), 11q22.3 (rs74911261, P=2.1 × 10−10) and 14q24.2 (rs4903064, P=2.2 × 10−24). Expression quantitative trait analyses suggest plausible candidate genes at these regions that may contribute to RCC susceptibility.

Published
2017

47. CAT-2003: A Novel Sterol Regulatory Element-Binding Protein Inhibitor That Reduces Steatohepatitis, Plasma Lipids, and Atherosclerosis in Apolipoprotein E*3-Leiden Mice

Author

Zimmer, M., Bista, P., Benson, E.L., Lee, D.Y., Liu, F., Picarella, D., Vega, R.B., Vu, C.B., Yeager, M., Ding, M., Liang, G., Horton, J.D., Kleemann, R., Kooistra, T., Morrison, M.C., Wielinga, P.Y., Milne, J.C., Jirousek, M.R., and Nichol, A.J.

Subjects
Life, Biomedical Innovation, lipids (amino acids, peptides, and proteins), ELSS - Earth, Life and Social Sciences, MHR - Metabolic Health Research, Biology, Healthy Living
Abstract

CAT-2003 is a novel conjugate of eicosapentaenoic acid (EPA) and niacin designed to be hydrolyzed by fatty acid amide hydrolase to release EPA inside cells at the endoplasmic reticulum. In cultured liver cells, CAT-2003 blocked the maturation of sterol regulatory element-binding protein (SREBP)-1 and SREBP-2 proteins and decreased the expression of multiple SREBP target genes, including HMGCR and PCSK9. Consistent with proprotein convertase subtilisin/kexin type 9 (PCSK9) reduction, both low-density lipoprotein receptor protein at the cell surface and low-density lipoprotein particle uptake were increased. In apolipoprotein E*3-Leiden mice fed a cholesterol-containing western diet, CAT-2003 decreased hepatic inflammation and steatosis as evidenced by fewer inflammatory cell aggregates in histopathologic sections, decreased nuclear factor kappa B activity in liver lysates, reduced inflammatory gene expression, reduced intrahepatic cholesteryl ester and triglyceride levels, and decreased liver mass. Plasma PCSK9 was reduced and hepatic low-density lipoprotein receptor protein expression was increased; plasma cholesterol and triglyceride levels were lowered. Aortic root segments showed reduction of several atherosclerotic markers, including lesion size, number, and severity. CAT-2003, when dosed in combination with atorvastatin, further lowered plasma cholesterol levels and decreased hepatic expression of SREBP target genes. Conclusion: SREBP inhibition is a promising new strategy for the prevention and treatment of diseases associated with abnormal lipid metabolism, such as atherosclerosis and nonalcoholic steatohepatitis.

Published
2017

48. Common colorectal cancer risk alleles contribute to the multiple colorectal adenoma phenotype, but do not influence colonic polyposis in FAP

