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101. Characterization of a novel 21-kb deletion, CFTRdele2, 3(21kb), in the CFTR gene: a cystic fibrosis mutation of Slavic origin common in Central and East Europe

Author

Doerk, T., Macek, M., Mekus, F., Tuemmler, B., Tzountzouris, J., Casals, T., Krebsova, A., Koudova, M., Sakmaryova, I., Vavrova, V., Zemkova, D., Ginter, E., Petrova, N.V., Ivaschenko, T., Baranov, V., Witt, M., Pogorzelski, A., Bal, J., Zekanowsky, C., Wagner, K., Stuhrmann, M., Bauer, I., Seydewitz, H.H., Neumann, T., Jakubiczka, S., and Sertić, Jadranka

Abstract

We report a large genomic deletion of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, viz. a deletion that is frequently observed in Central and Eastern Europe. The mutation, termed CFTRdele2, 3(21 kb), deletes 21, 080 bp spanning introns 1-3 of the CFTR gene. Transcript analyses have revealed that this deletion results in the loss of exons 2 and 3 in epithelial CFTR mRNA, thereby producing a premature termination signal within exon 4. In order to develop a simple polymerase chain reaction assay for this allele, we defined the end-points of the deletion at the DNA sequence level. We next screened for this mutation in a representative set of European and European-derived populations. Some 197 CF patients, including seven homozygotes, bearing this mutation have been identified during the course of our study. Clinical evaluation of CFTRdele2, 3(21 kb) homozygotes and a comparison of compound heterozygotes for deltaF508/CFTRdele2, 3(21 kb) with pairwise-matched deltaF508 homozygotes indicate that this deleton represents a severe mutation associated with pancreatic insufficiency and early age at diagnosis. Current data show that the mutation is particularly common in Czech (6.4% of all CF chromosomes), Russian (5.2%), Belorussian (3.3%), Austrian (2.6%), German (1.5%), Polish (1.5%), Slovenian (1.5%), Ukrainian (1.2%), and Slovak patients (1.1%). It has also been found in Lithuania, Latvia, Macedonia and Greece and has sporadically been observed in Canada, USA, France, Spain, Turkey, and UK, but not in CF patients from Bulgaria, Croatia, Romania or Serbia. Haplotype analysis has identified the same extragenic CF-haplotype XV-2c/KM.19 "A" and the same infrequent intragenic microsatellite haplotype 16-33-13 (IVS8CA-IVS17bTA-IVS17bCA) in all examined CFTRdele2, 3(21 kb) chromosomes, suggesting a common origin for this deletion. We conclude that the 21-kb deletion is a frequent and severe CF mutation in populations of Eastern- and Western-Slavic descent.

Published
2000

102. Evaluation of variation in the phosphoinositide-3-kinase catalytic subunit alpha oncogene and breast cancer risk

Author

Stevens, K. N., Garcia-Closas, M., Fredericksen, Z., Kosel, M., Pankratz, V. S., Hopper, J. L., Dite, G. S., Apicella, C., Southey, M. C., Schmidt, M. K., Broeks, A., Van 't Veer, L. J., Tollenaar, R. A. E. M., Fasching, P. A., Beckmann, M. W., Hein, A., Ekici, A. B., Johnson, N., Peto, J., Silva, I. dos Santos, Gibson, L., Sawyer, E., Tomlinson, I., Kerin, M. J., Chanock, S., Lissowska, J., Hunter, D. J., Hoover, R. N., Thomas, G. D., Milne, R. L., Perez, J. I. Arias, Gonzalez-Neira, A., Benitez, J., Burwinkel, B., Meindl, A., Schmutzler, R. K., Bartrar, C. R., Hamann, U., Ko, Y. D., Bruening, T., Chang-Claude, J., Hein, R., Wang-Gohrke, S., Doerk, T., Schuermann, P., Bremer, M., Hillemanns, P., Bogdanova, N., Zalutsky, J. V., Rogov, Y. I., Antonenkova, N., Lindblom, A., Margolin, S., Mannermaa, A., Kataja, V., Kosma, V-M, Hartikainen, J., Chenevix-Trench, G., Chen, X., Peterlongo, P., Bonanni, B., Bernard, L., Manoukian, S., Wang, X., Cerhan, J., Vachon, C. M., Olson, J., Giles, G. G., Baglietto, L., McLean, C. A., Severi, G., John, E. M., Miron, A., Winqvist, R., Pylkaes, K., Jukkola-Vuorinen, A., Grip, M., Andrulis, I., Knight, J. A., Glendon, G., Mulligan, A. M., Cox, A., Brock, I. W., Elliott, G., Cross, S. S., Pharoah, P. P., Dunning, A. M., Pooley, K. A., Humphreys, M. K., Wang, J., Kang, D., Yoo, K-Y, Noh, D-Y, Sangrajrang, S., Gabrieau, V., Brennan, P., Mckay, J., Anton-Culver, H., Ziogas, A., Couch, F. J., Easton, D. F., Stevens, K. N., Garcia-Closas, M., Fredericksen, Z., Kosel, M., Pankratz, V. S., Hopper, J. L., Dite, G. S., Apicella, C., Southey, M. C., Schmidt, M. K., Broeks, A., Van 't Veer, L. J., Tollenaar, R. A. E. M., Fasching, P. A., Beckmann, M. W., Hein, A., Ekici, A. B., Johnson, N., Peto, J., Silva, I. dos Santos, Gibson, L., Sawyer, E., Tomlinson, I., Kerin, M. J., Chanock, S., Lissowska, J., Hunter, D. J., Hoover, R. N., Thomas, G. D., Milne, R. L., Perez, J. I. Arias, Gonzalez-Neira, A., Benitez, J., Burwinkel, B., Meindl, A., Schmutzler, R. K., Bartrar, C. R., Hamann, U., Ko, Y. D., Bruening, T., Chang-Claude, J., Hein, R., Wang-Gohrke, S., Doerk, T., Schuermann, P., Bremer, M., Hillemanns, P., Bogdanova, N., Zalutsky, J. V., Rogov, Y. I., Antonenkova, N., Lindblom, A., Margolin, S., Mannermaa, A., Kataja, V., Kosma, V-M, Hartikainen, J., Chenevix-Trench, G., Chen, X., Peterlongo, P., Bonanni, B., Bernard, L., Manoukian, S., Wang, X., Cerhan, J., Vachon, C. M., Olson, J., Giles, G. G., Baglietto, L., McLean, C. A., Severi, G., John, E. M., Miron, A., Winqvist, R., Pylkaes, K., Jukkola-Vuorinen, A., Grip, M., Andrulis, I., Knight, J. A., Glendon, G., Mulligan, A. M., Cox, A., Brock, I. W., Elliott, G., Cross, S. S., Pharoah, P. P., Dunning, A. M., Pooley, K. A., Humphreys, M. K., Wang, J., Kang, D., Yoo, K-Y, Noh, D-Y, Sangrajrang, S., Gabrieau, V., Brennan, P., Mckay, J., Anton-Culver, H., Ziogas, A., Couch, F. J., and Easton, D. F.

