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 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.
| Original language | English |
|---|---|
| Article number | djv315 |
| Journal | Journal of the National Cancer Institute |
| Volume | 108 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - Feb 1 2016 |
ASJC Scopus subject areas
- Cancer Research
- Oncology
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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, D.; McGuffog, Lesley; Ellis, Steve; Feng, Bingjian; Buys, Saundra S.; Hopper, John; Southey, Melissa; Tesoriero, Andrea; James, Paul A.; Bruinsma, Fiona; Campbell, Ian; Broeks, Annegien; Schmidt, Marjanka K.; Hogervorst, Frans B.; Beckman, Matthias W.; Fasching, Peter A.; Fletcher, Olivia; Johnson, Nichola; Sawyer, Elinor J.; Riboli, E.; Banerjee, S.; Menon, Usha; Tomlinson, Ian P M; Burwinkel, Barbara; Hamann, Ute; Marme, Frederik; Rudolph, Anja; Janavicius, Ramunas; Tihomirova, Laima; Tung, Nadine; Garber, Judy E.; Cramer, Daniel; Terry, Kathryn L.; Poole, Elizabeth M.; Tworoger, Shelley S.; Dorfling, Cecilia M.; van Rensburg, Elizabeth J.; Godwin, Andrew K.; Guenel, Pascal; Truong, Therese; Stoppa-Lyonnet, Dominique; Damiola, Francesca; Mazoyer, Sylvie; Sinilnikova, Olga M.; Isaacs, Claudine; Maugard, Christine; Bojesen, Stig E.; Flyger, Henrik; Gerdes, Anne Marie; Hansen, Thomas v O; Jensen, Allen; Kjær, Susanne Krüger; Hogdall, Claus; Hogdall, Estrid; Pedersen, Inge Sokilde; Thomassen, Mads; Benitez, Javier; González-Neira, Anna; Osorio, Ana; Hoya, Miguel De La; Segura, Pedro Perez; Diez, Orland; Lazaro, Conxi; Brunet, Joan; Anton-Culver, Hoda; Eunjung, Lee; John, Esther M.; Neuhausen, Susan L.; Ding, Yuan Chun; Castillo, Danielle; Weitzel, Jeffrey; Ganz, Patricia A.; Nussbaum, Robert L.; Chan, Salina; Karlan, Beth Y.; Lester, Jenny; Wu, Anna; Gayther, Simon A.; Ramus, Susan J.; Sieh, Weiva; Whittermore, Alice S.; Monteiro, Alvaro N A; Phelan, Catherine M.; Terry, Mary Beth; Piedmonte, Marion; Offit, Kenneth; Robson, Mark E.; Levine, Douglas A.; Moysich, Kirsten B.; Cannioto, Rikki; Olson, Sara H.; Daly, Mary B.; Nathanson, Katherine L.; Domchek, Susan M.; Lu, Karen H.; Liang, Dong; Hildebrant, Michelle A T; Ness, R. B.; Modugno, Francesmary; Pearce, Leigh; Goodman, Marc T.; Thompson, Pamela J.; Brenner, Hermann; Butterbach, Katja; Meindl, Alfons; Hahnen, Eric; Wappenschmidt, Barbara; Brauch, Hiltrud; Brüning, Thomas; Blomqvist, Carl; Khan, Sofia; Nevanlinna, Heli; Pelttari, Liisa M.; Aittomäki, Kristiina; Butzow, Ralf; Bogdanova, Natalia V.; Dörk, Thilo; Lindblom, Annika; Margolin, Sara; Rantala, Johanna; Kosma, Veli Matti; Mannermaa, Arto; Lambrechts, Diether; Neven, Patrick; Claes, Kathleen; Van Maerken, Tom; Chang-Claude, Jenny; Flesch-Janys, Dieter; Heitz, Florian; Varon-Mateeva, Raymonda; Peterlongo, Paolo; Radice, Paolo; Viel, Alessandra; Barile, Monica; Peissel, Bernard