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1. Current and future diagnostic and treatment strategies for patients with invasive lobular breast cancer

Author

Van Baelen, K., Geukens, T., Maetens, M., Tjan-Heijnen, V., Lord, C.J., Linn, S., Bidard, F.-C., Richard, F., Yang, W.W., Steele, R.E., Pettitt, S.J., Van Ongeval, C., De Schepper, M., Isnaldi, E., Nevelsteen, I., Smeets, A., Punie, K., Voorwerk, L., Wildiers, H., Floris, G., Vincent-Salomon, A., Derksen, P.W.B., Neven, P., Senkus, E., Sawyer, E., Kok, M., and Desmedt, C.

Published
2022
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4. 52P Clinical characterization of HER2 low in patients with lobular breast cancer (ILC)

Author

Van Baelen, K., primary, Nguyen, H.L., additional, Richard, F., additional, Zels, G., additional, Karsten, M.M., additional, Marta, G. Nader, additional, Vermeulen, P., additional, Dirix, L.Y., additional, Wuyts, H., additional, Dordevic, A.D., additional, de Azambuja, E., additional, Larsimont, D., additional, Maetens, M., additional, Biganzoli, E., additional, Wildiers, H., additional, Smeets, A., additional, Nevelsteen, I., additional, Neven, P., additional, Floris, G., additional, and Desmedt, C., additional

Published
2023
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5. 14P Comparison of single-cell ERBB2 mRNA expression levels with HER2 status by immunohistochemistry reveals heterogeneity of the HER2-low status

Author

Richard, F., primary, De Schepper, M., additional, Geukens, T., additional, Vos, H., additional, Bassez, A., additional, Nguyen, H.L., additional, Maetens, M., additional, Wang, L., additional, Nevelsteen, I., additional, Wildiers, H., additional, Neven, P., additional, Punie, K., additional, Smeets, A., additional, Lambrechts, D., additional, Floris, G., additional, and Desmedt, C., additional

Published
2023
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7. P272 Manual lymph drainage does not substantially improve the effect of decongestive lymphatic therapy in people with breast cancer-related lymphoedema (EFforT-BCRL trial): a multicentre randomised trial

Author

De Vrieze, T., primary, Gebruers, N., additional, Nevelsteen, I., additional, Fieuws, S., additional, Thomis, S., additional, De Groef, A., additional, Tjalma, W., additional, Belgrado, J.-P., additional, Vandermeeren, L., additional, Monten, C., additional, Hanssens, M., additional, and Devoogdt, N., additional

Published
2023
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8. Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel

Author

Levi, H, Carmi, S, Rosset, S, Yerushalmi, R, Zick, A, Yablonski-Peretz, T, Wang, Q, Bolla, MK, Dennis, J, Michailidou, K, Lush, M, Ahearn, T, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Arndt, V, Augustinsson, A, Auvinen, P, Freeman, LB, Beckmann, M, Behrens, S, Bermisheva, M, Bodelon, C, Bogdanova, NV, Bojesen, SE, Brenner, H, Byers, H, Camp, N, Castelao, J, Chang-Claude, J, Chirlaque, M-D, Chung, W, Clarke, C, Collee, MJ, Colonna, S, Couch, F, Cox, A, Cross, SS, Czene, K, Daly, M, Devilee, P, Dork, T, Dossus, L, Eccles, DM, Eliassen, AH, Eriksson, M, Evans, G, Fasching, P, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Genkinger, J, Giles, GG, Goldberg, M, Guenel, P, Hall, P, Hamann, U, He, W, Hillemanns, P, Hollestelle, A, Hoppe, R, Hopper, J, Jakovchevska, S, Jakubowska, A, Jernstrom, H, John, E, Johnson, N, Jones, M, Vijai, J, Kaaks, R, Khusnutdinova, E, Kitahara, C, Koutros, S, Kristensen, V, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lejbkowicz, F, Lindblom, A, Loibl, S, Lori, A, Lubinski, J, Mannermaa, A, Manoochehri, M, Mavroudis, D, Menon, U, Mulligan, A, Murphy, R, Nevelsteen, I, Newman, WG, Obi, N, O'Brien, K, Offit, K, Olshan, A, Plaseska-Karanfilska, D, Olson, J, Panico, S, Park-Simon, T-W, Patel, A, Peterlongo, P, Rack, B, Radice, P, Rennert, G, Rhenius, V, Romero, A, Saloustros, E, Sandler, D, Schmidt, MK, Schwentner, L, Shah, M, Sharma, P, Simard, J, Southey, M, Stone, J, Tapper, WJ, Taylor, J, Teras, L, Toland, AE, Troester, M, Truong, T, van der Kolk, LE, Weinberg, C, Wendt, C, Yang, XR, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, P, Easton, DF, Ben-Sachar, S, Elefant, N, Shamir, R, Elkon, R, Levi, H, Carmi, S, Rosset, S, Yerushalmi, R, Zick, A, Yablonski-Peretz, T, Wang, Q, Bolla, MK, Dennis, J, Michailidou, K, Lush, M, Ahearn, T, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Arndt, V, Augustinsson, A, Auvinen, P, Freeman, LB, Beckmann, M, Behrens, S, Bermisheva, M, Bodelon, C, Bogdanova, NV, Bojesen, SE, Brenner, H, Byers, H, Camp, N, Castelao, J, Chang-Claude, J, Chirlaque, M-D, Chung, W, Clarke, C, Collee, MJ, Colonna, S, Couch, F, Cox, A, Cross, SS, Czene, K, Daly, M, Devilee, P, Dork, T, Dossus, L, Eccles, DM, Eliassen, AH, Eriksson, M, Evans, G, Fasching, P, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Genkinger, J, Giles, GG, Goldberg, M, Guenel, P, Hall, P, Hamann, U, He, W, Hillemanns, P, Hollestelle, A, Hoppe, R, Hopper, J, Jakovchevska, S, Jakubowska, A, Jernstrom, H, John, E, Johnson, N, Jones, M, Vijai, J, Kaaks, R, Khusnutdinova, E, Kitahara, C, Koutros, S, Kristensen, V, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lejbkowicz, F, Lindblom, A, Loibl, S, Lori, A, Lubinski, J, Mannermaa, A, Manoochehri, M, Mavroudis, D, Menon, U, Mulligan, A, Murphy, R, Nevelsteen, I, Newman, WG, Obi, N, O'Brien, K, Offit, K, Olshan, A, Plaseska-Karanfilska, D, Olson, J, Panico, S, Park-Simon, T-W, Patel, A, Peterlongo, P, Rack, B, Radice, P, Rennert, G, Rhenius, V, Romero, A, Saloustros, E, Sandler, D, Schmidt, MK, Schwentner, L, Shah, M, Sharma, P, Simard, J, Southey, M, Stone, J, Tapper, WJ, Taylor, J, Teras, L, Toland, AE, Troester, M, Truong, T, van der Kolk, LE, Weinberg, C, Wendt, C, Yang, XR, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, P, Easton, DF, Ben-Sachar, S, Elefant, N, Shamir, R, and Elkon, R

Abstract

BACKGROUND: Polygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women. METHODS: We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel. RESULTS: In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28). CONCLUSIONS: Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.

Published
2023

9. Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival.

Author

Morra, A, Schreurs, MAC, Andrulis, IL, Anton-Culver, H, Augustinsson, A, Beckmann, MW, Behrens, S, Bojesen, SE, Bolla, MK, Brauch, H, Broeks, A, Buys, SS, Camp, NJ, Castelao, JE, Cessna, MH, Chang-Claude, J, Chung, WK, Collaborators, N, Colonna, SV, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Dennis, J, Devilee, P, Dörk, T, Dunning, AM, Dwek, M, Easton, DF, Eccles, DM, Eriksson, M, Evans, DG, Fasching, PA, Fehm, TN, Figueroa, JD, Flyger, H, Gabrielson, M, Gago-Dominguez, M, García-Closas, M, García-Sáenz, JA, Genkinger, J, Grassmann, F, Gündert, M, Hahnen, E, Haiman, CA, Hamann, U, Harrington, PA, Hartikainen, JM, Hoppe, R, Hopper, JL, Houlston, RS, Howell, A, Investigators, A, Investigators, K, Jakubowska, A, Janni, W, Jernström, H, John, EM, Johnson, N, Jones, ME, Kristensen, VN, Kurian, AW, Lambrechts, D, Marchand, LL, Lindblom, A, Lubiński, J, Lux, MP, Mannermaa, A, Mavroudis, D, Mulligan, AM, Muranen, TA, Nevanlinna, H, Nevelsteen, I, Neven, P, Newman, WG, Obi, N, Offit, K, Olshan, AF, Park-Simon, T-W, Patel, AV, Peterlongo, P, Phillips, K-A, Plaseska-Karanfilska, D, Polley, EC, Presneau, N, Pylkäs, K, Rack, B, Radice, P, Rashid, MU, Rhenius, V, Robson, M, Romero, A, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Schuetze, S, Scott, C, Shah, M, Smichkoska, S, Southey, MC, Tapper, WJ, Teras, LR, Tollenaar, RAEM, Tomczyk, K, Tomlinson, I, Troester, MA, Vachon, CM, van Veen, EM, Wang, Q, Wendt, C, Wildiers, H, Winqvist, R, Ziogas, A, Hall, P, Pharoah, PDP, Adank, MA, Hollestelle, A, Schmidt, MK, Hooning, MJ, Morra, A, Schreurs, MAC, Andrulis, IL, Anton-Culver, H, Augustinsson, A, Beckmann, MW, Behrens, S, Bojesen, SE, Bolla, MK, Brauch, H, Broeks, A, Buys, SS, Camp, NJ, Castelao, JE, Cessna, MH, Chang-Claude, J, Chung, WK, Collaborators, N, Colonna, SV, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Dennis, J, Devilee, P, Dörk, T, Dunning, AM, Dwek, M, Easton, DF, Eccles, DM, Eriksson, M, Evans, DG, Fasching, PA, Fehm, TN, Figueroa, JD, Flyger, H, Gabrielson, M, Gago-Dominguez, M, García-Closas, M, García-Sáenz, JA, Genkinger, J, Grassmann, F, Gündert, M, Hahnen, E, Haiman, CA, Hamann, U, Harrington, PA, Hartikainen, JM, Hoppe, R, Hopper, JL, Houlston, RS, Howell, A, Investigators, A, Investigators, K, Jakubowska, A, Janni, W, Jernström, H, John, EM, Johnson, N, Jones, ME, Kristensen, VN, Kurian, AW, Lambrechts, D, Marchand, LL, Lindblom, A, Lubiński, J, Lux, MP, Mannermaa, A, Mavroudis, D, Mulligan, AM, Muranen, TA, Nevanlinna, H, Nevelsteen, I, Neven, P, Newman, WG, Obi, N, Offit, K, Olshan, AF, Park-Simon, T-W, Patel, AV, Peterlongo, P, Phillips, K-A, Plaseska-Karanfilska, D, Polley, EC, Presneau, N, Pylkäs, K, Rack, B, Radice, P, Rashid, MU, Rhenius, V, Robson, M, Romero, A, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Schuetze, S, Scott, C, Shah, M, Smichkoska, S, Southey, MC, Tapper, WJ, Teras, LR, Tollenaar, RAEM, Tomczyk, K, Tomlinson, I, Troester, MA, Vachon, CM, van Veen, EM, Wang, Q, Wendt, C, Wildiers, H, Winqvist, R, Ziogas, A, Hall, P, Pharoah, PDP, Adank, MA, Hollestelle, A, Schmidt, MK, and Hooning, MJ

Abstract

Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers. We aimed to assess the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Analyses were based on 82,701 women diagnosed with invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations of treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR(95%CI): 0.66 (0.55-0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR(95%CI) :1.30 (1.09-1.56)]. In conclusion, systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk. (Main MS: 3201 words).

