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

Huong D Meeks; Honglin Song; Kyriaki Michailidou; Manjeet K Bolla; Joe Dennis; Qin Wang; Daniel Barrowdale; Debra Frost; Lesley McGuffog; Steve Ellis; Bingjian Feng; Saundra S Buys; John L Hopper; Melissa C Southey; Andrea Tesoriero; Paul A James; Fiona Bruinsma; Ian G Campbell; Annegien Broeks; Marjanka K Schmidt; Frans B L Hogervorst; Matthias W Beckman; Peter A Fasching; Olivia Fletcher; Nichola Johnson; Elinor J Sawyer; Elio Riboli; Susana Banerjee; Usha Menon; Ian Tomlinson; Barbara Burwinkel; Ute Hamann; Frederik Marme; Anja Rudolph; Ramunas Janavicius; Laima Tihomirova; Nadine Tung; Judy Garber; Daniel Cramer; Kathryn L Terry; Elizabeth M Poole; Shelley S Tworoger; Cecilia M Dorfling; Elizabeth J van Rensburg; Andrew K Godwin; Stig E Bojesen; Anne-Marie Gerdes; Susanne K Kjaer; Claus Hogdall; Estrid Hogdall; EMBRACE

doi:10.1093/jnci/djv315

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

Huong D Meeks, Honglin Song, Kyriaki Michailidou, Manjeet K Bolla, Joe Dennis, Qin Wang, Daniel Barrowdale, Debra Frost, Lesley McGuffog, Steve Ellis, Bingjian Feng, Saundra S Buys, John L Hopper, Melissa C Southey, Andrea Tesoriero, Paul A James, Fiona Bruinsma, Ian G Campbell, Annegien Broeks, Marjanka K SchmidtFrans B L Hogervorst, Matthias W Beckman, Peter A Fasching, Olivia Fletcher, Nichola Johnson, Elinor J Sawyer, Elio Riboli, Susana Banerjee, Usha Menon, Ian Tomlinson, Barbara Burwinkel, Ute Hamann, Frederik Marme, Anja Rudolph, Ramunas Janavicius, Laima Tihomirova, Nadine Tung, Judy Garber, Daniel Cramer, Kathryn L Terry, Elizabeth M Poole, Shelley S Tworoger, Cecilia M Dorfling, Elizabeth J van Rensburg, Andrew K Godwin, Stig E Bojesen, Anne-Marie Gerdes, Susanne K Kjaer, Claus Hogdall, Estrid Hogdall, EMBRACE

Institut for Klinisk Medicin

56 Citationer (Scopus)

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 (OR_w) 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_w = 1.28, 95% CI = 1.17 to 1.40, P = 5.9×10^-6) and invasive ovarian cancer (OR_w = 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 (OR_w = 1.46, 95% CI = 1.2 to 1.70, P = 3.4×10^-5 and OR_w = 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.

Originalsprog	Engelsk
Artikelnummer	djv315
Tidsskrift	JNCI - Journal of the National Cancer Institute
Vol/bind	108
Udgave nummer	2
Antal sider	10
ISSN	0027-8874
DOI	https://doi.org/10.1093/jnci/djv315
Status	Udgivet - 1 feb. 2016

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Meeks, H. D., Song, H., Michailidou, K., Bolla, M. K., Dennis, J., Wang, Q., Barrowdale, D., Frost, D., McGuffog, L., Ellis, S., Feng, B., Buys, S. S., Hopper, J. L., Southey, M. C., Tesoriero, A., James, P. A., Bruinsma, F., Campbell, I. G., Broeks, A., ... EMBRACE (2016). BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers. JNCI - Journal of the National Cancer Institute, 108(2), [djv315]. https://doi.org/10.1093/jnci/djv315

Meeks, HD, Song, H, Michailidou, K, Bolla, MK, Dennis, J, Wang, Q, Barrowdale, D, Frost, D, McGuffog, L, Ellis, S, Feng, B, Buys, SS, Hopper, JL, Southey, MC, Tesoriero, A, James, PA, Bruinsma, F, Campbell, IG, Broeks, A, Schmidt, MK, Hogervorst, FBL, Beckman, MW, Fasching, PA, Fletcher, O, Johnson, N, Sawyer, EJ, Riboli, E, Banerjee, S, Menon, U, Tomlinson, I, Burwinkel, B, Hamann, U, Marme, F, Rudolph, A, Janavicius, R, Tihomirova, L, Tung, N, Garber, J, Cramer, D, Terry, KL, Poole, EM, Tworoger, SS, Dorfling, CM, van Rensburg, EJ, Godwin, AK, Bojesen, SE , Gerdes, A-M , Kjaer, SK , Hogdall, C , Hogdall, E & EMBRACE 2016, 'BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers', JNCI - Journal of the National Cancer Institute, bind 108, nr. 2, djv315. https://doi.org/10.1093/jnci/djv315