Gilles; Manoukian, Siranoush; Montagna, Marco; Oliani, Cristina; Peixoto, Ana; Teixeira, Manuel R.; Collavoli, Anita; Hallberg, Emily; Olson, Janet E.; Goode, Ellen L.; Hart, Steven N.; Shimelis, Hermela; Cunningham, Julie; Giles, Graham; Milne, Roger L.; Healey, Sue; Tucker, Kathy; Haiman, Christopher A.; Henderson, Brian E.; Goldberg, Mark S.; Tischkowitz, Marc; Simard, Jacques; Soucy, Penny; Eccles, Diana; Le, Nhu; Børresen-Dale, Anne Lise; Kristensen, Vessela; Salvesen, Helga B.; Bjorge, Line; Bandera, Elisa V.; Risch, Harvey A.; Zheng, Wei; Beeghly-Fadiel, Alicia; Cai, Hui; Pylkäs, Katri; Tollenaar, Robert A E M; Ouweland, Ans M W Van Der; Andrulis, Irene L.; Knight, Julia A.; Narod, Steven; Devilee, Peter; Winqvist, Robert; Figueroa, Jonine D.; Greene, Mark H.; Mai, Phuong L.; Loud, Jennifer T.; Garcia-Closas, Montse; Schoemaker, Minouk J.; Czene, Kamila; Darabi, Hatef; McNeish, Iain A.; Siddiquil, Nadeem; Glasspool, Rosalind; Kwong, A.; Park, Sue K.; Teo, Soo Hwang; Yoon, Sook Yee; Matsuo, Keitaro; Hosono, Satoyo; Woo, Yin Ling; Gao, Yu Tang; Foretova, Lenka; Singer, Christian F.; Rappaport-Feurhauser, Christine; Friedman, Eitan; Laitman, Yael; Rennert, Gad; Imyanitov, Evgeny; Hulick, Peter J.; Olopade, Olufunmilayo I.; Senter, Leigha; Olah, Edith; Doherty, Jennifer A.; Schildkraut, Joellen M.; Koppert, Linetta B.; Kiemeney, Lambartus; Massuger, Leon F A G; Cook, Linda S.; Pejovic, Tanja; Li, Jingmei; Borg, Ake; Öfverholm, Anna; Rossing, Mary Anne; Wentzensen, Nicolas; Henriksson, Karin; Cox, Angela; Cross, Simon S.; Pasini, Barbara; Shah, Mitul; Kabisch, Maria; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Gronwald, Jacek; Agnarsson, Bjarni A.; Kupryjanczyk, Jolanta; Moes-Sosnowska, Joanna; Fostira, Florentia; Konstantopoulou, Irene; Slager, Susan; Jones, Michael E.; Antoniou, Antonis C.; Berchuck, Andrew; Swerdlow, Anthony J.; Chenevix-Trench, Georgia; Dunning, Alison; Pharoah, Paul D P; Hall, Per; Easton, Douglas F.; Couch, Fergus J.; Spurdle, Amanda B.; Goldgar, David.
In: Journal of the National Cancer Institute, Vol. 108, No. 2, djv315, 01.02.2016.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers
AU - Meeks, Huong D.
AU - Song, Honglin
AU - Michailidou, Kyriaki
AU - Bolla, Manjeet K.
AU - Dennis, Joe
AU - Wang, Qin
AU - Barrowdale, Daniel
AU - Frost, D.
AU - McGuffog, Lesley
AU - Ellis, Steve
AU - Feng, Bingjian
AU - Buys, Saundra S.
AU - Hopper, John
AU - Southey, Melissa
AU - Tesoriero, Andrea
AU - James, Paul A.
AU - Bruinsma, Fiona
AU - Campbell, Ian
AU - Broeks, Annegien
AU - Schmidt, Marjanka K.
AU - Hogervorst, Frans B.
AU - Beckman, Matthias W.
AU - Fasching, Peter A.
AU - Fletcher, Olivia
AU - Johnson, Nichola
AU - Sawyer, Elinor J.
AU - Riboli, E.
AU - Banerjee, S.