Abstract

BACKGROUND: Somatic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival. The goal of this study was to evaluate the association between inherited variation in this oncogene and risk of breast cancer. METHODS: A single-nucleotide polymorphism from the PIK3CA locus that was associated with breast cancer in a study of Caucasian breast cancer cases and controls from the Mayo Clinic (MCBCS) was genotyped in 5436 cases and 5280 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study and in 30 949 cases and 29 788 controls from the Breast Cancer Association Consortium (BCAC). RESULTS: Rs1607237 was significantly associated with a decreased risk of breast cancer in MCBCS, CGEMS and all studies of white Europeans combined (odds ratio (OR) = 0.97, 95% confidence interval (CI) 0.95-0.99, P = 4.6 x 10(-3)), but did not reach significance in the BCAC replication study alone (OR = 0.98, 95% CI 0.96-1.01, P = 0.139). CONCLUSION: Common germline variation in PIK3CA does not have a strong influence on the risk of breast cancer British Journal of Cancer (2011) 105, 1934 - 1939. doi: 10.1038/bjc.2011.448 www.bjcancer.com Published online 27 October 2011 (C) 2011 Cancer Research UK

Published
2011

103. Polymorphisms in Stromal Genes and Susceptibility to Serous Epithelial Ovarian Cancer: A Report from the Ovarian Cancer Association Consortium

Author

Minna, JD, Amankwah, EK, Wang, Q, Schildkraut, JM, Tsai, Y-Y, Ramus, SJ, Fridley, BL, Beesley, J, Johnatty, SE, Webb, PM, Chenevix-Trench, G, Dale, LC, Lambrechts, D, Amant, F, Despierre, E, Vergote, I, Gayther, SA, Gentry-Maharaj, A, Menon, U, Chang-Claude, J, Wang-Gohrke, S, Anton-Culver, H, Ziogas, A, Doerk, T, Duerst, M, Antonenkova, N, Bogdanova, N, Brown, R, Flanagan, JM, Kaye, SB, Paul, J, Butzow, R, Nevanlinna, H, Campbell, I, Eccles, DM, Karlan, BY, Gross, J, Walsh, C, Pharoah, PDP, Song, H, Kjaer, SK, Hogdall, E, Hogdall, C, Lundvall, L, Nedergaard, L, Kiemeney, LALM, Massuger, LFAG, van Altena, AM, Vermeulen, SHHM, Le, ND, Brooks-Wilson, A, Cook, LS, Phelan, CM, Cunningham, JM, Vachon, CM, Vierkant, RA, Iversen, ES, Berchuck, A, Goode, EL, Sellers, TA, Kelemen, LE, Minna, JD, Amankwah, EK, Wang, Q, Schildkraut, JM, Tsai, Y-Y, Ramus, SJ, Fridley, BL, Beesley, J, Johnatty, SE, Webb, PM, Chenevix-Trench, G, Dale, LC, Lambrechts, D, Amant, F, Despierre, E, Vergote, I, Gayther, SA, Gentry-Maharaj, A, Menon, U, Chang-Claude, J, Wang-Gohrke, S, Anton-Culver, H, Ziogas, A, Doerk, T, Duerst, M, Antonenkova, N, Bogdanova, N, Brown, R, Flanagan, JM, Kaye, SB, Paul, J, Butzow, R, Nevanlinna, H, Campbell, I, Eccles, DM, Karlan, BY, Gross, J, Walsh, C, Pharoah, PDP, Song, H, Kjaer, SK, Hogdall, E, Hogdall, C, Lundvall, L, Nedergaard, L, Kiemeney, LALM, Massuger, LFAG, van Altena, AM, Vermeulen, SHHM, Le, ND, Brooks-Wilson, A, Cook, LS, Phelan, CM, Cunningham, JM, Vachon, CM, Vierkant, RA, Iversen, ES, Berchuck, A, Goode, EL, Sellers, TA, and Kelemen, LE

Abstract

Alterations in stromal tissue components can inhibit or promote epithelial tumorigenesis. Decorin (DCN) and lumican (LUM) show reduced stromal expression in serous epithelial ovarian cancer (sEOC). We hypothesized that common variants in these genes associate with risk. Associations with sEOC among Caucasians were estimated with odds ratios (OR) among 397 cases and 920 controls in two U.S.-based studies (discovery set), 436 cases and 1,098 controls in Australia (replication set 1) and a consortium of 15 studies comprising 1,668 cases and 4,249 controls (replication set 2). The discovery set and replication set 1 (833 cases and 2,013 controls) showed statistically homogeneous (P(heterogeneity)≥0.48) decreased risks of sEOC at four variants: DCN rs3138165, rs13312816 and rs516115, and LUM rs17018765 (OR = 0.6 to 0.9; P(trend) = 0.001 to 0.03). Results from replication set 2 were statistically homogeneous (P(heterogeneity)≥0.13) and associated with increased risks at DCN rs3138165 and rs13312816, and LUM rs17018765: all ORs = 1.2; P(trend)≤0.02. The ORs at the four variants were statistically heterogeneous across all 18 studies (P(heterogeneity)≤0.03), which precluded combining. In post-hoc analyses, interactions were observed between each variant and recruitment period (P(interaction)≤0.003), age at diagnosis (P(interaction) = 0.04), and year of diagnosis (P(interaction) = 0.05) in the five studies with available information (1,044 cases, 2,469 controls). We conclude that variants in DCN and LUM are not directly associated with sEOC, and that confirmation of possible effect modification of the variants by non-genetic factors is required.

Published
2011

104. Functional Polymorphisms in the TERT Promoter Are Associated with Risk of Serous Epithelial Ovarian and Breast Cancers

Author

Zhang, L, Beesley, J, Pickett, HA, Johnatty, SE, Dunning, AM, Chen, X, Li, J, Michailidou, K, Lu, Y, Rider, DN, Palmieri, RT, Stutz, MD, Lambrechts, D, Despierre, E, Lambrechts, S, Vergote, I, Chang-Claude, J, Nickels, S, Vrieling, A, Flesch-Janys, D, Wang-Gohrke, S, Eilber, U, Bogdanova, N, Antonenkova, N, Runnebaum, IB, Doerk, T, Goodman, MT, Lurie, G, Wilkens, LR, Matsuno, RK, Kiemeney, LA, Aben, KKH, Marees, T, Massuger, LFAG, Fridley, BL, Vierkant, RA, Bandera, EV, Olson, SH, Orlow, I, Rodriguez-Rodriguez, L, Cook, LS, Le, ND, Brooks-Wilson, A, Kelemen, LE, Campbell, I, Gayther, SA, Ramus, SJ, Gentry-Maharaj, A, Menon, U, Ahmed, S, Baynes, C, Pharoah, PD, Muir, K, Lophatananon, A, Chaiwerawattana, A, Wiangnon, S, Macgregor, S, Easton, DF, Reddel, RR, Goode, EL, Chenevix-Trench, G, Zhang, L, Beesley, J, Pickett, HA, Johnatty, SE, Dunning, AM, Chen, X, Li, J, Michailidou, K, Lu, Y, Rider, DN, Palmieri, RT, Stutz, MD, Lambrechts, D, Despierre, E, Lambrechts, S, Vergote, I, Chang-Claude, J, Nickels, S, Vrieling, A, Flesch-Janys, D, Wang-Gohrke, S, Eilber, U, Bogdanova, N, Antonenkova, N, Runnebaum, IB, Doerk, T, Goodman, MT, Lurie, G, Wilkens, LR, Matsuno, RK, Kiemeney, LA, Aben, KKH, Marees, T, Massuger, LFAG, Fridley, BL, Vierkant, RA, Bandera, EV, Olson, SH, Orlow, I, Rodriguez-Rodriguez, L, Cook, LS, Le, ND, Brooks-Wilson, A, Kelemen, LE, Campbell, I, Gayther, SA, Ramus, SJ, Gentry-Maharaj, A, Menon, U, Ahmed, S, Baynes, C, Pharoah, PD, Muir, K, Lophatananon, A, Chaiwerawattana, A, Wiangnon, S, Macgregor, S, Easton, DF, Reddel, RR, Goode, EL, and Chenevix-Trench, G

Abstract

Genetic variation at the TERT-CLPTM1L locus at 5p15.33 is associated with susceptibility to several cancers, including epithelial ovarian cancer (EOC). We have carried out fine-mapping of this region in EOC which implicates an association with a single nucleotide polymorphism (SNP) within the TERT promoter. We demonstrate that the minor alleles at rs2736109, and at an additional TERT promoter SNP, rs2736108, are associated with decreased breast cancer risk, and that the combination of both SNPs substantially reduces TERT promoter activity.

