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BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers

Meeks, Huong D.; Song, Honglin; Michailidou, Kyriaki; Bolla, Manjeet K.; Dennis, Joe; Wang, Qin; Barrowdale, Daniel; Frost, Debra; McGuffog, Lesley and Ellis, Steve, et al. (2016) In Journal of the National Cancer Institute 108(2).
Abstract

Background: The K3326X variant in BRCA2 (BRCA2∗c.9976A>T p.Lys3326∗rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormonerelated cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76637 cancer case patients and 83796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a... (More)

Background: The K3326X variant in BRCA2 (BRCA2∗c.9976A>T p.Lys3326∗rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormonerelated cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76637 cancer case patients and 83796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9×10-6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8×10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4×10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1×10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations.

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Journal of the National Cancer Institute
volume
108
issue
2
publisher
Oxford University Press
external identifiers
  • Scopus:84962488384
  • WOS:WOS:000371153900007
ISSN
0027-8874
DOI
10.1093/jnci/djv315
language
English
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yes
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677c69fe-7836-490b-8081-2c4dd114e7e3
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2016-06-02 14:36:05
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2016-11-25 08:14:17
@misc{677c69fe-7836-490b-8081-2c4dd114e7e3,
  abstract     = {<p>Background: The K3326X variant in BRCA2 (BRCA2∗c.9976A&gt;T p.Lys3326∗rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormonerelated cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76637 cancer case patients and 83796 control patients to estimate odds ratios (OR<sub>w</sub>) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (OR<sub>w</sub> = 1.28, 95% CI = 1.17 to 1.40, P = 5.9×10<sup>-6</sup>) and invasive ovarian cancer (OR<sub>w</sub> = 1.26, 95% CI = 1.10 to 1.43, P = 3.8×10<sup>-3</sup>). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (OR<sub>w</sub> = 1.46, 95% CI = 1.2 to 1.70, P = 3.4×10<sup>-5</sup> and OR<sub>w</sub> = 1.50, 95% CI = 1.28 to 1.76, P = 4.1×10<sup>-5</sup>, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations.</p>},
  author       = {Meeks, Huong D. and Song, Honglin and Michailidou, Kyriaki and Bolla, Manjeet K. and Dennis, Joe and Wang, Qin and Barrowdale, Daniel and Frost, Debra and McGuffog, Lesley and Ellis, Steve and Feng, Bingjian and Buys, Saundra S. and Hopper, John L. and Southey, Melissa C. and Tesoriero, Andrea and James, Paul A. and Bruinsma, Fiona and Campbell, Ian G. and Broeks, Annegien and Schmidt, Marjanka K. and Hogervorst, Frans B L and Beckman, Matthias W. and Fasching, Peter A. and Fletcher, Olivia and Johnson, Nichola and Sawyer, Elinor J. and Riboli, Elio and Banerjee, Susana and Menon, Usha and Tomlinson, Ian and Burwinkel, Barbara and Hamann, Ute and Marme, Frederik and Rudolph, Anja and Janavicius, Ramunas and Tihomirova, Laima and Tung, Nadine and Garber, Judy and Cramer, Daniel and Terry, Kathryn L. and Poole, Elizabeth M. and Tworoger, Shelley S. and Dorfling, Cecilia M. and Van Rensburg, Elizabeth J. and Godwin, Andrew K. and Guénel, Pascal and Truong, Thérèse and Stoppa-Lyonnet, Dominique and Damiola, Francesca and Mazoyer, Sylvie and Sinilnikova, Olga M. and Isaacs, Claudine and Maugard, Christine and Bojesen, Stig E. and Flyger, Henrik and Gerdes, Anne Marie and Hansen, Thomas V O and Jensen, Allen and Kjaer, Susanne K. and Hogdall, Claus and Hogdall, Estrid and Pedersen, Inge Sokilde and Thomassen, Mads and Benitez, Javier and González-Neira, Anna and Osorio, Ana and Hoya, Miguel De La and Segura, Pedro Perez and Diez, Orland and Lazaro, Conxi and Brunet, Joan and Anton-Culver, Hoda and Eunjung, Lee and John, Esther M. and Neuhausen, Susan