AU - Menon, Usha
AU - Tomlinson, Ian P M
AU - Burwinkel, Barbara
AU - Hamann, Ute
AU - Marme, Frederik
AU - Rudolph, Anja
AU - Janavicius, Ramunas
AU - Tihomirova, Laima
AU - Tung, Nadine
AU - Garber, Judy E.
AU - Cramer, Daniel
AU - Terry, Kathryn L.
AU - Poole, Elizabeth M.
AU - Tworoger, Shelley S.
AU - Dorfling, Cecilia M.
AU - van Rensburg, Elizabeth J.
AU - Godwin, Andrew K.
AU - Guenel, Pascal
AU - Truong, Therese
AU - Stoppa-Lyonnet, Dominique
AU - Damiola, Francesca
AU - Mazoyer, Sylvie
AU - Sinilnikova, Olga M.
AU - Isaacs, Claudine
AU - Maugard, Christine
AU - Bojesen, Stig E.
AU - Flyger, Henrik
AU - Gerdes, Anne Marie
AU - Hansen, Thomas v O
AU - Jensen, Allen
AU - Kjær, Susanne Krüger
AU - Hogdall, Claus
AU - Hogdall, Estrid
AU - Pedersen, Inge Sokilde
AU - Thomassen, Mads
AU - Benitez, Javier
AU - González-Neira, Anna
AU - Osorio, Ana
AU - Hoya, Miguel De La
AU - Segura, Pedro Perez
AU - Diez, Orland
AU - Lazaro, Conxi
AU - Brunet, Joan
AU - Anton-Culver, Hoda
AU - Eunjung, Lee
AU - John, Esther M.
AU - Neuhausen, Susan L.
AU - Ding, Yuan Chun
AU - Castillo, Danielle
AU - Weitzel, Jeffrey
AU - Ganz, Patricia A.
AU - Nussbaum, Robert L.
AU - Chan, Salina
AU - Karlan, Beth Y.
AU - Lester, Jenny
AU - Wu, Anna
AU - Gayther, Simon A.
AU - Ramus, Susan J.
AU - Sieh, Weiva
AU - Whittermore, Alice S.
AU - Monteiro, Alvaro N A
AU - Phelan, Catherine M.
AU - Terry, Mary Beth
AU - Piedmonte, Marion
AU - Offit, Kenneth
AU - Robson, Mark E.
AU - Levine, Douglas A.
AU - Moysich, Kirsten B.
AU - Cannioto, Rikki
AU - Olson, Sara H.
AU - Daly, Mary B.
AU - Nathanson, Katherine L.
AU - Domchek, Susan M.
AU - Lu, Karen H.
AU - Liang, Dong
AU - Hildebrant, Michelle A T
AU - Ness, R. B.
AU - Modugno, Francesmary
AU - Pearce, Leigh
AU - Goodman, Marc T.
AU - Thompson, Pamela J.
AU - Brenner, Hermann
AU - Butterbach, Katja
AU - Meindl, Alfons
AU - Hahnen, Eric
AU - Wappenschmidt, Barbara
AU - Brauch, Hiltrud
AU - Brüning, Thomas
AU - Blomqvist, Carl
AU - Khan, Sofia
AU - Nevanlinna, Heli
AU - Pelttari, Liisa M.
AU - Aittomäki, Kristiina
AU - Butzow, Ralf
AU - Bogdanova, Natalia V.
AU - Dörk, Thilo
AU - Lindblom, Annika
AU - Margolin, Sara
AU - Rantala, Johanna
AU - Kosma, Veli Matti
AU - Mannermaa, Arto
AU - Lambrechts, Diether
AU - Neven, Patrick
AU - Claes, Kathleen
AU - Van Maerken, Tom
AU - Chang-Claude, Jenny
AU - Flesch-Janys, Dieter
AU - Heitz, Florian
AU - Varon-Mateeva, Raymonda
AU - Peterlongo, Paolo
AU - Radice, Paolo
AU - Viel, Alessandra
AU - Barile, Monica
AU - Peissel, Bernard Gilles
AU - Manoukian, Siranoush
AU - Montagna, Marco
AU - Oliani, Cristina
AU - Peixoto, Ana
AU - Teixeira, Manuel R.
