PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS

Southey, M. C. et al. (2016) PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS. Journal of Medical Genetics, 53(12), pp. 800-811. (doi:10.1136/jmedgenet-2016-103839) (PMID:27595995) (PMCID:PMC5200636)

[img]
Preview
Text
128615.pdf - Published Version
Available under License Creative Commons Attribution.

439kB

Abstract

Background: The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods: We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results: For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10−5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10−8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions: This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Paul, Mr James and Mcneish, Professor Iain and Glasspool, Dr Rosalind
Authors: Southey, M. C., Goldgar, D. E., Winqvist, R., Pylkäs, K., Couch, F., Tischkowitz, M., Foulkes, W. D., Dennis, J., Michailidou, K., van Rensburg, E. J., Heikkinen, T., Nevanlinna, H., Hopper, J. L., Dörk, T., Claes, K. B., Reis-Filho, J., Teo, Z. L., Radice, P., Catucci, I., Peterlongo, P., Tsimiklis, H., Odefrey, F. A., Dowty, J. G., Schmidt, M. K., Broeks, A., Hogervorst, F. B., Verhoef, S., Carpenter, J., Clarke, C., Scott, R. J., Fasching, P. A., Haeberle, L., Ekici, A. B., Beckmann, M. W., Peto, J., Dos-Santos-Silva, I., Fletcher, O., Johnson, N., Bolla, M. K., Sawyer, E. J., Tomlinson, I., Kerin, M. J., Miller, N., Marme, F., Burwinkel, B., Yang, R., Guénel, P., Truong, T., Menegaux, F., Sanchez, M., Bojesen, S., Nielsen, S. F., Flyger, H., Benitez, J., Zamora, M. P., Perez, J. I. A., Menéndez, P., Anton-Culver, H., Neuhausen, S., Ziogas, A., Clarke, C. A., Brenner, H., Arndt, V., Stegmaier, C., Brauch, H., Brüning, T., Ko, Y.-D., Muranen, T. A., Aittomäki, K., Blomqvist, C., Bogdanova, N. V., Antonenkova, N. N., Lindblom, A., Margolin, S., Mannermaa, A., Kataja, V., Kosma, V.-M., Hartikainen, J. M., Spurdle, A. B., Wauters, E., Smeets, D., Beuselinck, B., Floris, G., Chang-Claude, J., Rudolph, A., Seibold, P., Flesch-Janys, D., Olson, J. E., Vachon, C., Pankratz, V. S., McLean, C., Haiman, C. A., Henderson, B. E., Schumacher, F., Le Marchand, L., Kristensen, V., Alnæs, G. G., Zheng, W., Hunter, D. J., Lindstrom, S., Hankinson, S. E., Kraft, P., Andrulis, I., Knight, J. A., Glendon, G., Mulligan, A. M., Jukkola-Vuorinen, A., Grip, M., Kauppila, S., Devilee, P., Tollenaar, R. A.E.M., Seynaeve, C., Hollestelle, A., Garcia-Closas, M., Figueroa, J., Chanock, S. J., Lissowska, J., Czene, K., Darabi, H., Eriksson, M., Eccles, D. M., Rafiq, S., Tapper, W. J., Gerty, S. M., Hooning, M. J., Martens, J. W.M., Collée, J. M., Tilanus-Linthorst, M., Hall, P., Li, J., Brand, J. S., Humphreys, K., Cox, A., Reed, M. W.R., Luccarini, C., Baynes, C., Dunning, A. M., Hamann, U., Torres, D., Ulmer, H. U., Rüdiger, T., Jakubowska, A., Lubinski, J., Jaworska, K., Durda, K., Slager, S., Toland, A. E., Ambrosone, C. B., Yannoukakos, D., Swerdlow, A., Ashworth, A., Orr, N., Jones, M., González-Neira, A., Pita, G., Alonso, M. R., Álvarez, N., Herrero, D., Tessier, D. C., Vincent, D., Bacot, F., Simard, J., Dumont, M., Soucy, P., Eeles, R., Muir, K., Wiklund, F., Gronberg, H., Schleutker, J., Nordestgaard, B. G., Weischer, M., Travis, R. C., Neal, D., Donovan, J. L., Hamdy, F. C., Khaw, K.