Published
2023

10. Corrigendum to “Current and future diagnostic and treatment strategies for patients with invasive lobular breast cancer”: [Annals of Oncology 33 (2022) 769–785, (S092375342201167X), (10.1016/j.annonc.2022.05.006)]

Author

Pathologie, Medisch Oncologische Disciplines, Cancer, Pathologie patiënten zorg, Pathologie Groep Derksen, Van Baelen, K., Geukens, T., Maetens, M., Tjan-Heijnen, V., Lord, C. J., Linn, S., Bidard, F. C., Richard, F., Yang, W. W., Steele, R. E., Pettitt, S. J., Van Ongeval, C., De Schepper, M., Isnaldi, E., Nevelsteen, I., Smeets, A., Punie, K., Voorwerk, L., Wildiers, H., Floris, G., Vincent Salomon, A., Derksen, P. W.B., Neven, P., Senkus, E., Sawyer, E., Kok, M., Desmedt, C., Pathologie, Medisch Oncologische Disciplines, Cancer, Pathologie patiënten zorg, Pathologie Groep Derksen, Van Baelen, K., Geukens, T., Maetens, M., Tjan-Heijnen, V., Lord, C. J., Linn, S., Bidard, F. C., Richard, F., Yang, W. W., Steele, R. E., Pettitt, S. J., Van Ongeval, C., De Schepper, M., Isnaldi, E., Nevelsteen, I., Smeets, A., Punie, K., Voorwerk, L., Wildiers, H., Floris, G., Vincent Salomon, A., Derksen, P. W.B., Neven, P., Senkus, E., Sawyer, E., Kok, M., and Desmedt, C.

Published
2023

11. Obesity-associated changes in molecular biology of primary breast cancer.

Author

Nguyen, H.L., Geukens, T., Maetens, M., Aparicio, S., Bassez, A., Borg, A., Brock, J., Broeks, A., Caldas, C., Cardoso, F., Schepper, M. De, Delorenzi, M., Drukker, C.A., Glas, A.M., Green, A.R., Isnaldi, E., Eyfjörð, J., Khout, H., Knappskog, S., Krishnamurthy, S., Lakhani, S.R., Langerod, A., Martens, J.W.M., McCart Reed, A.E., Murphy, L., Naulaerts, S., Nik-Zainal, S., Nevelsteen, I., Neven, P., Piccart, M., Poncet, C., Punie, K., Purdie, C., Rakha, E.A., Richardson, A., Rutgers, E., Vincent-Salomon, A., Simpson, P.T., Schmidt, M.K., Sotiriou, C., Span, P.N., Tan, K.T.B., Thompson, A., Tommasi, S., Baelen, K. van, Vijver, M. van de, Laere, S. van, n't Veer, L. va, Viale, G., Viari, A., Vos, H., Witteveen, A.T., Wildiers, H., Floris, G., Garg, A.D., Smeets, Ann, Lambrechts, D., Biganzoli, E., Richard, F., Desmedt, C., Nguyen, H.L., Geukens, T., Maetens, M., Aparicio, S., Bassez, A., Borg, A., Brock, J., Broeks, A., Caldas, C., Cardoso, F., Schepper, M. De, Delorenzi, M., Drukker, C.A., Glas, A.M., Green, A.R., Isnaldi, E., Eyfjörð, J., Khout, H., Knappskog, S., Krishnamurthy, S., Lakhani, S.R., Langerod, A., Martens, J.W.M., McCart Reed, A.E., Murphy, L., Naulaerts, S., Nik-Zainal, S., Nevelsteen, I., Neven, P., Piccart, M., Poncet, C., Punie, K., Purdie, C., Rakha, E.A., Richardson, A., Rutgers, E., Vincent-Salomon, A., Simpson, P.T., Schmidt, M.K., Sotiriou, C., Span, P.N., Tan, K.T.B., Thompson, A., Tommasi, S., Baelen, K. van, Vijver, M. van de, Laere, S. van, n't Veer, L. va, Viale, G., Viari, A., Vos, H., Witteveen, A.T., Wildiers, H., Floris, G., Garg, A.D., Smeets, Ann, Lambrechts, D., Biganzoli, E., Richard, F., and Desmedt, C.

Abstract

Item does not contain fulltext, Obesity is associated with an increased risk of developing breast cancer (BC) and worse prognosis in BC patients, yet its impact on BC biology remains understudied in humans. This study investigates how the biology of untreated primary BC differs according to patients' body mass index (BMI) using data from >2,000 patients. We identify several genomic alterations that are differentially prevalent in overweight or obese patients compared to lean patients. We report evidence supporting an ageing accelerating effect of obesity at the genetic level. We show that BMI-associated differences in bulk transcriptomic profile are subtle, while single cell profiling allows detection of more pronounced changes in different cell compartments. These analyses further reveal an elevated and unresolved inflammation of the BC tumor microenvironment associated with obesity, with distinct characteristics contingent on the estrogen receptor status. Collectively, our analyses imply that obesity is associated with an inflammaging-like phenotype. We conclude that patient adiposity may play a significant role in the heterogeneity of BC and should be considered for BC treatment tailoring.

Published
2023

12. Changes in leukoencephalopathy and serum neurofilament after (neo) adjuvant chemotherapy for breast cancer

Author

Schroyen, G., Sleurs, C., Ottenbourgs, T., Leenaerts, N., Nevelsteen, I., Melis, M., Smeets, A., Deprez, S., Sunaert, S., Schroyen, G., Sleurs, C., Ottenbourgs, T., Leenaerts, N., Nevelsteen, I., Melis, M., Smeets, A., Deprez, S., and Sunaert, S.

Abstract

Background: Previous case studies have provided evidence for chemotherapy-induced leukoencephalopathy in patients with breast cancer. However, prospective research is lacking. Hence, we investigated leukoencephalopathy before and after chemotherapy and its association with a serum neuroaxonal damage marker. Methods: This prospective cohort study included 40 patients receiving chemotherapy for breast cancer, and two age- and education-matched control groups, recruited between 2018 and 2021 (31-64 years of age). The latter control groups consisted of 39 chemotherapy-naive patients and 40 healthy women. Fluid-attenuated inversionrecovery magnetic resonance imaging was used for lesion volumetry (total, juxtacortical, periventricular, infratentorial, and deep white matter) and blood serum to measure neurofilament light chain (NfL) levels. Acquisition took place pre-chemotherapy and three months and one-year post-chemotherapy, or at corresponding intervals. Within/between group differences were compared using robust mixed-effects modeling, and associations between total lesion volume and serum-NfL with linear regression. Results: Stronger increases in deep white matter lesion volumes were observed shortly post-chemotherapy, compared with healthy women ( ss(standardized)=0.09, P-FDR<0.001). Increases in total lesion volume could mainly be attributed to enlargement of existing lesions (mean +/- SD, 0.12 +/- 0.16 mL), rather than development of new lesions (0.02 +/- 0.02 mL). A stronger increase in serum-NfL concentration was observed shortly postchemotherapy compared with both control groups (ss>0.70, p<0.004), neither of which showed any changes over time, whereas a decrease was observed compared with healthy women one-year post-chemotherapy (ss=0.54, p = 0.002). Serum-NfL concentrations were associated with lesion volume one-year post-chemotherapy (or at matched timepoint; ss=0.36, p = 0.010), whereas baseline or short-term post-t

Published
2023

13. Corrigendum to “Current and future diagnostic and treatment strategies for patients with invasive lobular breast cancer”

Author

Van Baelen, K., primary, Geukens, T., additional, Maetens, M., additional, Tjan-Heijnen, V., additional, Lord, C.J., additional, Linn, S., additional, Bidard, F.-C., additional, Richard, F., additional, Yang, W.W., additional, Steele, R.E., additional, Pettitt, S.J., additional, Van Ongeval, C., additional, De Schepper, M., additional, Isnaldi, E., additional, Nevelsteen, I., additional, Smeets, A., additional, Punie, K., additional, Voorwerk, L., additional, Wildiers, H., additional, Floris, G., additional, Vincent Salomon, A., additional, Derksen, P.W.B., additional, Neven, P., additional, Senkus, E., additional, Sawyer, E., additional, Kok, M., additional, and Desmedt, C., additional

Published
2022
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14. PredictCBC-2.0: a contralateral breast cancer risk prediction model developed and validated in similar to 200,000 patients (vol 24, 69, 2022)

Author

Giardiello, D., Hooning, M.J., Hauptmann, M., Keeman, R., Heemskerk-Gerritsen, B.A.M., Becher, H., Blomqvist, C., Bojesen, S.E., Bolla, M.K., Camp, N.J., Czene, K., Devilee, P., Eccles, D.M., Fasching, P.A., Figueroa, J.D., Flyger, H., Garcia-Closas, M., Haiman, C.A., Hamann, U., Hopper, J.L., Jakubowska, A., Leeuwen, F.E., Lindblom, A., Lubinski, J., Margolin, S., Martinez, M.E., Nevanlinna, H., Nevelsteen, I., Pelders, S., Pharoah, P.D.P., Siesling, S., Southey, M.C., Hout, A.H. van der, Hest, L.P. van, Chang-Claude, J., Hall, P., Easton, D.F., Steyerberg, E.W., and Schmidt, M.K.