L. and Ding, Yuan Chun and Castillo, Danielle and Weitzel, Jeffrey N. and Ganz, Patricia A. and Nussbaum, Robert L. and Chan, Salina B. and Karlan, Beth Y. and Lester, Jenny and Wu, Anna and Gayther, Simon and Ramus, Susan J. and Sieh, Weiva and Whittermore, Alice S. and Monteiro, Alvaro N A and Phelan, Catherine M. and Terry, Mary Beth and Piedmonte, Marion and Offit, Kenneth and Robson, Mark and Levine, Douglas and Moysich, Kirsten B. and Cannioto, Rikki and Olson, Sara H. and Daly, Mary B. and Nathanson, Katherine L. and Domchek, Susan M. and Lu, Karen H. and Liang, Dong and Hildebrant, Michelle A T and Ness, Roberta and Modugno, Francesmary and Pearce, Leigh and Goodman, Marc T. and Thompson, Pamela J. and Brenner, Hermann and Butterbach, Katja and Meindl, Alfons and Hahnen, Eric and Wappenschmidt, Barbara and Brauch, Hiltrud and Brüning, Thomas and Blomqvist, Carl and Khan, Sofia and Nevanlinna, Heli and Pelttari, Liisa M. and Aittomäki, Kristiina and Butzow, Ralf and Bogdanova, Natalia V. and Dörk, Thilo and Lindblom, Annika and Margolin, Sara and Rantala, Johanna and Kosma, Veli Matti and Mannermaa, Arto and Lambrechts, Diether and Neven, Patrick and Claes, Kathleen B M and Van Maerken, Tom and Chang-Claude, Jenny and Flesch-Janys, Dieter and Heitz, Florian and Varon-Mateeva, Raymonda and Peterlongo, Paolo and Radice, Paolo and Viel, Alessandra and Barile, Monica and Peissel, Bernard and Manoukian, Siranoush and Montagna, Marco and Oliani, Cristina and Peixoto, Ana and Teixeira, Manuel R. and Collavoli, Anita and Hallberg, Emily and Olson, Janet E. and Goode, Ellen L. and Hart, Steven N. and Shimelis, Hermela and Cunningham, Julie M. and Giles, Graham G. and Milne, Roger L. and Healey, Sue and Tucker, Kathy and Haiman, Christopher A. and Henderson, Brian E. and Goldberg, Mark S. and Tischkowitz, Marc and Simard, Jacques and Soucy, Penny and Eccles, Diana M. and Le, Nhu and Borresen-Dale, Anne Lise and Kristensen, Vessela and Salvesen, Helga B. and Bjorge, Line and Bandera, Elisa V. and Risch, Harvey and Zheng, Wei and Beeghly-Fadiel, Alicia and Cai, Hui and Pylkäs, Katri and Tollenaar, Robert A E M and Ouweland, Ans M W Van Der and Andrulis, Irene L. and Knight, Julia A. and Narod, Steven and Devilee, Peter and Winqvist, Robert and Figueroa, Jonine and Greene, Mark H. and Mai, Phuong L. and Loud, Jennifer T. and García-Closas, Montserrat and Schoemaker, Minouk J. and Czene, Kamila and Darabi, Hatef and McNeish, Iain and Siddiquil, Nadeem and Glasspool, Rosalind and Kwong, Ava and Park, Sue K. and Teo, Soo Hwang and Yoon, Sook Yee and Matsuo, Keitaro and Hosono, Satoyo and Woo, Yin Ling and Gao, Yu Tang and Foretova, Lenka and Singer, Christian F. and Rappaport-Feurhauser, Christine and Friedman, Eitan and Laitman, Yael and Rennert, Gad and Imyanitov, Evgeny N. and Hulick, Peter J. and Olopade, Olufunmilayo I. and Senter, Leigha and Olah, Edith and Doherty, Jennifer A. and Schildkraut, Joellen and Koppert, Linetta B. and Kiemeney, Lambertus A. and Massuger, Leon F A G and Cook, Linda S. and Pejovic, Tanja and Li, Jingmei and Borg, Åke and Öfverholm, Anna and Rossing, Mary Anne and Wentzensen, Nicolas and Henriksson, Karin and Cox, Angela and Cross, Simon S. and Pasini, Barbara J. and Shah, Mitul and Kabisch, Maria and Torres, Diana and Jakubowska, Anna and Lubinski, Jan and Gronwald, Jacek and Agnarsson, Bjarni A. and Kupryjanczyk, Jolanta and Moes-Sosnowska, Joanna and Fostira, Florentia and Konstantopoulou, Irene and Slager, Susan and Jones, Michael and Antoniou, Antonis C. and Berchuck, Andrew and Swerdlow, Anthony and Chenevix-Trench, Georgia and Dunning, Alison M. and Pharoah, Paul D P and Hall, Per and Easton, Douglas F. and Couch, Fergus J. and Spurdle, Amanda B. and Goldgar, David E.},
  issn         = {0027-8874},
  language     = {eng},
  month        = {02},
  number       = {2},
  publisher    = {ARRAY(0x9716590)},
  series       = {Journal of the National Cancer Institute},
  title        = {BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers},
  url          = {http://dx.doi.org/10.1093/jnci/djv315},
  volume       = {108},
  year         = {2016},
}