Published
2011

105. Evaluation of variation in the phosphoinositide-3-kinase catalytic subunit alpha oncogene and breast cancer risk

Author

Stevens, KN, Garcia-Closas, M, Fredericksen, Z, Kosel, M, Pankratz, VS, Hopper, JL, Dite, GS, Apicella, C, Southey, MC, Schmidt, MK, Broeks, A, Van 't Veer, LJ, Tollenaar, RAEM, Fasching, PA, Beckmann, MW, Hein, A, Ekici, AB, Johnson, N, Peto, J, Silva, IDS, Gibson, L, Sawyer, E, Tomlinson, I, Kerin, MJ, Chanock, S, Lissowska, J, Hunter, DJ, Hoover, RN, Thomas, GD, Milne, RL, Perez, JIA, Gonzalez-Neira, A, Benitez, J, Burwinkel, B, Meindl, A, Schmutzler, RK, Bartrar, CR, Hamann, U, Ko, YD, Bruening, T, Chang-Claude, J, Hein, R, Wang-Gohrke, S, Doerk, T, Schuermann, P, Bremer, M, Hillemanns, P, Bogdanova, N, Zalutsky, JV, Rogov, YI, Antonenkova, N, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, J, Chenevix-Trench, G, Chen, X, Peterlongo, P, Bonanni, B, Bernard, L, Manoukian, S, Wang, X, Cerhan, J, Vachon, CM, Olson, J, Giles, GG, Baglietto, L, McLean, CA, Severi, G, John, EM, Miron, A, Winqvist, R, Pylkaes, K, Jukkola-Vuorinen, A, Grip, M, Andrulis, I, Knight, JA, Glendon, G, Mulligan, AM, Cox, A, Brock, IW, Elliott, G, Cross, SS, Pharoah, PP, Dunning, AM, Pooley, KA, Humphreys, MK, Wang, J, Kang, D, Yoo, K-Y, Noh, D-Y, Sangrajrang, S, Gabrieau, V, Brennan, P, Mckay, J, Anton-Culver, H, Ziogas, A, Couch, FJ, Easton, DF, Stevens, KN, Garcia-Closas, M, Fredericksen, Z, Kosel, M, Pankratz, VS, Hopper, JL, Dite, GS, Apicella, C, Southey, MC, Schmidt, MK, Broeks, A, Van 't Veer, LJ, Tollenaar, RAEM, Fasching, PA, Beckmann, MW, Hein, A, Ekici, AB, Johnson, N, Peto, J, Silva, IDS, Gibson, L, Sawyer, E, Tomlinson, I, Kerin, MJ, Chanock, S, Lissowska, J, Hunter, DJ, Hoover, RN, Thomas, GD, Milne, RL, Perez, JIA, Gonzalez-Neira, A, Benitez, J, Burwinkel, B, Meindl, A, Schmutzler, RK, Bartrar, CR, Hamann, U, Ko, YD, Bruening, T, Chang-Claude, J, Hein, R, Wang-Gohrke, S, Doerk, T, Schuermann, P, Bremer, M, Hillemanns, P, Bogdanova, N, Zalutsky, JV, Rogov, YI, Antonenkova, N, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, J, Chenevix-Trench, G, Chen, X, Peterlongo, P, Bonanni, B, Bernard, L, Manoukian, S, Wang, X, Cerhan, J, Vachon, CM, Olson, J, Giles, GG, Baglietto, L, McLean, CA, Severi, G, John, EM, Miron, A, Winqvist, R, Pylkaes, K, Jukkola-Vuorinen, A, Grip, M, Andrulis, I, Knight, JA, Glendon, G, Mulligan, AM, Cox, A, Brock, IW, Elliott, G, Cross, SS, Pharoah, PP, Dunning, AM, Pooley, KA, Humphreys, MK, Wang, J, Kang, D, Yoo, K-Y, Noh, D-Y, Sangrajrang, S, Gabrieau, V, Brennan, P, Mckay, J, Anton-Culver, H, Ziogas, A, Couch, FJ, and Easton, DF

Abstract

BACKGROUND: Somatic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival. The goal of this study was to evaluate the association between inherited variation in this oncogene and risk of breast cancer. METHODS: A single-nucleotide polymorphism from the PIK3CA locus that was associated with breast cancer in a study of Caucasian breast cancer cases and controls from the Mayo Clinic (MCBCS) was genotyped in 5436 cases and 5280 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study and in 30 949 cases and 29 788 controls from the Breast Cancer Association Consortium (BCAC). RESULTS: Rs1607237 was significantly associated with a decreased risk of breast cancer in MCBCS, CGEMS and all studies of white Europeans combined (odds ratio (OR)=0.97, 95% confidence interval (CI) 0.95-0.99, P=4.6 × 10(-3)), but did not reach significance in the BCAC replication study alone (OR=0.98, 95% CI 0.96-1.01, P=0.139). CONCLUSION: Common germline variation in PIK3CA does not have a strong influence on the risk of breast cancer.

Published
2011

106. Common variants at 19p13 are associated with susceptibility to ovarian cancer.

Author

Bolton, K.L., Tyrer, J.P., Song, H., Ramus, S.J., Notaridou, M., Jones, C., Sher, T., Gentry-Maharaj, A., Wozniak, E., Tsai, Y.Y., Weidhaas, J., Paik, D., Berg, D.P.G. van den, Stram, D.O., Pearce, C.L., Wu, A.H., Brewster, W., Anton-Culver, H., Ziogas, A., Narod, S., Levine, D.A., Kaye, S.B., Brown, R., Paul, J., Flanagan, J., Sieh, W., McGuire, V., Whittemore, A.S., Campbell, I., Gore, M.E., Lissowska, J., Yang, H.P., Medrek, K., Gronwald, J., Lubinski, J., Jakubowska, A., Le, N.D., Cook, L.S., Keleman, L.E., Brook-Wilson, A., Massuger, L.F.A.G., Kiemeney, L.A.L.M., Aben, K.K.H., Altena, A.M. van, Houlston, R.S., Tomlinson, I., Palmieri, R.T., Moorman, P.G., Schildkraut, J., Iversen, E.S., Phelan, C.M., Vierkant, R.A., Cunningham, J.M., Goode, E.L., Fridley, B.L., Kruger-Kjaer, S., Blaeker, J., Hogdall, E., Hogdall, C., Gross, J., Karlan, B.Y., Ness, R.B., Edwards, R.P., Odunsi, K., Moyisch, K.B., Baker, J.A., Modugno, F., Heikkinenen, T., Butzow, R., Nevanlinna, H., Leminen, A., Bogdanova, N., Antonenkova, N., Doerk, T., Hillemanns, P., Durst, M., Runnebaum, I., Thompson, P.J., Carney, M.E., Goodman, M.T., Lurie, G., Wang-Gohrke, S., Hein, R., Chang-Claude, J., Rossing, M.A., Cushing-Haugen, K.L., Doherty, J., Chen, C., Rafnar, T., Besenbacher, S., Sulem, P., Stefansson, K., Birrer, M.J., Bolton, K.L., Tyrer, J.P., Song, H., Ramus, S.J., Notaridou, M., Jones, C., Sher, T., Gentry-Maharaj, A., Wozniak, E., Tsai, Y.Y., Weidhaas, J., Paik, D., Berg, D.P.G. van den, Stram, D.O., Pearce, C.L., Wu, A.H., Brewster, W., Anton-Culver, H., Ziogas, A., Narod, S., Levine, D.A., Kaye, S.B., Brown, R., Paul, J., Flanagan, J., Sieh, W., McGuire, V., Whittemore, A.S., Campbell, I., Gore, M.E., Lissowska, J., Yang, H.P., Medrek, K., Gronwald, J., Lubinski, J., Jakubowska, A., Le, N.D., Cook, L.S., Keleman, L.E., Brook-Wilson, A., Massuger, L.F.A.G., Kiemeney, L.A.L.M., Aben, K.K.H., Altena, A.M. van, Houlston, R.S., Tomlinson, I., Palmieri, R.T., Moorman, P.G., Schildkraut, J., Iversen, E.S., Phelan, C.M., Vierkant, R.A., Cunningham, J.M., Goode, E.L., Fridley, B.L., Kruger-Kjaer, S., Blaeker, J., Hogdall, E., Hogdall, C., Gross, J., Karlan, B.Y., Ness, R.B., Edwards, R.P., Odunsi, K., Moyisch, K.B., Baker, J.A., Modugno, F., Heikkinenen, T., Butzow, R., Nevanlinna, H., Leminen, A., Bogdanova, N., Antonenkova, N., Doerk, T., Hillemanns, P., Durst, M., Runnebaum, I., Thompson, P.J., Carney, M.E., Goodman, M.T., Lurie, G., Wang-Gohrke, S., Hein, R., Chang-Claude, J., Rossing, M.A., Cushing-Haugen, K.L., Doherty, J., Chen, C., Rafnar, T., Besenbacher, S., Sulem, P., Stefansson, K., and Birrer, M.J.