Published
2022

15. PredictCBC-2.0: a contralateral breast cancer risk prediction model developed and validated in ~ 200,000 patients

Author

Giardiello, D., Hooning, M.J., Hauptmann, M., Keeman, R., Heemskerk-Gerritsen, B.A.M., Becher, H., Blomqvist, C., Bojesen, S.E., Bolla, M.K., Camp, N.J., Czene, K., Devilee, P., Eccles, D.M., Fasching, P.A., Figueroa, J.D., Flyger, H., Garcia-Closas, M., Haiman, C.A., Hamann, U., Hopper, J.L., Jakubowska, A., Leeuwen, F.E., Lindblom, A., Lubinski, J., Margolin, S., Martinez, M.E., Nevanlinna, H., Nevelsteen, I., Pelders, S., Pharoah, P.D.P., Siesling, S., Southey, M.C., Hout, A.H. van der, Hest, L.P. van, Chang-Claude, J., Hall, P., Easton, D.F., Steyerberg, E.W., Schmidt, M.K., Medical Oncology, Public Health, Human genetics, CCA - Cancer Treatment and quality of life, Apollo - University of Cambridge Repository, Faculteit Medische Wetenschappen/UMCG, Medicum, HUS Comprehensive Cancer Center, Department of Oncology, Clinicum, University of Helsinki, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, and García-Closas, Montserrat [0000-0003-1033-2650]

Subjects
Clinical Decision-making, 3122 Cancers, Oncology and Carcinogenesis, Breast Neoplasms, BRCA1/2 germline mutation, Polygenic risk score, SDG 3 - Good Health and Well-being, Breast Cancer Genetic Predisposition, Risk Factors, Breast Cancer, Genetics, Humans, ddc:610, Oncology & Carcinogenesis, Contralateral Preventive Mastectomy, BCAC, Breast cancer genetic predisposition, Mastectomy, Germ-Line Mutation, Cancer, Polygenic Risk Score, Prevention, Research, Brca1/2 Germline Mutation, Risk prediction, Contralateral preventive mastectomy, Prophylactic Mastectomy, Prediction Performance, Contralateral breast cancer, Breast Cancer Association Consortium, Prediction performance, Contralateral Breast Cancer, Female, Risk Prediction, Bcac, Clinical decision-making
Abstract

Background Prediction of contralateral breast cancer (CBC) risk is challenging due to moderate performances of the known risk factors. We aimed to improve our previous risk prediction model (PredictCBC) by updated follow-up and including additional risk factors. Methods We included data from 207,510 invasive breast cancer patients participating in 23 studies. In total, 8225 CBC events occurred over a median follow-up of 10.2 years. In addition to the previously included risk factors, PredictCBC-2.0 included CHEK2 c.1100delC, a 313 variant polygenic risk score (PRS-313), body mass index (BMI), and parity. Fine and Gray regression was used to fit the model. Calibration and a time-dependent area under the curve (AUC) at 5 and 10 years were assessed to determine the performance of the models. Decision curve analysis was performed to evaluate the net benefit of PredictCBC-2.0 and previous PredictCBC models. Results The discrimination of PredictCBC-2.0 at 10 years was higher than PredictCBC with an AUC of 0.65 (95% prediction intervals (PI) 0.56–0.74) versus 0.63 (95%PI 0.54–0.71). PredictCBC-2.0 was well calibrated with an observed/expected ratio at 10 years of 0.92 (95%PI 0.34–2.54). Decision curve analysis for contralateral preventive mastectomy (CPM) showed the potential clinical utility of PredictCBC-2.0 between thresholds of 4 and 12% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers. Conclusions Additional genetic information beyond BRCA1/2 germline mutations improved CBC risk prediction and might help tailor clinical decision-making toward CPM or alternative preventive strategies. Identifying patients who benefit from CPM, especially in the general breast cancer population, remains challenging.

Published
2022
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16. Serum methylmalonic acid concentrations at breast cancer diagnosis are not associated with distant metastases

Author

Wu, Q., primary, Hatse, S., additional, García, J., additional, Altea-Manzano, P., additional, Billen, J., additional, Planque, M., additional, Vandekeere, A., additional, Lambrechts, Y., additional, Richard, F., additional, Laenen, A., additional, Punie, K., additional, Neven, P., additional, Nevelsteen, I., additional, Floris, G., additional, Desmedt, C., additional, Gomes, A., additional, Fendt, S.M., additional, and Wildiers, H., additional

Published
2022
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17. PredictCBC-2.0: a contralateral breast cancer risk prediction model developed and validated in ∼200,000 patients

Author

Giardiello, D, Hooning, MJ, Hauptmann, M, Keeman, R, Heemskerk-Gerritsen, BAM, Becher, H, Blomqvist, C, Bojesen, SE, Bolla, MK, Camp, NJ, Czene, K, Devilee, P, Eccles, DM, Fasching, PA, Figueroa, JD, Flyger, H, Garcia-Closas, M, Haiman, CA, Hamann, U, Hopper, JL, Jakubowska, A, Leeuwen, FE, Lindblom, A, Lubinski, J, Margolin, S, Martinez, ME, Nevanlinna, H, Nevelsteen, I, Pelders, S, Pharoah, PDP, Siesling, S, Southey, MC, van der Hout, AH, van Hest, LP, Chang-Claude, J, Hall, P, Easton, DF, Steyerberg, EW, Schmidt, MK, Giardiello, D, Hooning, MJ, Hauptmann, M, Keeman, R, Heemskerk-Gerritsen, BAM, Becher, H, Blomqvist, C, Bojesen, SE, Bolla, MK, Camp, NJ, Czene, K, Devilee, P, Eccles, DM, Fasching, PA, Figueroa, JD, Flyger, H, Garcia-Closas, M, Haiman, CA, Hamann, U, Hopper, JL, Jakubowska, A, Leeuwen, FE, Lindblom, A, Lubinski, J, Margolin, S, Martinez, ME, Nevanlinna, H, Nevelsteen, I, Pelders, S, Pharoah, PDP, Siesling, S, Southey, MC, van der Hout, AH, van Hest, LP, Chang-Claude, J, Hall, P, Easton, DF, Steyerberg, EW, and Schmidt, MK

Abstract

BACKGROUND: Prediction of contralateral breast cancer (CBC) risk is challenging due to moderate performances of the known risk factors. We aimed to improve our previous risk prediction model (PredictCBC) by updated follow-up and including additional risk factors. METHODS: We included data from 207,510 invasive breast cancer patients participating in 23 studies. In total, 8225 CBC events occurred over a median follow-up of 10.2 years. In addition to the previously included risk factors, PredictCBC-2.0 included CHEK2 c.1100delC, a 313 variant polygenic risk score (PRS-313), body mass index (BMI), and parity. Fine and Gray regression was used to fit the model. Calibration and a time-dependent area under the curve (AUC) at 5 and 10 years were assessed to determine the performance of the models. Decision curve analysis was performed to evaluate the net benefit of PredictCBC-2.0 and previous PredictCBC models. RESULTS: The discrimination of PredictCBC-2.0 at 10 years was higher than PredictCBC with an AUC of 0.65 (95% prediction intervals (PI) 0.56-0.74) versus 0.63 (95%PI 0.54-0.71). PredictCBC-2.0 was well calibrated with an observed/expected ratio at 10 years of 0.92 (95%PI 0.34-2.54). Decision curve analysis for contralateral preventive mastectomy (CPM) showed the potential clinical utility of PredictCBC-2.0 between thresholds of 4 and 12% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers. CONCLUSIONS: Additional genetic information beyond BRCA1/2 germline mutations improved CBC risk prediction and might help tailor clinical decision-making toward CPM or alternative preventive strategies. Identifying patients who benefit from CPM, especially in the general breast cancer population, remains challenging.

Published
2022

18. Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study

Author

Dixon-Suen, SC, Lewis, SJ, Martin, RM, English, DR, Boyle, T, Giles, GG, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Lush, M, Ahearn, TU, Ambrosone, CB, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Augustinsson, A, Auvinen, P, Beane Freeman, LE, Becher, H, Beckmann, MW, Behrens, S, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Brenner, H, Bruening, T, Buys, SS, Camp, NJ, Campa, D, Canzian, F, Castelao, JE, Cessna, MH, Chang-Claude, J, Chanock, SJ, Clarke, CL, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Doerk, T, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Goldberg, MS, Guenel, P, Guendert, M, Hahnen, E, Haiman, CA, Haeberle, L, Hakansson, N, Hall, P, Hamann, U, Hart, SN, Harvie, M, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoppe, R, Hopper, J, Howell, A, Hunter, DJ, Jakubowska, A, Janni, W, John, EM, Jung, A, Kaaks, R, Keeman, R, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lindblom, A, Loibl, S, Lubinski, J, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, Mavroudis, D, Menon, U, Mulligan, AM, Murphy, RA, Nevanlinna, H, Nevelsteen, I, Newman, WG, Offit, K, Olshan, AF, Olsson, H, Orr, N, Patel, A, Peto, J, Plaseska-Karanfilska, D, Presneau, N, Rack, B, Radice, P, Rees-Punia, E, Rennert, G, Rennert, HS, Romero, A, Saloustros, E, Sandler, DP, Schmidt, MK, Schmutzler, RK, Schwentner, L, Scott, C, Shah, M, Shu, X-O, Simard, J, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Tollenaar, RAEM, Troester, MA, Truong, T, Untch, M, Vachon, CM, Joseph, V, Wappenschmidt, B, Weinberg, CR, Wolk, A, Yannoukakos, D, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Easton, DF, Milne, RL, Lynch, BM, Dixon-Suen, SC, Lewis, SJ, Martin, RM, English, DR, Boyle, T, Giles, GG, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Lush, M, Ahearn, TU, Ambrosone, CB, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Augustinsson, A, Auvinen, P, Beane Freeman, LE, Becher, H, Beckmann, MW, Behrens, S, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Brenner, H, Bruening, T, Buys, SS, Camp, NJ, Campa, D, Canzian, F, Castelao, JE, Cessna, MH, Chang-Claude, J, Chanock, SJ, Clarke, CL, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Doerk, T, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Goldberg, MS, Guenel, P, Guendert, M, Hahnen, E, Haiman, CA, Haeberle, L, Hakansson, N, Hall, P, Hamann, U, Hart, SN, Harvie, M, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoppe, R, Hopper, J, Howell, A, Hunter, DJ, Jakubowska, A, Janni, W, John, EM, Jung, A, Kaaks, R, Keeman, R, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lindblom, A, Loibl, S, Lubinski, J, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, Mavroudis, D, Menon, U, Mulligan, AM, Murphy, RA, Nevanlinna, H, Nevelsteen, I, Newman, WG, Offit, K, Olshan, AF, Olsson, H, Orr, N, Patel, A, Peto, J, Plaseska-Karanfilska, D, Presneau, N, Rack, B, Radice, P, Rees-Punia, E, Rennert, G, Rennert, HS, Romero, A, Saloustros, E, Sandler, DP, Schmidt, MK, Schmutzler, RK, Schwentner, L, Scott, C, Shah, M, Shu, X-O, Simard, J, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Tollenaar, RAEM, Troester, MA, Truong, T, Untch, M, Vachon, CM, Joseph, V, Wappenschmidt, B, Weinberg, CR, Wolk, A, Yannoukakos, D, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Easton, DF, Milne, RL, and Lynch, BM

Abstract

OBJECTIVES: Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics. METHODS: We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity. RESULTS: Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger). CONCLUSION: Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer r

Published
2022

19. PredictCBC-2.0: a contralateral breast cancer risk prediction model developed and validated in ∼ 200,000 patients (vol 24, 69, 2022)

Author

Giardiello, D, Hooning, MJ, Hauptmann, M, Keeman, R, Heemskerk-Gerritsen, BAM, Becher, H, Blomqvist, C, Bojesen, SE, Bolla, MK, Camp, NJ, Czene, K, Devilee, P, Eccles, DM, Fasching, PA, Figueroa, JD, Flyger, H, Garcia-Closas, M, Haiman, CA, Hamann, U, Hopper, JL, Jakubowska, A, Leeuwen, FE, Lindblom, A, Lubinski, J, Margolin, S, Martinez, ME, Nevanlinna, H, Nevelsteen, I, Pelders, S, Pharoah, PDP, Siesling, S, Southey, MC, van der Hout, AH, van Hest, LP, Chang-Claude, J, Hall, P, Easton, DF, Steyerberg, EW, Schmidt, MK, Giardiello, D, Hooning, MJ, Hauptmann, M, Keeman, R, Heemskerk-Gerritsen, BAM, Becher, H, Blomqvist, C, Bojesen, SE, Bolla, MK, Camp, NJ, Czene, K, Devilee, P, Eccles, DM, Fasching, PA, Figueroa, JD, Flyger, H, Garcia-Closas, M, Haiman, CA, Hamann, U, Hopper, JL, Jakubowska, A, Leeuwen, FE, Lindblom, A, Lubinski, J, Margolin, S, Martinez, ME, Nevanlinna, H, Nevelsteen, I, Pelders, S, Pharoah, PDP, Siesling, S, Southey, MC, van der Hout, AH, van Hest, LP, Chang-Claude, J, Hall, P, Easton, DF, Steyerberg, EW, and Schmidt, MK