-T., Stanford, J. L., Blot, W. J., Thibodeau, S., Schaid, D. J., Kelley, J. L., Maier, C., Kibel, A. S., Cybulski, C., Cannon-Albright, L., Butterbach, K., Park, J., Kaneva, R., Batra, J., Teixeira, M. R., Kote-Jarai, Z., Amin Al Olama, A., Benlloch, S., Renner, S. P., Hartmann, A., Hein, A., Ruebner, M., Lambrechts, D., Van Nieuwenhuysen, E., Vergote, I., Lambretchs, S., Doherty, J. A., Rossing, M. A., Nickels, S., Eilber, U., Wang-Gohrke, S., Odunsi, K., Sucheston-Campbell, L. E., Friel, G., Lurie, G., Killeen, J. L., Wilkens, L. R., Goodman, M. T., Runnebaum, I., Hillemanns, P. A., Pelttari, L. M., Butzow, R., Modugno, F., Edwards, R. P., Ness, R. B., Moysich, K. B., du Bois, A., Heitz, F., Harter, P., Kommoss, S., Karlan, B. Y., Walsh, C., Lester, J., Jensen, A., Kjaer, S. K., Høgdall, E., Peissel, B., Bonanni, B., Bernard, L., Goode, E. L., Fridley, B. L., Vierkant, R. A., Cunningham, J. M., Larson, M. C., Fogarty, Z. C., Kalli, K. R., Liang, D., Lu, K. H., Hildebrandt, M. A.T., Wu, X., Levine, D. A., Dao, F., Bisogna, M., Berchuck, A., Iversen, E. S., Marks, J. R., Akushevich, L., Cramer, D. W., Schildkraut, J., Terry, K. L., Poole, E. M., Stampfer, M., Tworoger, S. S., Bandera, E. V., Orlow, I., Olson, S. H., Bjorge, L., Salvesen, H. B., van Altena, A. M., Aben, K. K.H., Kiemeney, L. A., Massuger, L. F.A.G., Pejovic, T., Bean, Y., Brooks-Wilson, A., Kelemen, L. E., Cook, L. S., Le, N. D., Górski, B., Gronwald, J., Menkiszak, J., Høgdall, C. K., Lundvall, L., Nedergaard, L., Engelholm, S. A., Dicks, E., Tyrer, J., Campbell, I., McNeish, I., Paul, J., Siddiqui, N., Glasspool, R., Whittemore, A. S., Rothstein, J. H., McGuire, V., Sieh, W., Cai, H., Shu, X.-O., Teten, R. T., Sutphen, R., McLaughlin, J. R., Narod, S. A., Phelan, C. M., Monteiro, A. N., Fenstermacher, D., Lin, H.-Y., Permuth, J. B., Sellers, T. A., Chen, Y. A., Tsai, Y.-Y., Chen, Z., Gentry-Maharaj, A., Gayther, S. A., Ramus, S. J., Menon, U., Wu, A. H., Pearce, C. L., Van Den Berg, D., Pike, M. C., Dansonka-Mieszkowska, A., Plisiecka-Halasa, J., Moes-Sosnowska, J., Kupryjanczyk, J., Pharoah, P. D., Song, H., Winship, I., Chenevix-Trench, G., Giles, G. G., Tavtigian, S. V., Easton, D. F., and Milne, R. L.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Journal of Medical Genetics
Publisher:BMJ Publishing Group
ISSN:0022-2593
ISSN (Online):1468-6244
Published Online:05 September 2016
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Journal of Medical Genetics 53(12): 800-811
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record