AU - Collavoli, Anita
AU - Hallberg, Emily
AU - Olson, Janet E.
AU - Goode, Ellen L.
AU - Hart, Steven N.
AU - Shimelis, Hermela
AU - Cunningham, Julie
AU - Giles, Graham
AU - Milne, Roger L.
AU - Healey, Sue
AU - Tucker, Kathy
AU - Haiman, Christopher A.
AU - Henderson, Brian E.
AU - Goldberg, Mark S.
AU - Tischkowitz, Marc
AU - Simard, Jacques
AU - Soucy, Penny
AU - Eccles, Diana
AU - Le, Nhu
AU - Børresen-Dale, Anne Lise
AU - Kristensen, Vessela
AU - Salvesen, Helga B.
AU - Bjorge, Line
AU - Bandera, Elisa V.
AU - Risch, Harvey A.
AU - Zheng, Wei
AU - Beeghly-Fadiel, Alicia
AU - Cai, Hui
AU - Pylkäs, Katri
AU - Tollenaar, Robert A E M
AU - Ouweland, Ans M W Van Der
AU - Andrulis, Irene L.
AU - Knight, Julia A.
AU - Narod, Steven
AU - Devilee, Peter
AU - Winqvist, Robert
AU - Figueroa, Jonine D.
AU - Greene, Mark H.
AU - Mai, Phuong L.
AU - Loud, Jennifer T.
AU - Garcia-Closas, Montse
AU - Schoemaker, Minouk J.
AU - Czene, Kamila
AU - Darabi, Hatef
AU - McNeish, Iain A.
AU - Siddiquil, Nadeem
AU - Glasspool, Rosalind
AU - Kwong, A.
AU - Park, Sue K.
AU - Teo, Soo Hwang
AU - Yoon, Sook Yee
AU - Matsuo, Keitaro
AU - Hosono, Satoyo
AU - Woo, Yin Ling
AU - Gao, Yu Tang
AU - Foretova, Lenka
AU - Singer, Christian F.
AU - Rappaport-Feurhauser, Christine
AU - Friedman, Eitan
AU - Laitman, Yael
AU - Rennert, Gad
AU - Imyanitov, Evgeny
AU - Hulick, Peter J.
AU - Olopade, Olufunmilayo I.
AU - Senter, Leigha
AU - Olah, Edith
AU - Doherty, Jennifer A.
AU - Schildkraut, Joellen M.
AU - Koppert, Linetta B.
AU - Kiemeney, Lambartus
AU - Massuger, Leon F A G
AU - Cook, Linda S.
AU - Pejovic, Tanja
AU - Li, Jingmei
AU - Borg, Ake
AU - Öfverholm, Anna
AU - Rossing, Mary Anne
AU - Wentzensen, Nicolas
AU - Henriksson, Karin
AU - Cox, Angela
AU - Cross, Simon S.
AU - Pasini, Barbara
AU - Shah, Mitul
AU - Kabisch, Maria
AU - Torres, Diana
AU - Jakubowska, Anna
AU - Lubinski, Jan
AU - Gronwald, Jacek
AU - Agnarsson, Bjarni A.
AU - Kupryjanczyk, Jolanta
AU - Moes-Sosnowska, Joanna
AU - Fostira, Florentia
AU - Konstantopoulou, Irene
AU - Slager, Susan
AU - Jones, Michael E.
AU - Antoniou, Antonis C.
AU - Berchuck, Andrew
AU - Swerdlow, Anthony J.
AU - Chenevix-Trench, Georgia
AU - Dunning, Alison
AU - Pharoah, Paul D P
AU - Hall, Per
AU - Easton, Douglas F.
AU - Couch, Fergus J.
AU - Spurdle, Amanda B.
AU - Goldgar, David
PY - 2016/2/1
Y1 - 2016/2/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84962488384&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84962488384&partnerID=8YFLogxK
U2 - 10.1093/jnci/djv315
DO - 10.1093/jnci/djv315
M3 - Article
VL - 108
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
SN - 0027-8874
IS - 2
M1 - djv315
ER -