Published
2022

20. Current and future diagnostic and treatment strategies for patients with invasive lobular breast cancer

Author

Pathologie, Cancer, Pathologie Groep Derksen, Van Baelen, K, Geukens, T, Maetens, M, Tjan-Heijnen, V, Lord, C J, Linn, S, Bidard, F-C, Richard, F, Yang, W W, Steele, R E, Pettitt, S J, Van Ongeval, C, De Schepper, M, Isnaldi, E, Nevelsteen, I, Smeets, A, Punie, K, Voorwerk, L, Wildiers, H, Floris, G, Vincent-Salomon, A, Derksen, P W B, Neven, P, Senkus, E, Sawyer, E, Kok, M, Desmedt, C, Pathologie, Cancer, Pathologie Groep Derksen, Van Baelen, K, Geukens, T, Maetens, M, Tjan-Heijnen, V, Lord, C J, Linn, S, Bidard, F-C, Richard, F, Yang, W W, Steele, R E, Pettitt, S J, Van Ongeval, C, De Schepper, M, Isnaldi, E, Nevelsteen, I, Smeets, A, Punie, K, Voorwerk, L, Wildiers, H, Floris, G, Vincent-Salomon, A, Derksen, P W B, Neven, P, Senkus, E, Sawyer, E, Kok, M, and Desmedt, C

Published
2022

21. 51P The development of a predictive model for risk results of the 70-gene signature

Author

Slembrouck, L., primary, Sebastian, I., additional, Martinez, A.A., additional, Vanden Bempt, I., additional, Wildiers, H., additional, Smeets, A., additional, Van Rompuy, A-S., additional, Weltens, C., additional, Punie, K., additional, Van Nieuwenhuysen, E., additional, Han, S., additional, Nevelsteen, I., additional, Neven, P., additional, and Floris, G., additional

Published
2021
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22. Transcriptome-wide association study of breast cancer risk by estrogen-receptor status.

Author

Eriksson M., Peterlongo P., Peto J., Pharoah P.D.P., Phillips K.-A., Plaseska-Karanfilska D., Poppe B., Pradhan N., Prajzendanc K., Presneau N., Punie K., Pylkas K., Radice P., Rantala J., Rashid M.U., Rennert G., Risch H.A., Robson M., Romero A., Saloustros E., Sandler D.P., Santos C., Sawyer E.J., Schmidt M.K., Schmidt D.F., Schmutzler R.K., Schoemaker M.J., Scott R.J., Sharma P., Shu X.-O., Simard J., Singer C.F., Skytte A.-B., Soucy P., Southey M.C., Spinelli J.J., Spurdle A.B., Stone J., Swerdlow A.J., Tapper W.J., Taylor J.A., Teixeira M.R., Terry M.B., Teule A., Thomassen M., Thone K., Thull D.L., Tischkowitz M., Toland A.E., Tollenaar R.A.E.M., Torres D., Truong T., Tung N., Vachon C.M., van Asperen C.J., van den Ouweland A.M.W., van Rensburg E.J., Vega A., Viel A., Vieiro-Balo P., Wang Q., Wappenschmidt B., Weinberg C.R., Weitzel J.N., Wendt C., Winqvist R., Yang X.R., Yannoukakos D., Ziogas A., Milne R.L., Easton D.F., Chenevix-Trench G., Zheng W., Kraft P., Jiang X., Feng H., Gusev A., Pasaniuc B., Wu L., Long J., Abu-full Z., Aittomaki K., Andrulis I.L., Anton-Culver H., Antoniou A.C., Arason A., Arndt V., Aronson K.J., Arun B.K., Asseryanis E., Auer P.L., Azzollini J., Balmana J., Barkardottir R.B., Barnes D.R., Barrowdale D., Beckmann M.W., Behrens S., Benitez J., Bermisheva M., Bialkowska K., Blanco A., Blomqvist C., Boeckx B., Bogdanova N.V., Bojesen S.E., Bolla M.K., Bonanni B., Borg A., Brauch H., Brenner H., Briceno I., Broeks A., Bruning T., Burwinkel B., Cai Q., Caldes T., Caligo M.A., Campbell I., Canisius S., Campa D., Carter B.D., Carter J., Castelao J.E., Chang-Claude J., Chanock S.J., Christiansen H., Chung W.K., Claes K.B.M., Clarke C.L., Couch F.J., Cox A., Cross S.S., Cybulski C., Czene K., Daly M.B., de la Hoya M., De Leeneer K., Dennis J., Devilee P., Diez O., Domchek S.M., Dork T., dos-Santos-Silva I., Dunning A.M., Dwek M., Eccles D.M., Ejlertsen B., Ellberg C., Engel C., Fasching P.A., Fletcher O., Flyger H., Fostira F., Friedman E., Fritschi L., Frost D., Gabrielson M., Ganz P.A., Gapstur S.M., Garber J., Garcia-Closas M., Garcia-Saenz J.A., Gaudet M.M., Giles G.G., Glendon G., Godwin A.K., Goldberg M.S., Goldgar D.E., Gonzalez-Neira A., Greene M.H., Gronwald J., Guenel P., Haiman C.A., Hall P., Hamann U., Hake C., He W., Heyworth J., Hogervorst F.B.L., Hollestelle A., Hooning M.J., Hoover R.N., Hopper J.L., Huang G., Hulick P.J., Humphreys K., Imyanitov E.N., Isaacs C., Jakimovska M., Jakubowska A., James P., Janavicius R., Jankowitz R.C., John E.M., Johnson N., Joseph V., Jung A., Karlan B.Y., Khusnutdinova E., Kiiski J.I., Konstantopoulou I., Kristensen V.N., Laitman Y., Lambrechts D., Lazaro C., Leroux D., Leslie G., Lester J., Lesueur F., Lindor N., Lindstrom S., Lo W.-Y., Loud J.T., Lubinski J., Makalic E., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Martens J.W.M., Martinez M.E., Matricardi L., Maurer T., Mavroudis D., McGuffog L., Meindl A., Menon U., Michailidou K., Kapoor P.M., Miller A., Montagna M., Moreno F., Moserle L., Mulligan A.M., Muranen T.A., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Nevelsteen I., Nielsen F.C., Nikitina-Zake L., Offit K., Olah E., Olopade O.I., Olsson H., Osorio A., Papp J., Park-Simon T.-W., Parsons M.T., Pedersen I.S., Peixoto A., Eriksson M., Peterlongo P., Peto J., Pharoah P.D.P., Phillips K.-A., Plaseska-Karanfilska D., Poppe B., Pradhan N., Prajzendanc K., Presneau N., Punie K., Pylkas K., Radice P., Rantala J., Rashid M.U., Rennert G., Risch H.A., Robson M., Romero A., Saloustros E., Sandler D.P., Santos C., Sawyer E.J., Schmidt M.K., Schmidt D.F., Schmutzler R.K., Schoemaker M.J., Scott R.J., Sharma P., Shu X.-O., Simard J., Singer C.F., Skytte A.-B., Soucy P., Southey M.C., Spinelli J.J., Spurdle A.B., Stone J., Swerdlow A.J., Tapper W.J., Taylor J.A., Teixeira M.R., Terry M.B., Teule A., Thomassen M., Thone K., Thull D.L., Tischkowitz M., Toland A.E., Tollenaar R.A.E.M., Torres D., Truong T., Tung N., Vachon C.M., van Asperen C.J., van den Ouweland A.M.W., van Rensburg E.J., Vega A., Viel A., Vieiro-Balo P., Wang Q., Wappenschmidt B., Weinberg C.R., Weitzel J.N., Wendt C., Winqvist R., Yang X.R., Yannoukakos D., Ziogas A., Milne R.L., Easton D.F., Chenevix-Trench G., Zheng W., Kraft P., Jiang X., Feng H., Gusev A., Pasaniuc B., Wu L., Long J., Abu-full Z., Aittomaki K., Andrulis I.L., Anton-Culver H., Antoniou A.C., Arason A., Arndt V., Aronson K.J., Arun B.K., Asseryanis E., Auer P.L., Azzollini J., Balmana J., Barkardottir R.B., Barnes D.R., Barrowdale D., Beckmann M.W., Behrens S., Benitez J., Bermisheva M., Bialkowska K., Blanco A., Blomqvist C., Boeckx B., Bogdanova N.V., Bojesen S.E., Bolla M.K., Bonanni B., Borg A., Brauch H., Brenner H., Briceno I., Broeks A., Bruning T., Burwinkel B., Cai Q., Caldes T., Caligo M.A., Campbell I., Canisius S., Campa D., Carter B.D., Carter J., Castelao J.E., Chang-Claude J., Chanock S.J., Christiansen H., Chung W.K., Claes K.B.M., Clarke C.L., Couch F.J., Cox A., Cross S.S., Cybulski C., Czene K., Daly M.B., de la Hoya M., De Leeneer K., Dennis J., Devilee P., Diez O., Domchek S.M., Dork T., dos-Santos-Silva I., Dunning A.M., Dwek M., Eccles D.M., Ejlertsen B., Ellberg C., Engel C., Fasching P.A., Fletcher O., Flyger H., Fostira F., Friedman E., Fritschi L., Frost D., Gabrielson M., Ganz P.A., Gapstur S.M., Garber J., Garcia-Closas M., Garcia-Saenz J.A., Gaudet M.M., Giles G.G., Glendon G., Godwin A.K., Goldberg M.S., Goldgar D.E., Gonzalez-Neira A., Greene M.H., Gronwald J., Guenel P., Haiman C.A., Hall P., Hamann U., Hake C., He W., Heyworth J., Hogervorst F.B.L., Hollestelle A., Hooning M.J., Hoover R.N., Hopper J.L., Huang G., Hulick P.J., Humphreys K., Imyanitov E.N., Isaacs C., Jakimovska M., Jakubowska A., James P., Janavicius R., Jankowitz R.C., John E.M., Johnson N., Joseph V., Jung A., Karlan B.Y., Khusnutdinova E., Kiiski J.I., Konstantopoulou I., Kristensen V.N., Laitman Y., Lambrechts D., Lazaro C., Leroux D., Leslie G., Lester J., Lesueur F., Lindor N., Lindstrom S., Lo W.-Y., Loud J.T., Lubinski J., Makalic E., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Martens J.W.M., Martinez M.E., Matricardi L., Maurer T., Mavroudis D., McGuffog L., Meindl A., Menon U., Michailidou K., Kapoor P.M., Miller A., Montagna M., Moreno F., Moserle L., Mulligan A.M., Muranen T.A., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Nevelsteen I., Nielsen F.C., Nikitina-Zake L., Offit K., Olah E., Olopade O.I., Olsson H., Osorio A., Papp J., Park-Simon T.-W., Parsons M.T., Pedersen I.S., and Peixoto A.