Abstract

Contains fulltext : 89441.pdf (publisher's version ) (Closed access)

Published
2010

107. Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics

Author

Leal, SM, Garcia-Closas, M, Hall, P, Nevanlinna, H, Pooley, K, Morrison, J, Richesson, DA, Bojesen, SE, Nordestgaard, BG, Axelsson, CK, Arias, JI, Milne, RL, Ribas, G, Gonzalez-Neira, A, Benitez, J, Zamora, P, Brauch, H, Justenhoven, C, Hamann, U, Ko, Y-D, Bruening, T, Haas, S, Doerk, T, Schuermann, P, Hillemanns, P, Bogdanova, N, Bremer, M, Karstens, JH, Fagerholm, R, Aaltonen, K, Aittomaki, K, Von Smitten, K, Blomqvist, C, Mannermaa, A, Uusitupa, M, Eskelinen, M, Tengstrom, M, Kosma, V-M, Kataja, V, Chenevix-Trench, G, Spurdle, AB, Beesley, J, Chen, X, Devilee, P, Van Asperen, CJ, Jacobi, CE, Tollenaar, RAEM, Huijts, PEA, Klijn, JGM, Chang-Claude, J, Kropp, S, Slanger, T, Flesch-Janys, D, Mutschelknauss, E, Salazar, R, Wang-Gohrke, S, Couch, F, Goode, EL, Olson, JE, Vachon, C, Fredericksen, ZS, Giles, GG, Baglietto, L, Severi, G, Hopper, JL, English, DR, Southey, MC, Haiman, CA, Henderson, BE, Kolonel, LN, Le Marchand, L, Stram, DO, Hunter, DJ, Hankinson, SE, Cox, DG, Tamimi, R, Kraft, P, Sherman, ME, Chanock, SJ, Lissowska, J, Brinton, LA, Peplonska, B, Hooning, MJ, Meijers-Heijboer, H, Collee, JM, Van den Ouweland, A, Uitterlinden, AG, Liu, J, Lin, LY, Yuqing, L, Humphreys, K, Czene, K, Cox, A, Balasubramanian, SP, Cross, SS, Reed, MWR, Blows, F, Driver, K, Dunning, A, Tyrer, J, Ponder, BAJ, Sangrajrang, S, Brennan, P, Mckay, J, Odefrey, F, Gabrieau, V, Sigurdson, A, Doody, M, Struewing, JP, Alexander, B, Easton, DF, Pharoah, PD, Leal, SM, Garcia-Closas, M, Hall, P, Nevanlinna, H, Pooley, K, Morrison, J, Richesson, DA, Bojesen, SE, Nordestgaard, BG, Axelsson, CK, Arias, JI, Milne, RL, Ribas, G, Gonzalez-Neira, A, Benitez, J, Zamora, P, Brauch, H, Justenhoven, C, Hamann, U, Ko, Y-D, Bruening, T, Haas, S, Doerk, T, Schuermann, P, Hillemanns, P, Bogdanova, N, Bremer, M, Karstens, JH, Fagerholm, R, Aaltonen, K, Aittomaki, K, Von Smitten, K, Blomqvist, C, Mannermaa, A, Uusitupa, M, Eskelinen, M, Tengstrom, M, Kosma, V-M, Kataja, V, Chenevix-Trench, G, Spurdle, AB, Beesley, J, Chen, X, Devilee, P, Van Asperen, CJ, Jacobi, CE, Tollenaar, RAEM, Huijts, PEA, Klijn, JGM, Chang-Claude, J, Kropp, S, Slanger, T, Flesch-Janys, D, Mutschelknauss, E, Salazar, R, Wang-Gohrke, S, Couch, F, Goode, EL, Olson, JE, Vachon, C, Fredericksen, ZS, Giles, GG, Baglietto, L, Severi, G, Hopper, JL, English, DR, Southey, MC, Haiman, CA, Henderson, BE, Kolonel, LN, Le Marchand, L, Stram, DO, Hunter, DJ, Hankinson, SE, Cox, DG, Tamimi, R, Kraft, P, Sherman, ME, Chanock, SJ, Lissowska, J, Brinton, LA, Peplonska, B, Hooning, MJ, Meijers-Heijboer, H, Collee, JM, Van den Ouweland, A, Uitterlinden, AG, Liu, J, Lin, LY, Yuqing, L, Humphreys, K, Czene, K, Cox, A, Balasubramanian, SP, Cross, SS, Reed, MWR, Blows, F, Driver, K, Dunning, A, Tyrer, J, Ponder, BAJ, Sangrajrang, S, Brennan, P, Mckay, J, Odefrey, F, Gabrieau, V, Sigurdson, A, Doody, M, Struewing, JP, Alexander, B, Easton, DF, and Pharoah, PD

Abstract

A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27-1.36)) than ER-negative (1.08 (1.03-1.14)) disease (P for heterogeneity = 10(-13)). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10(-5), 10(-8), 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10(-4), respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09-1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83-0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding

Published
2008

108. Inhibitor-Immunology-Study

Author

Wermes, C., primary, Eifrig, B., primary, Holstein, K., primary, Pollmann, H., primary, Siegmund, B., primary, Eberl, W., primary, Kemkes-Matthes, B., primary, Bidlingmaier, C., primary, Kurnik, K., primary, Lischetzki, G., primary, Nimtz-Talaska, A., primary, Eisert, R., primary, Bogdanova, N., primary, Doerk, T., primary, Sykora, K.-W., primary, and Wieland, I., additional

Published
2011
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116. Inhibitor-Immunology-Study

Author

Wieland, I., Wermes, C., Eifrig, B., Holstein, K., Pollmann, H., Siegmund, B., Eberl, W., Kemkes-Matthes, B., Bidlingmaier, C., Kurnik, K., Lischetzki, G., Nimtz-Talaska, A., Eisert, R., Bogdanova, N., Doerk, T., and Sykora, K.-W.

Published
2011
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117. Resonance enhanced coherent anti-stokes raman scattering and laser induced fluorescence applied to CH radicals: a comparative study.

Author

Doerk, T., Hertl, M., Pfelzer, B., Hädrich, S., Jauernik, P., and Uhlenbusch, J.

Subjects
*RAMAN effect, *FLUORESCENCE, *RADICALS (Chemistry)
Abstract

Compares the applicability of the resonance enhanced anti-stokes raman scattering method with the laser induced fluorescence in relation to chemical radicals. Features of the method; Nonthermal rotational population distributions yielded by the techniques.