@article{7295adcfb7fd4efbbc1ae47e15ea8c5e,

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

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.",

keywords = "Adult, Aged, BRCA2 Protein, Breast Neoplasms, Codon, Terminator, Female, Genetic Predisposition to Disease, Heterozygote, Humans, Logistic Models, Lysine, Male, Middle Aged, Neoplasm Invasiveness, Odds Ratio, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Risk Assessment, Risk Factors, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't",

author = "Meeks, {Huong D} and Honglin Song and Kyriaki Michailidou and Bolla, {Manjeet K} and Joe Dennis and Qin Wang and Daniel Barrowdale and Debra Frost and Lesley McGuffog and Steve Ellis and Bingjian Feng and Buys, {Saundra S} and Hopper, {John L} and Southey, {Melissa C} and Andrea Tesoriero and James, {Paul A} and Fiona Bruinsma and Campbell, {Ian G} and Annegien Broeks and Schmidt, {Marjanka K} and Hogervorst, {Frans B L} and Beckman, {Matthias W} and Fasching, {Peter A} and Olivia Fletcher and Nichola Johnson and Sawyer, {Elinor J} and Elio Riboli and Susana Banerjee and Usha Menon and Ian Tomlinson and Barbara Burwinkel and Ute Hamann and Frederik Marme and Anja Rudolph and Ramunas Janavicius and Laima Tihomirova and Nadine Tung and Judy Garber and Daniel Cramer 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 Bojesen, {Stig E} and Anne-Marie Gerdes and Kjaer, {Susanne K} and Claus Hogdall and Estrid Hogdall and EMBRACE",

year = "2016",

month = feb,

day = "1",

doi = "10.1093/jnci/djv315",

language = "English",

volume = "108",

journal = "National Cancer Institute. Journal (Print)",

issn = "0027-8874",

publisher = "Oxford University Press",

number = "2",

}

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, Debra

AU - McGuffog, Lesley

AU - Ellis, Steve

AU - Feng, Bingjian

AU - Buys, Saundra S

AU - Hopper, John L

AU - Southey, Melissa C

AU - Tesoriero, Andrea

AU - James, Paul A

AU - Bruinsma, Fiona

AU - Campbell, Ian G

AU - Broeks, Annegien

AU - Schmidt, Marjanka K

AU - Hogervorst, Frans B L

AU - Beckman, Matthias W

AU - Fasching, Peter A

AU - Fletcher, Olivia

AU - Johnson, Nichola

AU - Sawyer, Elinor J

AU - Riboli, Elio

AU - Banerjee, Susana

AU - Menon, Usha

AU - Tomlinson, Ian

AU - Burwinkel, Barbara

AU - Hamann, Ute

AU - Marme, Frederik

AU - Rudolph, Anja

AU - Janavicius, Ramunas

AU - Tihomirova, Laima

AU - Tung, Nadine

AU - Garber, Judy

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 - Bojesen, Stig E

AU - Gerdes, Anne-Marie

AU - Kjaer, Susanne K

AU - Hogdall, Claus

AU - Hogdall, Estrid

AU - EMBRACE

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.

KW - Adult

KW - Aged

KW - BRCA2 Protein

KW - Breast Neoplasms

KW - Codon, Terminator

KW - Female

KW - Genetic Predisposition to Disease

KW - Heterozygote

KW - Humans

KW - Logistic Models

KW - Lysine

KW - Male

KW - Middle Aged

KW - Neoplasm Invasiveness

KW - Odds Ratio

KW - Ovarian Neoplasms

KW - Polymorphism, Single Nucleotide

KW - Prostatic Neoplasms

KW - Risk Assessment

KW - Risk Factors

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1093/jnci/djv315

DO - 10.1093/jnci/djv315

M3 - Journal article

C2 - 26586665

SN - 0027-8874

VL - 108

JO - National Cancer Institute. Journal (Print)

JF - National Cancer Institute. Journal (Print)

IS - 2

M1 - djv315

ER -

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

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