Abstract

Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer.Copyright © 2020 The Authors. Genetic Epidemiology published by Wiley Periodicals, Inc.

Published
2020

23. Transcriptome-wide association study of breast cancer risk by estrogen-receptor status

Author

Feng, H. (Helian), Gusev, A. (Alexander), Pasaniuc, B. (Bogdan), Wu, L. (Lang), Long, J. (Jirong), Abu-full, Z. (Zomoroda), Aittomäki, K. (Kristiina), Andrulis, I.L. (Irene L.), Anton-Culver, H. (Hoda), Antoniou, A.C. (Antonis C.), Arason, A. (Adalgeir), Arndt, V. (Volker), Aronson, K.J. (Kristan J.), Arun, B.K. (Banu), Asseryanis, E. (Ella), Auer, P.L. (Paul L.), Azzollini, J., Balmaña, J. (Judith), Barkardottir, R.B. (Rosa B.), Barnes, D. (Daniel), Barrowdale, D. (Daniel), Beckmann, M.W. (Matthias), Behrens, T.W. (Timothy), Benítez, J. (Javier), Bermisheva, M. (Marina), Białkowska, K. (Katarzyna), Blanco, A. (Ana), Blomqvist, C. (Carl), Boeckx, B. (Bram), Bogdanova, N.V. (Natalia V.), Bojesen, S.E. (Stig), Bolla, M.K. (Manjeet K.), Bonnani, B. (Bernardo), Borg, Å. (Åke), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Briceno, I. (Ignacio), Broeks, A. (Annegien), Brüning, T. (Thomas), Burwinkel, B. (Barbara), Cai, Q. (Qiuyin), Caldes, T. (Trinidad), Caligo, M.A. (Maria A.), Campbell, I. (Ian), Canisius, S. (Sander), Campa, D. (Daniele), Carter, B.D. (Brian D.), Carter, J. (Jonathan), Castelao, J.E. (Jose ), Chang-Claude, J. (Jenny), Chanock, S.J. (Stephen), Christiansen, H. (Hans), Chung, W. (Wendy), Claes, K.B.M. (Kathleen B. M.), Clarke, C. (Christine), Couch, F.J. (Fergus), Cox, A. (Angela), Cross, S.S. (Simon S.), Cybulski, C. (Cezary), Czene, K. (Kamila), Daly, M.B. (Mary), de la Hoya, M. (Miguel), De Leeneer, K. (Kim), Dennis, J. (Joe), Devilee, P. (Peter), Diez, O. (Orland), Domchek, S.M. (Susan), Dörk, T. (Thilo), Santos Silva, I. (Isabel) dos, Dunning, A.M. (Alison M.), Dwek, M. (Miriam), Eccles, D.M. (Diana M.), Ejlertsen, B. (Bent), Ellberg, C. (Carolina), Engel, C. (Christoph), Eriksson, M. (Mikael), Fasching, P.A. (Peter), Fletcher, O. (Olivia), Flyger, H. (Henrik), Fostira, F. (Florentia), Friedman, E. (Eitan), Fritschi, L. (Lin), Frost, D. (Debra), Gabrielson, M. (Marike), Ganz, P.A. (Patricia A.), Gapstur, S.M. (Susan M.), Garber, J. (Judy), García-Closas, M. (Montserrat), García-Sáenz, J.A. (José A.), Gaudet, M.M. (Mia M.), Giles, G.G. (Graham G.), Glendon, G. (Gord), Godwin, A.K. (Andrew), Goldberg, M.S. (Mark), Radice, P. (Paolo), González-Neira, A. (Anna), Greene, M.H. (Mark H.), Gronwald, J. (Jacek), Guénel, P. (Pascal), Haiman, C.A. (Christopher), Hall, P. (Per), Hamann, U. (Ute), Hake, C. (Christopher), He, W. (Wei), Heyworth, J. (Jane), Hogervorst, F.B.L. (Frans B.L.), Hollestelle, A. (Antoinette), Hooning, M.J. (Maartje J.), Hoover, R.N. (Robert), Hopper, J.L. (John), Huang, G. (Guanmengqian), Hulick, P.J. (Peter J.), Humphreys, K. (Keith), Imyanitov, E.N. (Evgeny), Isaacs, C. (Claudine), Jakimovska, M. (Milena), Jakubowska, A. (Anna), James, M. (Margaret), Janavicius, R. (Ramunas), Jankowitz, R.C. (Rachel C.), John, E.M. (Esther), Johnson, N. (Nichola), Joseph, V. (Vijai), Jung, A. (Audrey), Karlan, B.Y. (Beth), Khusnutdinova, E.K. (Elza), Kiiski, J.I. (Johanna I.), Konstantopoulou, I. (Irene), Kristensen, V. (Vessela), Laitman, Y. (Yael), Lambrechts, D. (Diether), Lázaro, C. (Conxi), Leroux, D. (Dominique), Leslie, G. (Goska), Lester, J. (Jenny), Lesueur, F. (Fabienne), Lindor, N.M. (Noralane), Lindström, S. (Sara), Lo, W.-Y. (Wing-Yee), Loud, J.T. (Jennifer T.), Lubinski, J. (Jan), Makalic, E. (Enes), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Manoukian, S. (Siranoush), Margolin, S. (Sara), Martens, J.W.M. (John), Martinez, M.E. (Maria E.), Matricardi, L. (Laura), Maurer, T. (Tabea), Mavroudis, D. (Dimitris), McGuffog, L. (Lesley), Meindl, A. (Alfons), Menon, U. (Usha), Michailidou, K. (Kyriaki), Kapoor, P.M. (Pooja M.), Miller, A. (Austin), Montagna, M. (Marco), Moreno, F. (Fernando), Moserle, L. (Lidia), Mulligan, A.-M. (Anna-Marie), Muranen, T.A. (Taru A.), Nathanson, K.L. (Katherine), Floris, O.A.M., Nevanlinna, H. (Heli), Nevelsteen, I. (Ines), Nielsen, F. (Finn), Nikitina-Zake, L. (Liene), Offit, K. (Kenneth), Olah, E., Olopade, O.I. (Olofunmilayo), Olsson, H. (Håkan), Osorio, A. (Ana), Papp, J. (Janos), Park-Simon, T.-W. (Tjoung-Won), Parsons, M. (Marilyn), Pedersen, I.S. (Inge S.), Peixoto, A. (Ana), Peterlongo, P. (Paolo), Peto, J. (Julian), Pharoah, P.D.P. (Paul), Phillips, K.-A. (Kelly-Anne), Plaseska-Karanfilska, D. (Dijana), Poppe, B. (Bruce), Pradhan, N. (Nisha), Prajzendanc, K. (Karolina), Presneau, N. (Nadege), Punie, K. (Kevin), Pylkäs, K. (Katri), Rantala, J. (Johanna), Rashid, M.U. (Muhammad), Rennert, G. (Gad), Risch, H.A. (Harvey A.), Robson, M. (Mark), Romero, A. (Atocha), Saloustros, E. (Emmanouil), Sandler, D.P. (Dale P.), Santos, C. (Catarina), Sawyer, E.J. (Elinor), Schmidt, M.K. (Marjanka), Schmidt, D.F. (Daniel), Schmutzler, R.K. (Rita), Schoemaker, M.J. (Minouk J.), Scott, R.J. (Rodney), Sharma, P. (Priyanka), Shu, X.-O. (Xiao-Ou), Simard, J. (Jacques), Singer, C.F. (Christian), Skytte, A.-B. (Anne-Bine), Soucy, P. (Penny), Southey, M.C. (Melissa), Spinelli, J.J. (John J.), Spurdle, A.B. (Amanda), Stone, J. (Jennifer), Swerdlow, A.J. (Anthony ), Tapper, W.J. (William J.), Taylor, J.A. (Jack A.), Teixeira, P.J., Terry, M.B. (Mary Beth), Teulé, A. (Alex), Thomassen, M. (Mads), Thöne, K. (Kathrin), Thull, D.L. (Darcy L.), Tischkowitz, M. (Marc), Toland, A.E. (Amanda), Tollenaar, R.A.E.M. (Rob), Torres, D. (Diana), Truong, T. (Thérèse), Tung, N. (Nadine), Vachon, C. (Celine), van Asperen, C.J. (Christi J.), Ouweland, A.M.W. (Ans) van den, Rensburg, E.J. (Elizabeth) van, Vega, A. (Ana), Viel, A. (Alessandra), Vieiro-Balo, P. (Paula), Wang, Q. (Qin), Wappenschmidt, B. (Barbara), Weinberg, C.R. (Clarice R.), Weitzel, J.N. (Jeffrey), Wendt, C. (Camilla), Winqvist, R. (Robert), Yang, X.R. (Xiaohong R.), Yannoukakos, D. (Drakoulis), Ziogas, A. (Argyrios), Milne, R.L. (Roger), Adamo, P. (Pio) d', Chenevix-Trench, G. (Georgia), Zheng, W. (Wei), Kraft, P. (Peter), Jiang, X. (Xia), Feng, H. (Helian), Gusev, A. (Alexander), Pasaniuc, B. (Bogdan), Wu, L. (Lang), Long, J. (Jirong), Abu-full, Z. (Zomoroda), Aittomäki, K. (Kristiina), Andrulis, I.L. (Irene L.), Anton-Culver, H. (Hoda), Antoniou, A.C. (Antonis C.), Arason, A. (Adalgeir), Arndt, V. (Volker), Aronson, K.J. (Kristan J.), Arun, B.K. (Banu), Asseryanis, E. (Ella), Auer, P.L. (Paul L.), Azzollini, J., Balmaña, J. (Judith), Barkardottir, R.B. (Rosa B.), Barnes, D. (Daniel), Barrowdale, D. (Daniel), Beckmann, M.W. (Matthias), Behrens, T.W. (Timothy), Benítez, J. (Javier), Bermisheva, M. (Marina), Białkowska, K. (Katarzyna), Blanco, A. (Ana), Blomqvist, C. (Carl), Boeckx, B. (Bram), Bogdanova, N.V. (Natalia V.), Bojesen, S.E. (Stig), Bolla, M.K. (Manjeet K.), Bonnani, B. (Bernardo), Borg, Å. (Åke), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Briceno, I. (Ignacio), Broeks, A. (Annegien), Brüning, T. (Thomas), Burwinkel, B. (Barbara), Cai, Q. (Qiuyin), Caldes, T. (Trinidad), Caligo, M.A. (Maria A.), Campbell, I. (Ian), Canisius, S. (Sander), Campa, D. (Daniele), Carter, B.D. (Brian D.), Carter, J. (Jonathan), Castelao, J.E. (Jose ), Chang-Claude, J. (Jenny), Chanock, S.J. (Stephen), Christiansen, H. (Hans), Chung, W. (Wendy), Claes, K.B.M. (Kathleen B. M.), Clarke, C. (Christine), Couch, F.J. (Fergus), Cox, A. (Angela), Cross, S.S. (Simon S.), Cybulski, C. (Cezary), Czene, K. (Kamila), Daly, M.B. (Mary), de la Hoya, M. (Miguel), De Leeneer, K. (Kim), Dennis, J. (Joe), Devilee, P. (Peter), Diez, O. (Orland), Domchek, S.M. (Susan), Dörk, T. (Thilo), Santos Silva, I. (Isabel) dos, Dunning, A.M. (Alison M.), Dwek, M. (Miriam), Eccles, D.M. (Diana M.), Ejlertsen, B. (Bent), Ellberg, C. (Carolina), Engel, C. (Christoph), Eriksson, M. (Mikael), Fasching, P.A. (Peter), Fletcher, O. (Olivia), Flyger, H. (Henrik), Fostira, F. (Florentia), Friedman, E. (Eitan), Fritschi, L. (Lin), Frost, D. (Debra), Gabrielson, M. (Marike), Ganz, P.A. (Patricia A.), Gapstur, S.M. (Susan M.), Garber, J. (Judy), García-Closas, M. (Montserrat), García-Sáenz, J.A. (José A.), Gaudet, M.M. (Mia M.), Giles, G.G. (Graham G.), Glendon, G. (Gord), Godwin, A.K. (Andrew), Goldberg, M.S. (Mark), Radice, P. (Paolo), González-Neira, A. (Anna), Greene, M.H. (Mark H.), Gronwald, J. (Jacek), Guénel, P. (Pascal), Haiman, C.A. (Christopher), Hall, P. (Per), Hamann, U. (Ute), Hake, C. (Christopher), He, W. (Wei), Heyworth, J. (Jane), Hogervorst, F.B.L. (Frans B.L.), Hollestelle, A. (Antoinette), Hooning, M.J. (Maartje J.), Hoover, R.N. (Robert), Hopper, J.L. (John), Huang, G. (Guanmengqian), Hulick, P.J. (Peter J.), Humphreys, K. (Keith), Imyanitov, E.N. (Evgeny), Isaacs, C. (Claudine), Jakimovska, M. (Milena), Jakubowska, A. (Anna), James, M. (Margaret), Janavicius, R. (Ramunas), Jankowitz, R.C. (Rachel C.), John, E.M. (Esther), Johnson, N. (Nichola), Joseph, V. (Vijai), Jung, A. (Audrey), Karlan, B.Y. (Beth), Khusnutdinova, E.K. (Elza), Kiiski, J.I. (Johanna I.), Konstantopoulou, I. (Irene), Kristensen, V. (Vessela), Laitman, Y. (Yael), Lambrechts, D. (Diether), Lázaro, C. (Conxi), Leroux, D. (Dominique), Leslie, G. (Goska), Lester, J. (Jenny), Lesueur, F. (Fabienne), Lindor, N.M. (Noralane), Lindström, S. (Sara), Lo, W.-Y. (Wing-Yee), Loud, J.T. (Jennifer T.), Lubinski, J. (Jan), Makalic, E. (Enes), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Manoukian, S. (Siranoush), Margolin, S. (Sara), Martens, J.W.M. (John), Martinez, M.E. (Maria E.), Matricardi, L. (Laura), Maurer, T. (Tabea), Mavroudis, D. (Dimitris), McGuffog, L. (Lesley), Meindl, A. (Alfons), Menon, U. (Usha), Michailidou, K. (Kyriaki), Kapoor, P.M. (Pooja M.), Miller, A. (Austin), Montagna, M. (Marco), Moreno, F. (Fernando), Moserle, L. (Lidia), Mulligan, A.-M. (Anna-Marie), Muranen, T.A. (Taru A.), Nathanson, K.L. (Katherine), Floris, O.A.M., Nevanlinna, H. (Heli), Nevelsteen, I. (Ines), Nielsen, F. (Finn), Nikitina-Zake, L. (Liene), Offit, K. (Kenneth), Olah, E., Olopade, O.I. (Olofunmilayo), Olsson, H. (Håkan), Osorio, A. (Ana), Papp, J. (Janos), Park-Simon, T.-W. (Tjoung-Won), Parsons, M. (Marilyn), Pedersen, I.S. (Inge S.), Peixoto, A. (Ana), Peterlongo, P. (Paolo), Peto, J. (Julian), Pharoah, P.D.P. (Paul), Phillips, K.-A. (Kelly-Anne), Plaseska-Karanfilska, D. (Dijana), Poppe, B. (Bruce), Pradhan, N. (Nisha), Prajzendanc, K. (Karolina), Presneau, N. (Nadege), Punie, K. (Kevin), Pylkäs, K. (Katri), Rantala, J. (Johanna), Rashid, M.U. (Muhammad), Rennert, G. (Gad), Risch, H.A. (Harvey A.), Robson, M. (Mark), Romero, A. (Atocha), Saloustros, E. (Emmanouil), Sandler, D.P. (Dale P.), Santos, C. (Catarina), Sawyer, E.J. (Elinor), Schmidt, M.K. (Marjanka), Schmidt, D.F. (Daniel), Schmutzler, R.K. (Rita), Schoemaker, M.J. (Minouk J.), Scott, R.J. (Rodney), Sharma, P. (Priyanka), Shu, X.-O. (Xiao-Ou), Simard, J. (Jacques), Singer, C.F. (Christian), Skytte, A.-B. (Anne-Bine), Soucy, P. (Penny), Southey, M.C. (Melissa), Spinelli, J.J. (John J.), Spurdle, A.B. (Amanda), Stone, J. (Jennifer), Swerdlow, A.J. (Anthony ), Tapper, W.J. (William J.), Taylor, J.A. (Jack A.), Teixeira, P.J., Terry, M.B. (Mary Beth), Teulé, A. (Alex), Thomassen, M. (Mads), Thöne, K. (Kathrin), Thull, D.L. (Darcy L.), Tischkowitz, M. (Marc), Toland, A.E. (Amanda), Tollenaar, R.A.E.M. (Rob), Torres, D. (Diana), Truong, T. (Thérèse), Tung, N. (Nadine), Vachon, C. (Celine), van Asperen, C.J. (Christi J.), Ouweland, A.M.W. (Ans) van den, Rensburg, E.J. (Elizabeth) van, Vega, A. (Ana), Viel, A. (Alessandra), Vieiro-Balo, P. (Paula), Wang, Q. (Qin), Wappenschmidt, B. (Barbara), Weinberg, C.R. (Clarice R.), Weitzel, J.N. (Jeffrey), Wendt, C. (Camilla), Winqvist, R. (Robert), Yang, X.R. (Xiaohong R.), Yannoukakos, D. (Drakoulis), Ziogas, A. (Argyrios), Milne, R.L. (Roger), Adamo, P. (Pio) d', Chenevix-Trench, G. (Georgia), Zheng, W. (Wei), Kraft, P. (Peter), and Jiang, X. (Xia)