Published
1997

118. Evaluation of variation in the phosphoinositide-3-kinase catalytic subunit alpha oncogene and breast cancer risk

Author

Stevens, K N, Garcia-Closas, M, Fredericksen, Z, Kosel, M, Pankratz, V S, Hopper, J L, Dite, G S, Apicella, C, Southey, M C, Schmidt, M K, Broeks, A, Van ‘t Veer, L J, Tollenaar, R A E M, Fasching, P A, Beckmann, M W, Hein, A, Ekici, A B, Johnson, N, Peto, J, dos Santos Silva, I, Gibson, L, Sawyer, E, Tomlinson, I, Kerin, M J, Chanock, S, Lissowska, J, Hunter, David J., Hoover, R N, Thomas, G D, Milne, R L, Pérez, JI Arias, González-Neira, A, Benítez, J, Burwinkel, B, Meindl, A, Schmutzler, R K, Bartrar, C R, Hamann, U, Ko, Y D, Brüning, T, Chang-Claude, J, Hein, R, Wang-Gohrke, S, Dörk, T, Schürmann, P, Bremer, M, Hillemanns, P, Bogdanova, N, Zalutsky, J V, Rogov, Y I, Antonenkova, N, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, J, Chenevix-Trench, G, Chen, X, Peterlongo, P, Bonanni, B, Bernard, L, Manoukian, S, Wang, X, Cerhan, J, Vachon, C M, Olson, J, Giles, G G, Baglietto, L, McLean, C A, Severi, G, John, E M, Miron, Alexander, Winqvist, R, Pylkäs, K, Jukkola-Vuorinen, A, Grip, M, Andrulis, I, Knight, J A, Glendon, G, Mulligan, A M, Cox, A, Brock, I W, Elliott, G, Cross, S S, Pharoah, P P, Dunning, A M, Pooley, K A, Humphreys, M K, Wang, J, Kang, D, Yoo, K-Y, Noh, D-Y, Sangrajrang, S, Gabrieau, V, Brennan, P, McKay, J, Anton-Culver, H, Ziogas, A, Couch, F J, and Easton, D F

Subjects
genetic susceptibility, neoplasms, association study
Abstract

Background: Somatic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival. The goal of this study was to evaluate the association between inherited variation in this oncogene and risk of breast cancer. Methods: A single-nucleotide polymorphism from the PIK3CA locus that was associated with breast cancer in a study of Caucasian breast cancer cases and controls from the Mayo Clinic (MCBCS) was genotyped in 5436 cases and 5280 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study and in 30 949 cases and 29 788 controls from the Breast Cancer Association Consortium (BCAC). Results: Rs1607237 was significantly associated with a decreased risk of breast cancer in MCBCS, CGEMS and all studies of white Europeans combined (odds ratio (OR)=0.97, 95% confidence interval (CI) 0.95–0.99, P=4.6 × \(10^{−3}\)), but did not reach significance in the BCAC replication study alone (OR=0.98, 95% CI 0.96–1.01, P=0.139). Conclusion: Common germline variation in PIK3CA does not have a strong influence on the risk of breast cancer.

Published
2011
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123. European experts consensus: BRCA/homologous recombination deficiency testing in first-line ovarian cancer

Author

I. Vergote, A. González-Martín, I. Ray-Coquard, P. Harter, N. Colombo, P. Pujol, D. Lorusso, M.R. Mirza, B. Brasiuniene, R. Madry, J.D. Brenton, M.G.E.M. Ausems, R. Büttner, D. Lambrechts, M. Ausems, J. Brenton, M. Abreu, S. Balboni, S. Banerjee, M. Barberis, M.P. Barretina Ginesta, J.-F. Baurain, M. Bignami, L. Bjorge, P. Blecharz, I. Bruchim, M. Capilna, N. Cerana, A. Cicchetti, D. Collins, N. Concin, M. D’Incalci, B. Davidson, T. de la Motte Rouge, P. De Iaco, F. Demirkiran, H. Denys, T. Doerk, A. Dorum, A. Ferrero, A.P. Fidalgo, M. Genuardi, L. Gladieff, R. Glasspool, C. Grimm, M. Gultekin, E. Hahnen, A. Hasenburg, A. Hegmane, V. Heinzelmann, E. Hogdall, R. Janavicius, S. Jarmalaite, R. Kalachand, R. Kaneva, S. Kilickap, R. Kocian, D. Kolencik, R. Kristeleit, A. Kryzhanivska, A. Leary, B. Lemley, M. Ligtenberg, J.A. López-Guerrero, C.J. Lord, E. Avall-Lundqvist, J. Maenpaa, S. Mahner, F. Marmé, C. Marth, I. McNeish, S. Merkelbach-Bruse, M. Mourits, N. Normanno, A. Oaknin, K. Ojamaa, C. Papdimitriou, F. Penault-Llorca, A.M. Perrone, S. Pignata, E. Pikarsky, E. Rouleau, M. Rubio, A. Sapino, B. Schmalfeldt, J. Sehouli, R. Shapira, K.D. Steffensen, V. Sukhin, J. Syrios, Z. Szallasi, C. Taskiran, M. Terzic, M. Tischkowitz, I. Toth, K. Van de Vijver, M.A. Vardar, B. Wasag, P. Wimberger, E. Witteveen, Vergote I., Gonzalez-Martin A., Ray-Coquard I., Harter P., Colombo N., Pujol P., Lorusso D., Mirza M.R., Brasiuniene B., Madry R., Brenton J.D., Ausems M.G.E.M., Buttner R., Lambrechts D., Ausems M., Brenton J., Abreu M., Balboni S., Banerjee S., Barberis M., Barretina Ginesta M.P., Baurain J.-F., Bignami M., Bjorge L., Blecharz P., Bruchim I., Capilna M., Cerana N., Cicchetti A., Collins D., Concin N., D'Incalci M., Davidson B., de la Motte Rouge T., De Iaco P., Demirkiran F., Denys H., Doerk T., Dorum A., Ferrero A., Fidalgo A.P., Genuardi M., Gladieff L., Glasspool R., Grimm C., Gultekin M., Hahnen E., Hasenburg A., Hegmane A., Heinzelmann V., Hogdall E., Janavicius R., Jarmalaite S., Kalachand R., Kaneva R., Kilickap S., Kocian R., Kolencik D., Kristeleit R., Kryzhanivska A., Leary A., Lemley B., Ligtenberg M., Lopez-Guerrero J.A., Lord C.J., Avall-Lundqvist E., Maenpaa J., Mahner S., Marme F., Marth C., McNeish I., Merkelbach-Bruse S., Mourits M., Normanno N., Oaknin A., Ojamaa K., Papdimitriou C., Penault-Llorca F., Perrone A.M., Pignata S., Pikarsky E., Rouleau E., Rubio M., Sapino A., Schmalfeldt B., Sehouli J., Shapira R., Steffensen K.D., Sukhin V., Syrios J., Szallasi Z., Taskiran C., Terzic M., Tischkowitz M., Toth I., Van de Vijver K., Vardar M.A., Wasag B., Wimberger P., Witteveen E., Vergote, I, Gonzalez-Martin, A, Ray-Coquard, I, Harter, P, Colombo, N, Pujol, P, Lorusso, D, Mirza, M, Brasiuniene, B, Madry, R, Brenton, J, Ausems, M, Buttner, R, Lambrechts, D, Abreu, M, Balboni, S, Banerjee, S, Barberis, M, Barretina Ginesta, M, Baurain, J, Bignami, M, Bjorge, L, Blecharz, P, Bruchim, I, Capilna, M, Cerana, N, Cicchetti, A, Collins, D, Concin, N, D'Incalci, M, Davidson, B, de la Motte Rouge, T, De Iaco, P, Demirkiran, F, Denys, H, Doerk, T, Dorum, A, Ferrero, A, Fidalgo, A, Genuardi, M, Gladieff, L, Glasspool, R, Grimm, C, Gultekin, M, Hahnen, E, Hasenburg, A, Hegmane, A, Heinzelmann, V, Hogdall, E, Janavicius, R, Jarmalaite, S, Kalachand, R, Kaneva, R, Kilickap, S, Kocian, R, Kolencik, D, Kristeleit, R, Kryzhanivska, A, Leary, A, Lemley, B, Ligtenberg, M, Lopez-Guerrero, J, Lord, C, Avall-Lundqvist, E, Maenpaa, J, Mahner, S, Marme, F, Marth, C, Mcneish, I, Merkelbach-Bruse, S, Mourits, M, Normanno, N, Oaknin, A, Ojamaa, K, Papdimitriou, C, Penault-Llorca, F, Perrone, A, Pignata, S, Pikarsky, E, Rouleau, E, Rubio, M, Sapino, A, Schmalfeldt, B, Sehouli, J, Shapira, R, Steffensen, K, Sukhin, V, Syrios, J, Szallasi, Z, Taskiran, C, Terzic, M, Tischkowitz, M, Toth, I, Van de Vijver, K, Vardar, M, Wasag, B, Wimberger, P, and Witteveen, E