Author

Cheng, T. H. T., Gorman, M., Martin, L., Barclay, E., Casey, G., Newcomb, P. A., Conti, D. V., Schumacher, F. R., Gallinger, S., Lindor, N. M., Hopper, J., Jenkins, M., Hunter, D. J., Kraft, P., Jacobs, K. B., Cox, D. G., Yeager, M., Hankinson, S. E., Wacholder, S., Wang, Z., Welch, R., Hutchinson, A., Wang, J., Yu, K., Chatterjee, N., Orr, N., Willett, W. C., Colditz, G. A., Ziegler, R. G., Berg, C. D., Buys, S. S., McCarty, C. A., Feigelson, H. S., Calle, E. E., Thun, M. J., Hayes, R. B., Tucker, M., Gerhard, D. S., Fraumeni, J. F., Jr., Hoover, R. N., Thomas, G., Chanock, S. J., Ciampa, J., Gonzalez-Bosquet, J., Berndt, S., Amundadottir, L., Diver, W. R., Albanes, D., Virtamo, J., Weinstein, S. J., Cancel-Tassin, G., Cussenot, O., Valeri, A., Andriole, G. L., Crawford, E. D., Haiman, C. A., Henderson, B., Kolonel, L., March, L. L., Siddiq, A., Riboli, E., Key, T. J., Kaaks, R., Isaacs, W., Isaacs, S., Wiley, K. E., Gronberg, H., Wiklund, F., Stattin, P., Xu, J., Zheng, S. L., Sun, J., Vatten, L. J., Hveem, K., Kumle, M., Purdue, M. P., Johansson, M., Zelenika, D., Toro, J. R., Scelo, G., Moore, L. E., Prokhortchouk, E., Wu, X., Kiemeney, L. A., Gaborieau, V., Chow, W. -H., Zaridze, D., Matveev, V., Lubinski, J., Trubicka, J., Szeszenia-Dabrowska, N., Lissowska, J., Rudnai, P., Fabianova, E., Bucur, A., Bencko, V., Foretova, L., Janout, V., Boffetta, P., Colt, J. S., Davis, F. G., Schwartz, K. L., Banks, R. E., Selby, P. J., Harnden, P., Hsing, A. W., Grubb, R. L., III, Boeing, H., Vineis, P., Clavel-Chapelon, F., Palli, D., Tumino, R., Krogh, V., Panico, S., Duell, E. J., Quirós, J. R., Sanchez, M. -J., Navarro, C., Ardanaz, E., Dorronsoro, M., Khaw, K. -T., Allen, N. E., Bueno-de-Mesquita, H. B., Peeters, P. H. M., Trichopoulos, D., Linseisen, J., Ljungberg, B., Overvad, K., Tjønnel, Romieu, I., Mukeria, A., Shangina, O., Stevens, V. L., Gapstur, S. M., Pharoah, P. D., Easton, D. F., Njølstad, I., Tell, G. S., Stoltenberg, C., Kumar, R., Koppova, K., Benhamou, S., Oosterwijk, E., Vermeulen, S. H., Aben, K. K. H., Van Der Marel, S. L., Ye, Y., Wood, C. G., Pu, X., Mazur, A. M., Boulygina, E. S., Chekanov, N. N., Foglio, M., Lechner, D., Gut, I., Heath, S., Blanche, H., Skryabin, K. G., McKay, J. D., Rothman, N., Lathrop, M., Brennan, P., Saunders, B., Thomas, H., Clark, S., Tomlinson, I., and Cheng, T.H.T. and Gorman, M. and Martin, L. and Barclay, E. and Casey, G. and Newcomb, P.A. and Conti, D.V. and Schumacher, F.R. and Gallinger, S. and Lindor, N.M. and Hopper, J. and Jenkins, M. and Hunter, D.J. and Kraft, P. and Jacobs, K.B. and Cox, D.G. and Yeager, M. and Hankinson, S.E. and Wacholder, S. and Wang, Z. and Welch, R. and Hutchinson, A. and Wang, J. and Yu, K. and Chatterjee, N. and Orr, N. and Willett, W.C. and Colditz, G.A. and Ziegler, R.G. and Berg, C.D. and Buys, S.S. and McCarty, C.A. and Feigelson, H.S. and Calle, E.E. and Thun, M.J. and Hayes, R.B. and Tucker, M. and Gerhard, D.S. and Fraumeni, J.F., Jr. and Hoover, R.N. and Thomas, G. and Chanock, S.J. and Ciampa, J. and Gonzalez-Bosquet, J. and Berndt, S. and Amundadottir, L. and Diver, W.R. and Albanes, D. and Virtamo, J. and Weinstein, S.J. and Cancel-Tassin, G. and Cussenot, O. and Valeri, A. and Andriole, G.L. and Crawford, E.D. and Haiman, C.A. and Henderson, B. and Kolonel, L. and Marchand, L.L. and Siddiq, A. and Riboli, E. and Key, T.J. and Kaaks, R. and Isaacs, W. and Isaacs, S. and Wiley, K.E. and Gronberg, H. and Wiklund, F. and Stattin, P. and Xu, J. and Zheng, S.L. and Sun, J. and Vatten, L.J. and Hveem, K. and Kumle, M. and Purdue, M.P. and Johansson, M. and Zelenika, D. and Toro, J.R. and Scelo, G. and Moore, L.E. and Prokhortchouk, E. and Wu, X. and Kiemeney, L.A. and Gaborieau, V. and Chow, W.-H. and Zaridze, D. and Matveev, V. and Lubinski, J. and Trubicka, J. and Szeszenia-Dabrowska, N. and Lissowska, J. and Rudnai, P. and Fabianova, E. and Bucur, A. and Bencko, V. and Foretova, L. and Janout, V. and Boffetta, P. and Colt, J.S. and Davis, F.G. and Schwartz, K.L. and Banks, R.E. and Selby, P.J. and Harnden, P. and Hsing, A.W. and Grubb, R.L., III and Boeing, H. and Vineis, P. and Clavel-Chapelon, F. and Palli, D. and Tumino, R. and Krogh, V. and Panico, S. and Duell, E.J. and Quirós, J.R. and Sanchez, M.-J. and Navarro, C. and Ardanaz, E. and Dorronsoro, M. and Khaw, K.-T. and Allen, N.E. and Bueno-de-Mesquita, H.B. and Peeters, P.H.M. and Trichopoulos, D. and Linseisen, J. and Ljungberg, B. and Overvad, K. and Tjønneland, A. and Romieu, I. and Mukeria, A. and Shangina, O. and Stevens, V.L. and Gapstur, S.M. and Pharoah, P.D. and Easton, D.F. and Njølstad, I. and Tell, G.S. and Stoltenberg, C. and Kumar, R. and Koppova, K. and Benhamou, S. and Oosterwijk, E. and Vermeulen, S.H. and Aben, K.K.H. and Van Der Marel, S.L. and Ye, Y. and Wood, C.G. and Pu, X. and Mazur, A.M. and Boulygina, E.S. and Chekanov, N.N. and Foglio, M. and Lechner, D. and Gut, I. and Heath, S. and Blanche, H. and Skryabin, K.G. and McKay, J.D. and Rothman, N. and Lathrop, M. and Brennan, P. and Saunders, B. and Thomas, H. and Clark, S. and Tomlinson, I.