Abstract

Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER−). We further compared associations with ER+ and ER− subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER– breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER− breast cancer.

Published
2020
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24. Transcriptome-wide association study of breast cancer risk by estrogen-receptor status

Author

Feng, H, Gusev, A, Pasaniuc, B, Wu, L, Long, J, Abu-full, Z, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Arason, A, Arndt, V, Aronson, KJ, Arun, BK, Asseryanis, E, Auer, PL, Azzollini, J, Balmana, J, Barkardottir, RB, Barnes, DR, Barrowdale, D, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bialkowska, K, Blanco, A, Blomqvist, C, Boeckx, B, Bogdanova, NV, Bojesen, SE, Bolla, MK, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Briceno, I, Broeks, A, Bruening, T, Burwinkel, B, Cai, Q, Caldes, T, Caligo, MA, Campbell, I, Canisius, S, Campa, D, Carter, BD, Carter, J, Castelao, JE, Chang-Claude, J, Chanock, SJ, Christiansen, H, Chung, WK, Claes, KBM, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Cybulski, C, Czene, K, Daly, MB, de la Hoya, M, De Leeneer, K, Dennis, J, Devilee, P, Diez, O, Domchek, SM, Doerk, T, dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Ejlertsen, B, Ellberg, C, Engel, C, Eriksson, M, Fasching, PA, Fletcher, O, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gabrielson, M, Ganz, PA, Gapstur, SM, Garber, J, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, P, Haiman, CA, Hall, P, Hamann, U, Hake, C, He, W, Heyworth, J, Hogervorst, FBL, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Huang, G, Hulick, PJ, Humphreys, K, Imyanitov, EN, Isaacs, C, Jakimovska, M, Jakubowska, A, James, P, Janavicius, R, Jankowitz, RC, John, EM, Johnson, N, Joseph, V, Jung, A, Karlan, BY, Khusnutdinova, E, Kiiski, J, Konstantopoulou, I, Kristensen, VN, Laitman, Y, Lambrechts, D, Lazaro, C, Leroux, D, Leslie, G, Lester, J, Lesueur, F, Lindor, N, Lindstrom, S, Lo, W-Y, Loud, JT, Lubinski, J, Makalic, E, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martens, JWM, Martinez, ME, Matricardi, L, Maurer, T, Mavroudis, D, McGuffog, L, Meindl, A, Menon, U, Michailidou, K, Kapoor, PM, Miller, A, Montagna, M, Moreno, F, Moserle, L, Mulligan, AM, Muranen, TA, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nevelsteen, I, Nielsen, FC, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, O, Olsson, H, Osorio, A, Papp, J, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peixoto, A, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Plaseska-Karanfilska, D, Poppe, B, Pradhan, N, Prajzendanc, K, Presneau, N, Punie, K, Pylkas, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Risch, HA, Robson, M, Romero, A, Saloustros, E, Sandler, DP, Santos, C, Sawyer, EJ, Schmidt, MK, Schmidt, DF, Schmutzler, RK, Schoemaker, MJ, Scott, RJ, Sharma, P, Shu, X-O, Simard, J, Singer, CF, Skytte, A-B, Soucy, P, Southey, MC, Spinelli, JJ, Spurdle, AB, Stone, J, Swerdlow, AJ, Tapper, WJ, Taylor, JA, Teixeira, MR, Terry, MB, Teule, A, Thomassen, M, Thoene, K, Thull, DL, Tischkowitz, M, Toland, AE, Tollenaar, RAEM, Torres, D, Truong, T, Tung, N, Vachon, CM, van Asperen, CJ, van den Ouweland, AMW, van Rensburg, EJ, Vega, A, Viel, A, Vieiro-Balo, P, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, J, Wendt, C, Winqvist, R, Yang, XR, Yannoukakos, D, Ziogas, A, Milne, RL, Easton, DF, Chenevix-Trench, G, Zheng, W, Kraft, P, Jiang, X, Feng, H, Gusev, A, Pasaniuc, B, Wu, L, Long, J, Abu-full, Z, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Arason, A, Arndt, V, Aronson, KJ, Arun, BK, Asseryanis, E, Auer, PL, Azzollini, J, Balmana, J, Barkardottir, RB, Barnes, DR, Barrowdale, D, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bialkowska, K, Blanco, A, Blomqvist, C, Boeckx, B, Bogdanova, NV, Bojesen, SE, Bolla, MK, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Briceno, I, Broeks, A, Bruening, T, Burwinkel, B, Cai, Q, Caldes, T, Caligo, MA, Campbell, I, Canisius, S, Campa, D, Carter, BD, Carter, J, Castelao, JE, Chang-Claude, J, Chanock, SJ, Christiansen, H, Chung, WK, Claes, KBM, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Cybulski, C, Czene, K, Daly, MB, de la Hoya, M, De Leeneer, K, Dennis, J, Devilee, P, Diez, O, Domchek, SM, Doerk, T, dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Ejlertsen, B, Ellberg, C, Engel, C, Eriksson, M, Fasching, PA, Fletcher, O, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gabrielson, M, Ganz, PA, Gapstur, SM, Garber, J, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, P, Haiman, CA, Hall, P, Hamann, U, Hake, C, He, W, Heyworth, J, Hogervorst, FBL, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Huang, G, Hulick, PJ, Humphreys, K, Imyanitov, EN, Isaacs, C, Jakimovska, M, Jakubowska, A, James, P, Janavicius, R, Jankowitz, RC, John, EM, Johnson, N, Joseph, V, Jung, A, Karlan, BY, Khusnutdinova, E, Kiiski, J, Konstantopoulou, I, Kristensen, VN, Laitman, Y, Lambrechts, D, Lazaro, C, Leroux, D, Leslie, G, Lester, J, Lesueur, F, Lindor, N, Lindstrom, S, Lo, W-Y, Loud, JT, Lubinski, J, Makalic, E, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martens, JWM, Martinez, ME, Matricardi, L, Maurer, T, Mavroudis, D, McGuffog, L, Meindl, A, Menon, U, Michailidou, K, Kapoor, PM, Miller, A, Montagna, M, Moreno, F, Moserle, L, Mulligan, AM, Muranen, TA, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nevelsteen, I, Nielsen, FC, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, O, Olsson, H, Osorio, A, Papp, J, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peixoto, A, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Plaseska-Karanfilska, D, Poppe, B, Pradhan, N, Prajzendanc, K, Presneau, N, Punie, K, Pylkas, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Risch, HA, Robson, M, Romero, A, Saloustros, E, Sandler, DP, Santos, C, Sawyer, EJ, Schmidt, MK, Schmidt, DF, Schmutzler, RK, Schoemaker, MJ, Scott, RJ, Sharma, P, Shu, X-O, Simard, J, Singer, CF, Skytte, A-B, Soucy, P, Southey, MC, Spinelli, JJ, Spurdle, AB, Stone, J, Swerdlow, AJ, Tapper, WJ, Taylor, JA, Teixeira, MR, Terry, MB, Teule, A, Thomassen, M, Thoene, K, Thull, DL, Tischkowitz, M, Toland, AE, Tollenaar, RAEM, Torres, D, Truong, T, Tung, N, Vachon, CM, van Asperen, CJ, van den Ouweland, AMW, van Rensburg, EJ, Vega, A, Viel, A, Vieiro-Balo, P, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, J, Wendt, C, Winqvist, R, Yang, XR, Yannoukakos, D, Ziogas, A, Milne, RL, Easton, DF, Chenevix-Trench, G, Zheng, W, Kraft, P, and Jiang, X