Subjects
Oncology, medicine.medical_specialty, MAINTENANCE THERAPY, CARCINOMA, Genetic counseling, BRCA, Delphi method, Carcinoma, Ovarian Epithelial, Poly(ADP-ribose) Polymerase Inhibitors, Gene mutation, Settore MED/03 - GENETICA MEDICA, BREAST, DOUBLE-BLIND, BRCA1/2, Internal medicine, Genetic predisposition, Medicine and Health Sciences, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Medicine, Humans, BRCA2 MUTATIONS, OLAPARIB PLUS BEVACIZUMAB, Genetic testing, Ovarian Neoplasms, Ovarian Neoplasms/diagnosis, medicine.diagnostic_test, business.industry, MISMATCH REPAIR DEFICIENCY, PARP inhibition, mainstream genetic testing, Recombinational DNA Repair, Hematology, SOMATIC MUTATIONS, GERMLINE MUTATIONS, Poly(ADP-ribose) Polymerase Inhibitors/pharmacology, medicine.disease, FALLOPIAN-TUBE, Carcinoma, Ovarian Epithelial/genetics, ovarian cancer, homologous recombination deficiency, DNA mismatch repair, Female, business, Homologous recombination, Ovarian cancer, human activities, genetic counselling
Abstract

BACKGROUND: Homologous recombination repair (HRR) enables fault-free repair of double-stranded DNA breaks. HRR deficiency is predicted to occur in around half of high-grade serous ovarian carcinomas. Ovarian cancers harbouring HRR deficiency typically exhibit sensitivity to poly-ADP ribose polymerase inhibitors (PARPi). Current guidelines recommend a range of approaches for genetic testing to identify predictors of sensitivity to PARPi in ovarian cancer and to identify genetic predisposition. DESIGN: To establish a European-wide consensus for genetic testing (including the genetic care pathway), decision making and clinical management of patients with recently diagnosed advanced ovarian cancer, and the validity of biomarkers to predict the effectiveness of PARPi in the first-line setting. The collaborative European experts' consensus group consisted of a steering committee (n = 14) and contributors (n = 84). A (modified) Delphi process was used to establish consensus statements based on a systematic literature search, conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. RESULTS: A consensus was reached on 34 statements amongst 98 caregivers (including oncologists, pathologists, clinical geneticists, genetic researchers, and patient advocates). The statements concentrated on (i) the value of testing for BRCA1/2 mutations and HRR deficiency testing, including when and whom to test; (ii) the importance of developing new and better HRR deficiency tests; (iii) the importance of germline non-BRCA HRR and mismatch repair gene mutations for predicting familial risk, but not for predicting sensitivity to PARPi, in the first-line setting; (iv) who should be able to inform patients about genetic testing, and what training and education should these caregivers receive. CONCLUSION: These consensus recommendations, from a multidisciplinary panel of experts from across Europe, provide clear guidance on the use of BRCA and HRR deficiency testing for recently diagnosed patients with advanced ovarian cancer. ispartof: ANNALS OF ONCOLOGY vol:33 issue:3 pages:276-287 ispartof: location:England status: published

Published
2022

130. No Evidence That Genetic Variation in the Myeloid-Derived Suppressor Cell Pathway Influences Ovarian Cancer Survival.

Author

Sucheston-Campbell LE, Cannioto R, Clay AI, Etter JL, Eng KH, Liu S, Battaglia S, Hu Q, Szender JB, Minlikeeva A, Joseph JM, Mayor P, Abrams SI, Segal BH, Wallace PK, Soh KT, Zsiros E, Anton-Culver H, Bandera EV, Beckmann MW, Berchuck A, Bjorge L, Bruegl A, Campbell IG, Campbell SP, Chenevix-Trench G, Cramer DW, Dansonka-Mieszkowska A, Dao F, Diergaarde B, Doerk T, Doherty JA, du Bois A, Eccles D, Engelholm SA, Fasching PA, Gayther SA, Gentry-Maharaj A, Glasspool RM, Goodman MT, Gronwald J, Harter P, Hein A, Heitz F, Hillemmanns P, Høgdall C, Høgdall EV, Huzarski T, Jensen A, Johnatty SE, Jung A, Karlan BY, Klapdor R, Kluz T, Konopka B, Kjær SK, Kupryjanczyk J, Lambrechts D, Lester J, Lubiński J, Levine DA, Lundvall L, McGuire V, McNeish IA, Menon U, Modugno F, Ness RB, Orsulic S, Paul J, Pearce CL, Pejovic T, Pharoah P, Ramus SJ, Rothstein J, Rossing MA, Rübner M, Schildkraut JM, Schmalfeldt B, Schwaab I, Siddiqui N, Sieh W, Sobiczewski P, Song H, Terry KL, Van Nieuwenhuysen E, Vanderstichele A, Vergote I, Walsh CS, Webb PM, Wentzensen N, Whittemore AS, Wu AH, Ziogas A, Odunsi K, Chang-Claude J, Goode EL, and Moysich KB

Subjects
Carcinoma, Ovarian Epithelial, Female, Genetic Association Studies, Humans, Neoplasms, Glandular and Epithelial immunology, Ovarian Neoplasms immunology, Genetic Variation, Myeloid-Derived Suppressor Cells immunology, Neoplasms, Glandular and Epithelial genetics, Neoplasms, Glandular and Epithelial mortality, Ovarian Neoplasms genetics, Ovarian Neoplasms mortality
Abstract

Background: The precise mechanism by which the immune system is adversely affected in cancer patients remains poorly understood, but the accumulation of immunosuppressive/protumorigenic myeloid-derived suppressor cells (MDSCs) is thought to be a prominent mechanism contributing to immunologic tolerance of malignant cells in epithelial ovarian cancer (EOC). To this end, we hypothesized genetic variation in MDSC pathway genes would be associated with survival after EOC diagnoses. Methods: We measured the hazard of death due to EOC within 10 years of diagnosis, overall and by invasive subtype, attributable to SNPs in 24 genes relevant in the MDSC pathway in 10,751 women diagnosed with invasive EOC. Versatile Gene-based Association Study and the admixture likelihood method were used to test gene and pathway associations with survival. Results: We did not identify individual SNPs that were significantly associated with survival after correction for multiple testing ( P < 3.5 × 10 -5 ), nor did we identify significant associations between the MDSC pathway overall, or the 24 individual genes and EOC survival. Conclusions: In this well-powered analysis, we observed no evidence that inherited variations in MDSC-associated SNPs, individual genes, or the collective genetic pathway contributed to EOC survival outcomes. Impact: Common inherited variation in genes relevant to MDSCs was not associated with survival in women diagnosed with invasive EOC. Cancer Epidemiol Biomarkers Prev; 26(3); 420-4. ©2016 AACR ., (©2016 American Association for Cancer Research.)

Published
2017
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131. Corrigendum: Common variants at 19p13 are associated with susceptibility to ovarian cancer.