Subjects
Male, pathogenesi, genetic association, phenotype, Adenomatous Polyposis Coli Protein, colorectal cancer, Colorectal Neoplasm, cancer risk, gene frequency, Polymorphism, Single Nucleotide, Article, DNA glycosyltransferase, adult, DNA glycosylase MutY, colon polyposi, single nucleotide polymorphism, genetic variability, middle aged, controlled study, Genetic Predisposition to Disease, human, DNA Glycosylase, Germ-Line Mutation, Aged, colorectal adenoma, Allele, modifier gene, Genes, Modifier, disease predisposition, APC protein, human, major clinical study, digestive system diseases, human tissue, APC protein, female, priority journal, Adenomatous Polyposis Coli, germline mutation, familial colon polyposi, adenoma, single nucleotide polymorphism, Adenoma, genetic, genetic predisposition
Abstract

The presence of multiple (5-100) colorectal adenomas suggests an inherited predisposition, but the genetic aetiology of this phenotype is undetermined if patients test negative for Mendelian polyposis syndromes such as familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). We investigated whether 18 common colorectal cancer (CRC) predisposition single-nucleotide polymorphisms (SNPs) could help to explain some cases with multiple adenomas who phenocopied FAP or MAP, but had no pathogenic APC or MUTYH variant. No multiple adenoma case had an outlying number of CRC SNP risk alleles, but multiple adenoma patients did have a significantly higher number of risk alleles than population controls (P = 5.7 × 10-7). The association was stronger in those with ≥ 10 adenomas. The CRC SNPs accounted for 4.3% of the variation in multiple adenoma risk, with three SNPs (rs6983267, rs10795668, rs3802842) explaining 3.0% of the variation. In FAP patients, the CRC risk score did not differ significantly from the controls, as we expected given the overwhelming effect of pathogenic germline APC variants on the phenotype of these cases. More unexpectedly, we found no evidence that the CRC SNPs act as modifier genes for the number of colorectal adenomas in FAP patients. In conclusion, common colorectal tumour risk alleles contribute to the development of multiple adenomas in patients without pathogenic germline APC or MUTYH variants. This phenotype may have 'polygenic' or monogenic origins. The risk of CRC in relatives of multiple adenoma cases is probably much lower for cases with polygenic disease, and this should be taken into account when counselling such patients. © 2015 Macmillan Publishers Limited All rights reserved.

Published
2015

49. Air Force Compliance Study

Author

Grabbs, W., primary, Yeager, M., primary, Robinson, J., primary, Fox, K., primary, Elequin, V., primary, Ketchum, N., primary, Jackson, W., primary, and Pavuk, M., primary

Published
2006
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