Abstract

Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer.

Published
2020

29. Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer.

Author

Herold N., Rantala J., Rennert G., Risch H.A., Saloustros E., Sanden K., Sawyer E.J., Schmidt M.K., Schmutzler R.K., Sharma P., Shu X.-O., Simard J., Singer C.F., Soucy P., Southey M.C., Spinelli J.J., Spurdle A.B., Stone J., Swerdlow A.J., Tapper W.J., Taylor J.A., Teixeira M.R., Terry M.B., Teule A., Thomassen M., Thone K., Thull D.L., Tischkowitz M., Toland A.E., Torres D., Truong T., Tung N., Vachon C.M., van Asperen C.J., van den Ouweland A.M.W., van Rensburg E.J., Vega A., Viel A., Wang Q., Wappenschmidt B., Weitzel J.N., Wendt C., Winqvist R., Yang X.R., Yannoukakos D., Ziogas A., Kraft P., Antoniou A.C., Zheng W., Easton D.F., Milne R.L., Beesley J., Chenevix-Trench G., Ferreira M.A., Gamazon E.R., Al-Ejeh F., Aittomaki K., Andrulis I.L., Anton-Culver H., Arason A., Arndt V., Aronson K.J., Arun B.K., Asseryanis E., Azzollini J., Balmana J., Barnes D.R., Barrowdale D., Beckmann M.W., Behrens S., Benitez J., Bermisheva M., Bialkowska K., Blomqvist C., Bogdanova N.V., Bojesen S.E., Bolla M.K., Borg A., Brauch H., Brenner H., Broeks A., Burwinkel B., Caldes T., Caligo M.A., Campa D., Campbell I., Canzian F., Carter J., Carter B.D., Castelao J.E., Chang-Claude J., Chanock S.J., Christiansen H., Chung W.K., Claes K.B.M., Clarke C.L., Adlard J., Ahmed M., Barwell J., Brady A., Brewer C., Cook J., Davidson R., Donaldson A., Eason J., Eeles R., Evans D.G., Gregory H., Hanson H., Henderson A., Hodgson S., Izatt L., Kennedy M.J., Lalloo F., Miller C., Morrison P.J., Ong K.-R., Perkins J., Porteous M.E., Rogers M.T., Side L.E., Snape K., Walker L., Harrington P.A., Arnold N., Auber B., Bogdanova-Markov N., Borde J., Caliebe A., Ditsch N., Dworniczak B., Engert S., Faust U., Gehrig A., Hahnen E., Hauke J., Hentschel J., Honisch E., Just W., Kast K., Larsen M., Lemke J., Nguyen H.P., Niederacher D., Ott C.-E., Platzer K., Pohl-Rescigno E., Ramser J., Rhiem K., Steinemann D., Sutter C., Varon-Mateeva R., Wang-Gohrke S., Weber B.H.F., Prieur F., Pujol P., Sagne C., Sevenet N., Sobol H., Sokolowska J., Stoppa-Lyonnet D., Venat-Bouvet L., Couch F.J., Cox A., Cross S.S., Czene K., Daly M.B., de la Hoya M., Dennis J., Devilee P., Diez O., Dork T., Dunning A.M., Dwek M., Eccles D.M., Ejlertsen B., Ellberg C., Engel C., Eriksson M., Fasching P.A., Fletcher O., Flyger H., Friedman E., Frost D., Gabrielson M., Gago-Dominguez M., Ganz P.A., Gapstur S.M., Garber J., Garcia-Closas M., Garcia-Saenz J.A., Gaudet M.M., Giles G.G., Glendon G., Godwin A.K., Goldberg M.S., Goldgar D.E., Gonzalez-Neira A., Greene M.H., Gronwald J., Guenel P., Haiman C.A., Hall P., Hamann U., He W., Heyworth J., Hogervorst F.B.L., Hollestelle A., Hoover R.N., Hopper J.L., Hulick P.J., Humphreys K., Imyanitov E.N., Balleine R., Baxter R., Braye S., Carpenter J., Dahlstrom J., Forbes J., Lee S.C., Marsh D., Morey A., Pathmanathan N., Simpson P., Spigelman A., Wilcken N., Yip D., Heemskerk-Gerritsen B.A.M., Rookus M.A., Seynaeve C.M., van der Baan F.H., van der Hout A.H., van der Kolk L.E., van der Luijt R.B., van Deurzen C.H.M., van Doorn H.C., van Engelen K., van Hest L., van Os T.A.M., Verhoef S., Vogel M.J., Wijnen J.T., Miron A., Kapuscinski M., Bane A., Ross E., Buys S.S., Conner T.A., Isaacs C., Jakimovska M., Jakubowska A., James P.A., Janavicius R., Jankowitz R.C., John E.M., Johnson N., Joseph V., Karlan B.Y., Khusnutdinova E., Kiiski J.I., Ko Y.-D., Jones M.E., Konstantopoulou I., Kristensen V.N., Laitman Y., Lambrechts D., Lazaro C., Leslie G., Lester J., Lesueur F., Lindstrom S., Long J., Loud J.T., Lubinski J., Makalic E., Mannermaa A., Manoochehri M., Margolin S., Maurer T., Mavroudis D., McGuffog L., Meindl A., Menon U., Michailidou K., Miller A., Montagna M., Moreno F., Moserle L., Mulligan A.M., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Nevelsteen I., Nielsen F.C., Nikitina-Zake L., Nussbaum R.L., Offit K., Olah E., Olopade O.I., Olsson H., Osorio A., Papp J., Park-Simon T.-W., Parsons M.T., Pedersen I.S., Peixoto A., Peterlongo P., Pharoah P.D.P., Plaseska-Karanfilska D., Poppe B., Presneau N., Radice P., Herold N., Rantala J., Rennert G., Risch H.A., Saloustros E., Sanden K., Sawyer E.J., Schmidt M.K., Schmutzler R.K., Sharma P., Shu X.-O., Simard J., Singer C.F., Soucy P., Southey M.C., Spinelli J.J., Spurdle A.B., Stone J., Swerdlow A.J., Tapper W.J., Taylor J.A., Teixeira M.R., Terry M.B., Teule A., Thomassen M., Thone K., Thull D.L., Tischkowitz M., Toland A.E., Torres D., Truong T., Tung N., Vachon C.M., van Asperen C.J., van den Ouweland A.M.W., van Rensburg E.J., Vega A., Viel A., Wang Q., Wappenschmidt B., Weitzel J.N., Wendt C., Winqvist R., Yang X.R., Yannoukakos D., Ziogas A., Kraft P., Antoniou A.C., Zheng W., Easton D.F., Milne R.L., Beesley J., Chenevix-Trench G., Ferreira M.A., Gamazon E.R., Al-Ejeh F., Aittomaki K., Andrulis I.L., Anton-Culver H., Arason A., Arndt V., Aronson K.J., Arun B.K., Asseryanis E., Azzollini J., Balmana J., Barnes D.R., Barrowdale D., Beckmann M.W., Behrens S., Benitez J., Bermisheva M., Bialkowska K., Blomqvist C., Bogdanova N.V., Bojesen S.E., Bolla M.K., Borg A., Brauch H., Brenner H., Broeks A., Burwinkel B., Caldes T., Caligo M.A., Campa D., Campbell I., Canzian F., Carter J., Carter B.D., Castelao J.E., Chang-Claude J., Chanock S.J., Christiansen H., Chung W.K., Claes K.B.M., Clarke C.L., Adlard J., Ahmed M., Barwell J., Brady A., Brewer C., Cook J., Davidson R., Donaldson A., Eason J., Eeles R., Evans D.G., Gregory H., Hanson H., Henderson A., Hodgson S., Izatt L., Kennedy M.J., Lalloo F., Miller C., Morrison P.J., Ong K.-R., Perkins J., Porteous M.E., Rogers M.T., Side L.E., Snape K., Walker L., Harrington P.A., Arnold N., Auber B., Bogdanova-Markov N., Borde J., Caliebe A., Ditsch N., Dworniczak B., Engert S., Faust U., Gehrig A., Hahnen E., Hauke J., Hentschel J., Honisch E., Just W., Kast K., Larsen M., Lemke J., Nguyen H.P., Niederacher D., Ott C.-E., Platzer K., Pohl-Rescigno E., Ramser J., Rhiem K., Steinemann D., Sutter C., Varon-Mateeva R., Wang-Gohrke S., Weber B.H.F., Prieur F., Pujol P., Sagne C., Sevenet N., Sobol H., Sokolowska J., Stoppa-Lyonnet D., Venat-Bouvet L., Couch F.J., Cox A., Cross S.S., Czene K., Daly M.B., de la Hoya M., Dennis J., Devilee P., Diez O., Dork T., Dunning A.M., Dwek M., Eccles D.M., Ejlertsen B., Ellberg C., Engel C., Eriksson M., Fasching P.A., Fletcher O., Flyger H., Friedman E., Frost D., Gabrielson M., Gago-Dominguez M., Ganz P.A., Gapstur S.M., Garber J., Garcia-Closas M., Garcia-Saenz J.A., Gaudet M.M., Giles G.G., Glendon G., Godwin A.K., Goldberg M.S., Goldgar D.E., Gonzalez-Neira A., Greene M.H., Gronwald J., Guenel P., Haiman C.A., Hall P., Hamann U., He W., Heyworth J., Hogervorst F.B.L., Hollestelle A., Hoover R.N., Hopper J.L., Hulick P.J., Humphreys K., Imyanitov E.N., Balleine R., Baxter R., Braye S., Carpenter J., Dahlstrom J., Forbes J., Lee S.C., Marsh D., Morey A., Pathmanathan N., Simpson P., Spigelman A., Wilcken N., Yip D., Heemskerk-Gerritsen B.A.M., Rookus M.A., Seynaeve C.M., van der Baan F.H., van der Hout A.H., van der Kolk L.E., van der Luijt R.B., van Deurzen C.H.M., van Doorn H.C., van Engelen K., van Hest L., van Os T.A.M., Verhoef S., Vogel M.J., Wijnen J.T., Miron A., Kapuscinski M., Bane A., Ross E., Buys S.S., Conner T.A., Isaacs C., Jakimovska M., Jakubowska A., James P.A., Janavicius R., Jankowitz R.C., John E.M., Johnson N., Joseph V., Karlan B.Y., Khusnutdinova E., Kiiski J.I., Ko Y.-D., Jones M.E., Konstantopoulou I., Kristensen V.N., Laitman Y., Lambrechts D., Lazaro C., Leslie G., Lester J., Lesueur F., Lindstrom S., Long J., Loud J.T., Lubinski J., Makalic E., Mannermaa A., Manoochehri M., Margolin S., Maurer T., Mavroudis D., McGuffog L., Meindl A., Menon U., Michailidou K., Miller A., Montagna M., Moreno F., Moserle L., Mulligan A.M., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Nevelsteen I., Nielsen F.C., Nikitina-Zake L., Nussbaum R.L., Offit K., Olah E., Olopade O.I., Olsson H., Osorio A., Papp J., Park-Simon T.-W., Parsons M.T., Pedersen I.S., Peixoto A., Peterlongo P., Pharoah P.D.P., Plaseska-Karanfilska D., Poppe B., Presneau N., and Radice P.