Author

Bolton KL, Tyrer J, Song H, Ramus SJ, Notaridou M, Jones C, Sher T, Gentry-Maharaj A, Wozniak E, Tsai YY, Weidhaas J, Paik D, Van Den Berg DJ, Stram DO, Pearce CL, Wu AH, Brewster W, Anton-Culver H, Ziogas A, Narod SA, Levine DA, Kaye SB, Brown R, Paul J, Flanagan J, Sieh W, McGuire V, Whittemore AS, Campbell I, Gore ME, Lissowska J, Yang HP, Medrek K, Gronwald J, Lubinski J, Jakubowska A, Le ND, Cook LS, Kelemen LE, Brooks-Wilson A, Massuger LF, Kiemeney LA, Aben KK, van Altena AM, Houlston R, Tomlinson I, Palmieri RT, Moorman PG, Schildkraut J, Iversen ES, Phelan C, Vierkant RA, Cunningham JM, Goode EL, Fridley BL, Kruger-Kjaer S, Blaeker J, Hogdall E, Hogdall C, Gross J, Karlan BY, Ness RB, Edwards RP, Odunsi K, Moyisch KB, Baker JA, Modugno F, Heikkinenen T, Butzow R, Nevanlinna H, Leminen A, Bogdanova N, Antonenkova N, Doerk T, Hillemanns P, Dürst M, Runnebaum I, Thompson PJ, Carney ME, Goodman MT, Lurie G, Wang-Gohrke S, Hein R, Chang-Claude J, Rossing MA, Cushing-Haugen KL, Doherty J, Chen C, Rafnar T, Besenbacher S, Sulem P, Stefansson K, Birrer MJ, Terry KL, Hernandez D, Cramer DW, Vergote I, Amant F, Lambrechts D, Despierre E, Fasching PA, Beckmann MW, Thiel FC, Ekici AB, Chen X, Johnatty SE, Webb PM, Beesley J, Chanock S, Garcia-Closas M, Sellers T, Easton DF, Berchuck A, Chenevix-Trench G, Pharoah PD, and Gayther SA

Published
2016
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132. Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci.

Author

Amin Al Olama A, Benlloch S, Antoniou AC, Giles GG, Severi G, Neal DE, Hamdy FC, Donovan JL, Muir K, Schleutker J, Henderson BE, Haiman CA, Schumacher FR, Pashayan N, Pharoah PD, Ostrander EA, Stanford JL, Batra J, Clements JA, Chambers SK, Weischer M, Nordestgaard BG, Ingles SA, Sorensen KD, Orntoft TF, Park JY, Cybulski C, Maier C, Doerk T, Dickinson JL, Cannon-Albright L, Brenner H, Rebbeck TR, Zeigler-Johnson C, Habuchi T, Thibodeau SN, Cooney KA, Chappuis PO, Hutter P, Kaneva RP, Foulkes WD, Zeegers MP, Lu YJ, Zhang HW, Stephenson R, Cox A, Southey MC, Spurdle AB, FitzGerald L, Leongamornlert D, Saunders E, Tymrakiewicz M, Guy M, Dadaev T, Little SJ, Govindasami K, Sawyer E, Wilkinson R, Herkommer K, Hopper JL, Lophatonanon A, Rinckleb AE, Kote-Jarai Z, Eeles RA, and Easton DF

Subjects
Adult, Aged, Aged, 80 and over, Alleles, Genetic Variation, Genotype, Humans, Male, Middle Aged, Odds Ratio, Risk Factors, Genetic Predisposition to Disease, Genome-Wide Association Study, Prostatic Neoplasms genetics, Risk Assessment
Abstract

Background: Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of prostate cancer., Methods: We genotyped 25 prostate cancer susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived age-specific absolute risks of developing prostate cancer by PRS stratum and family history., Results: The prostate cancer risk for men in the top 1% of the PRS distribution was 30.6 (95% CI, 16.4-57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI, 3.2-5.5) fold compared with the median risk. The absolute risk of prostate cancer by age of 85 years was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation = 0.09)., Conclusions: Risk profiling can identify men at substantially increased or reduced risk of prostate cancer. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of prostate cancer. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles., Impact: We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs., (©2015 American Association for Cancer Research.)

Published
2015
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133. Evaluation of a new multiplex real-time polymerase chain reaction assay for the detection of human papillomavirus infections in a referral population.

Author

Jentschke M, Soergel P, Lange V, Kocjan B, Doerk T, Luyten A, Petry KU, Poljak M, and Hillemanns P

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Colposcopy, Female, Humans, Middle Aged, Vaginal Smears, Young Adult, Human papillomavirus 16 isolation & purification, Human papillomavirus 18 isolation & purification, Papillomavirus Infections diagnosis, Real-Time Polymerase Chain Reaction methods, Uterine Cervical Neoplasms virology, Uterine Cervical Dysplasia virology
Abstract

Objectives: Human papillomavirus (HPV) testing is an important part of cervical cancer screening and management of women with atypical screening results. This study was conducted to evaluate the analytical and clinical performance of the Abbott RealTime High-Risk HPV assay (RealTime) in a referral population, in comparison to the Qiagen Hybrid Capture 2 High-Risk HPV DNA Test (hc2)., Methods: RealTime is a new polymerase chain reaction assay that detects 14 high-risk HPV genotypes with simultaneous differentiation between HPV 16 and HPV 18. Five hundred forty-five routine cervical smear samples (ThinPrep) from women who were referred to 2 German colposcopy clinics were included in the study. All samples were tested with both assays for the detection of high-risk HPV DNA. Specimens with repeatedly discordant results were genotyped by Linear Array (Roche) and in-house polymerase chain reaction assays., Results: Both assays showed excellent overall agreement (92.8%; κ = 0.86) on 545 samples. Analytical sensitivity of RealTime was comparable to that of hc2 (97.6% vs 95.1%, P = 0.189), whereas RealTime demonstrated significantly higher analytical specificity compared with hc2 (100% vs 93.1%, P < 0.0001). RealTime showed no cross-reactivity with untargeted HPV genotypes in this study. The clinical performance of the assays was evaluated based on histology results available from 319 women (90 nonpathological, 73 cervical intraepithelial neoplasia [CIN] 1, 75 CIN 2, 74 CIN 3, and 7 invasive cancers). High-risk HPV detection rates observed in women with CIN 1, CIN 2+, and CIN 3+ diagnosis, respectively, were comparable for both assays: 47.9%, 92.3%, and 97.5% (RealTime) and 47.9%, 92.3%, and 93.8% (hc2). Detection of HPV 16/18 with RealTime was highly correlated with severity of dysplasia: less than CIN 2, 30.5%; CIN 2+, 59.0%; CIN 3+, 71.6%., Conclusions: These results support the use of RealTime for routine detection of HPV infections in a referral population.

Published
2012
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134. Inhibitor-immunology-study. Evaluation of inhibitor development in haemophilia B.

Author

Wieland I, Wermes C, Eifrig B, Holstein K, Pollmann H, Siegmund B, Eberl W, Kemkes-Matthes B, Bidlingmaier C, Kurnik K, Lischetzki G, Nimtz-Talaska A, Eisert R, Bogdanova N, Doerk T, and Sykora KW

Subjects
Adolescent, Child, Child, Preschool, Female, Humans, Male, Young Adult, Blood Coagulation Factor Inhibitors blood, Blood Coagulation Factor Inhibitors genetics, Genes, MHC Class II genetics, Genetic Predisposition to Disease genetics, Hemophilia B blood, Hemophilia B genetics, Polymorphism, Single Nucleotide genetics
Abstract

Unlabelled: The development of inhibitors in haemophilia B is one of the most important complications of replacement therapy, affecting mortality and morbidity. Inhibitor development is based on complex immunological factors, and to date, only little is known about its underlying mechanisms. Here, we present first results of the haemophilia B group of our Inhibitor-Immunology study., Patients, Methods: So far we have analysed 15 patients with haemophilia B. Four of them developed a high titre inhibitor; the remaining 11 had no inhibitor. We evaluated 9 SNPs in 8 genes (CD40, CTLA-4 , IL-1β, IL-10, TLR2 , TLR4, TLR9, TNF-α). We compared the distribution of these alleles between inhibitor and non-inhibitor haemophilia B patients and between haemophilia B patients and a normal male control population. HLA typing was performed in all patients. Results, discussion: There appears to be a trend towards a skewed distribution of TLR 9, IL-10 and CTLA4 alleles in haemophilia B patients. Due to the limited number these differences are, however, not statistically significant. The t-test of all patients with inhibitor versus without inhibitor was significant for HLA-A*03 and DPB1*0401 and borderline for DRB1*0201.

Published
2011

135. Common variants at 19p13 are associated with susceptibility to ovarian cancer.

Author

Bolton KL, Tyrer J, Song H, Ramus SJ, Notaridou M, Jones C, Sher T, Gentry-Maharaj A, Wozniak E, Tsai YY, Weidhaas J, Paik D, Van Den Berg DJ, Stram DO, Pearce CL, Wu AH, Brewster W, Anton-Culver H, Ziogas A, Narod SA, Levine DA, Kaye SB, Brown R, Paul J, Flanagan J, Sieh W, McGuire V, Whittemore AS, Campbell I, Gore ME, Lissowska J, Yang HP, Medrek K, Gronwald J, Lubinski J, Jakubowska A, Le ND, Cook LS, Kelemen LE, Brooks-Wilson A, Massuger LF, Kiemeney LA, Aben KK, van Altena AM, Houlston R, Tomlinson I, Palmieri RT, Moorman PG, Schildkraut J, Iversen ES, Phelan C, Vierkant RA, Cunningham JM, Goode EL, Fridley BL, Kruger-Kjaer S, Blaeker J, Hogdall E, Hogdall C, Gross J, Karlan BY, Ness RB, Edwards RP, Odunsi K, Moyisch KB, Baker JA, Modugno F, Heikkinenen T, Butzow R, Nevanlinna H, Leminen A, Bogdanova N, Antonenkova N, Doerk T, Hillemanns P, Dürst M, Runnebaum I, Thompson PJ, Carney ME, Goodman MT, Lurie G, Wang-Gohrke S, Hein R, Chang-Claude J, Rossing MA, Cushing-Haugen KL, Doherty J, Chen C, Rafnar T, Besenbacher S, Sulem P, Stefansson K, Birrer MJ, Terry KL, Hernandez D, Cramer DW, Vergote I, Amant F, Lambrechts D, Despierre E, Fasching PA, Beckmann MW, Thiel FC, Ekici AB, Chen X, Johnatty SE, Webb PM, Beesley J, Chanock S, Garcia-Closas M, Sellers T, Easton DF, Berchuck A, Chenevix-Trench G, Pharoah PD, and Gayther SA

Subjects
Adenocarcinoma, Clear Cell genetics, Adenocarcinoma, Clear Cell pathology, Adenocarcinoma, Mucinous genetics, Adenocarcinoma, Mucinous pathology, Biomarkers, Tumor genetics, Case-Control Studies, Cystadenocarcinoma, Serous genetics, Cystadenocarcinoma, Serous pathology, Endometrial Neoplasms genetics, Endometrial Neoplasms pathology, Female, Gene Expression Profiling, Genotype, Humans, Middle Aged, Oligonucleotide Array Sequence Analysis, Ovarian Neoplasms pathology, Ovary metabolism, Ovary pathology, Polymorphism, Single Nucleotide genetics, Tumor Cells, Cultured, Adaptor Proteins, Signal Transducing genetics, Chromosomes, Human, Pair 19 genetics, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Ovarian Neoplasms genetics
Abstract

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in the developed world, accounting for 4% of the deaths from cancer in women. We performed a three-phase genome-wide association study of EOC survival in 8,951 individuals with EOC (cases) with available survival time data and a parallel association analysis of EOC susceptibility. Two SNPs at 19p13.11, rs8170 and rs2363956, showed evidence of association with survival (overall P = 5 × 10⁻⁴ and P = 6 × 10⁻⁴, respectively), but they did not replicate in phase 3. However, the same two SNPs demonstrated genome-wide significance for risk of serous EOC (P = 3 × 10⁻⁹ and P = 4 × 10⁻¹¹, respectively). Expression analysis of candidate genes at this locus in ovarian tumors supported a role for the BRCA1-interacting gene C19orf62, also known as MERIT40, which contains rs8170, in EOC development.

Published
2010
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136. Genetic determination of chromosomal radiosensitivities in G0- and G2-phase human lymphocytes.

Author

Borgmann K, Haeberle D, Doerk T, Busjahn A, Stephan G, and Dikomey E

Subjects
Adolescent, Adult, Dose-Response Relationship, Radiation, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Statistics, Nonparametric, Twins, Monozygotic genetics, Chromosomes radiation effects, G2 Phase genetics, Lymphocytes radiation effects, Radiation Tolerance genetics
Abstract

Background and Purpose: The radiosensitivity of human lymphocytes measured using a G0- or G2-assay has been linked with an individual's risk of developing normal tissue complications following radiotherapy. This study was performed to increase basic knowledge of the genetics of the human radiation response, and chromosomal aberration induction in particular., Materials and Methods: The study was carried out with blood samples taken from 15 monozygotic twin pairs. G0-assay was performed for cells irradiated with 6 Gy counting only deletions and G2-assay for cells irradiated with 0.5 Gy scoring only chromatid breaks., Results: The mean number of deletions measured at 6 Gy for all 30 samples using the G0-assay amounted to 2.96+/-0.37 (means+/-SD), which corresponds to a coefficient of variation (CV) of 13%. There is a highly significant intra-pair correlation for this number among twins (r(2)=0.911) demonstrating that this parameter is mostly determined by genetic factors. According to the mean number of deletions, a theoretical classification based on the definition < or = MV-SD as resistant, MV+/-SD as normal and > or = MV+SD as sensitive was made, identifying two pairs as sensitive or resistant, respectively, while nine were normal and two pairs are intermediate. For chromatid breaks measured at 0.5 Gy with the G2-assay the mean number was 1.35+/-0.42 (means+/-SD) corresponding to a CV of 31%. There was again a strong intra-pair correlation among twins with r(2)=0.837 showing that this sensitivity is also determined mostly by genetic factors. There was, however, no inter-assay correlation between the G0- and G2-sensitivity (r(2)=0.006) demonstrating that these two sensitivities depend on different genetic factors., Conclusion: The chromosomal radiosensitivity of lymphocytes as defined by G0- or G2-assay is largely determined by different genetic factors, which may allow the use of genetic profiling as an indicator of the respective individual radiosensitivity.

Published
2007
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138. Mutation analysis in 46 German families with familial hypercholesterolemia: identification of 8 new mutations. Mutations in brief no. 226. Online.

Author

Ebhardt M, Schmidt H, Doerk T, Tietge U, Haas R, Manns MP, Schmidtke J, and Stuhrmann M

Subjects
Apolipoprotein B-100, Apolipoproteins B genetics, DNA Mutational Analysis, Frameshift Mutation, Genetic Testing, Germany, Humans, Point Mutation, Receptors, LDL genetics, Hyperlipoproteinemia Type II genetics, Mutation
Abstract

In order to obtain a survey of the mutations being prevalent in Northern Germany and to enable molecular genetic testing for families with clinically diagnosed familial hypercholesterolemia (FH), we screened 46 unrelated German individuals with elevated LDL levels for mutations in the 18 exons and their flanking intron sequences including the promotor region of the LDL receptor (LDLR) gene. In addition, we tested all patients for the presence of mutations in the gene coding for apolipoprotein B-100 (apoB-100). We detected 15 mutations affecting the LDLR gene, 8 of which, designated A29S, 195insAT, 313+1insG, 553insG, 680insGGACAAATCTG, D200N, E267K and L411V have not yet been reported. One patient is heterozygous for the double mutant N543H and 2393del9Bp. Two patients carried the mutation R3500Q (Arg-->Glu) within the apoB-100 gene.

Published
1999
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