Abstract

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.Copyright © 2019, The Author(s).

Published
2019

30. Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer

Author

Ferreira, MA, Gamazon, ER, Al-Ejeh, F, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arason, A, Arndt, V, Aronson, KJ, Arun, BK, Asseryanis, E, Azzollini, J, Balmana, J, Barnes, DR, Barrowdale, D, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bialkowska, K, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bolla, MK, Borg, A, Brauch, H, Brenner, H, Broeks, A, Burwinkel, B, Caldes, T, Caligo, MA, Campa, D, Campbell, I, Canzian, F, Carter, J, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Christiansen, H, Chung, WK, Claes, KBM, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, de la Hoya, M, Dennis, J, Devilee, P, Diez, O, Doerk, T, Dunning, AM, Dwek, M, Eccles, DM, Ejlertsen, B, Ellberg, C, Engel, C, Eriksson, M, Fasching, PA, Fletcher, O, Flyger, H, Friedman, E, Frost, D, Gabrielson, M, Gago-Dominguez, M, Ganz, PA, Gapstur, SM, Garber, J, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, P, Haiman, CA, Hall, P, Hamann, U, He, W, Heyworth, J, Hogervorst, FBL, Hollestelle, A, Hoover, RN, Hopper, JL, Hulick, PJ, Humphreys, K, Imyanitov, EN, Isaacs, C, Jakimovska, M, Jakubowska, A, James, PA, Janavicius, R, Jankowitz, RC, John, EM, Johnson, N, Joseph, V, Karlan, BY, Khusnutdinova, E, Kiiski, J, Ko, Y-D, Jones, ME, Konstantopoulou, I, Kristensen, VN, Laitman, Y, Lambrechts, D, Lazaro, C, Leslie, G, Lester, J, Lesueur, F, Lindstrom, S, Long, J, Loud, JT, Lubinski, J, Makalic, E, Mannermaa, A, Manoochehri, M, Margolin, S, Maurer, T, Mavroudis, D, McGuffog, L, Meindl, A, Menon, U, Michailidou, K, Miller, A, Montagna, M, Moreno, F, Moserle, L, Mulligan, AM, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nevelsteen, I, Nielsen, FC, Nikitina-Zake, L, Nussbaum, RL, Offit, K, Olah, E, Olopade, O, Olsson, H, Osorio, A, Papp, J, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peixoto, A, Peterlongo, P, Pharoah, PDP, Plaseska-Karanfilska, D, Poppe, B, Presneau, N, Radice, P, Rantala, J, Rennert, G, Risch, HA, Saloustros, E, Sanden, K, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Sharma, P, Shu, X-O, Simard, J, Singer, CF, Soucy, P, Southey, MC, Spinelli, JJ, Spurdle, AB, Stone, J, Swerdlow, AJ, Tapper, WJ, Taylor, JA, Teixeira, MR, Terry, MB, Teule, A, Thomassen, M, Thoene, K, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Truong, T, Tung, N, Vachon, CM, van Asperen, CJ, van den Ouweland, AMW, van Rensburg, EJ, Vega, A, Viel, A, Wang, Q, Wappenschmidt, B, Weitzel, JN, Wendt, C, Winqvist, R, Yang, XR, Yannoukakos, D, Ziogas, A, Kraft, P, Antoniou, AC, Zheng, W, Easton, DF, Milne, RL, Beesley, J, Chenevix-Trench, G, Arnold, N, Auber, B, Bogdanova-Markov, N, Borde, J, Caliebe, A, Ditsch, N, Dworniczak, B, Engert, S, Faust, U, Gehrig, A, Hahnen, E, Hauke, J, Hentschel, J, Herold, N, Honisch, E, Just, W, Kast, K, Larsen, M, Lemke, J, Huu, PN, Niederacher, D, Ott, C-E, Platzer, K, Pohl-Rescigno, E, Ramser, J, Rhiem, K, Steinemann, D, Sutter, C, Varon-Mateeva, R, Wang-Gohrke, S, Weber, BHF, Prieur, F, Pujol, P, Sagne, C, Sevenet, N, Sobol, H, Sokolowska, J, Stoppa-Lyonnet, D, Venat-Bouvet, L, Adlard, J, Ahmed, M, Barwell, J, Brady, A, Brewer, C, Cook, J, Davidson, R, Donaldson, A, Eason, J, Eeles, R, Evans, DG, Gregory, H, Hanson, H, Henderson, A, Hodgson, S, Izatt, L, Kennedy, MJ, Lalloo, F, Miller, C, Morrison, PJ, Ong, K-R, Perkins, J, Porteous, ME, Rogers, MT, Side, LE, Snape, K, Walker, L, Harrington, PA, Heemskerk-Gerritsen, BAM, Rookus, MA, Seynaeve, CM, van der Baan, FH, van der Hout, AH, van der Kolk, LE, van der Luijt, RB, van Deurzen, CHM, van Doorn, HC, van Engelen, K, van Hest, L, van Os, TAM, Verhoef, S, Vogel, MJ, Wijnen, JT, Miron, A, Kapuscinski, M, Bane, A, Ross, E, Buys, SS, Conner, TA, Balleine, R, Baxter, R, Braye, S, Carpenter, J, Dahlstrom, J, Forbes, J, Lee, SC, Marsh, D, Morey, A, Pathmanathan, N, Simpson, P, Spigelman, A, Wilcken, N, Yip, D, Ferreira, MA, Gamazon, ER, Al-Ejeh, F, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arason, A, Arndt, V, Aronson, KJ, Arun, BK, Asseryanis, E, Azzollini, J, Balmana, J, Barnes, DR, Barrowdale, D, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bialkowska, K, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bolla, MK, Borg, A, Brauch, H, Brenner, H, Broeks, A, Burwinkel, B, Caldes, T, Caligo, MA, Campa, D, Campbell, I, Canzian, F, Carter, J, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Christiansen, H, Chung, WK, Claes, KBM, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, de la Hoya, M, Dennis, J, Devilee, P, Diez, O, Doerk, T, Dunning, AM, Dwek, M, Eccles, DM, Ejlertsen, B, Ellberg, C, Engel, C, Eriksson, M, Fasching, PA, Fletcher, O, Flyger, H, Friedman, E, Frost, D, Gabrielson, M, Gago-Dominguez, M, Ganz, PA, Gapstur, SM, Garber, J, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, P, Haiman, CA, Hall, P, Hamann, U, He, W, Heyworth, J, Hogervorst, FBL, Hollestelle, A, Hoover, RN, Hopper, JL, Hulick, PJ, Humphreys, K, Imyanitov, EN, Isaacs, C, Jakimovska, M, Jakubowska, A, James, PA, Janavicius, R, Jankowitz, RC, John, EM, Johnson, N, Joseph, V, Karlan, BY, Khusnutdinova, E, Kiiski, J, Ko, Y-D, Jones, ME, Konstantopoulou, I, Kristensen, VN, Laitman, Y, Lambrechts, D, Lazaro, C, Leslie, G, Lester, J, Lesueur, F, Lindstrom, S, Long, J, Loud, JT, Lubinski, J, Makalic, E, Mannermaa, A, Manoochehri, M, Margolin, S, Maurer, T, Mavroudis, D, McGuffog, L, Meindl, A, Menon, U, Michailidou, K, Miller, A, Montagna, M, Moreno, F, Moserle, L, Mulligan, AM, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nevelsteen, I, Nielsen, FC, Nikitina-Zake, L, Nussbaum, RL, Offit, K, Olah, E, Olopade, O, Olsson, H, Osorio, A, Papp, J, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peixoto, A, Peterlongo, P, Pharoah, PDP, Plaseska-Karanfilska, D, Poppe, B, Presneau, N, Radice, P, Rantala, J, Rennert, G, Risch, HA, Saloustros, E, Sanden, K, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Sharma, P, Shu, X-O, Simard, J, Singer, CF, Soucy, P, Southey, MC, Spinelli, JJ, Spurdle, AB, Stone, J, Swerdlow, AJ, Tapper, WJ, Taylor, JA, Teixeira, MR, Terry, MB, Teule, A, Thomassen, M, Thoene, K, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Truong, T, Tung, N, Vachon, CM, van Asperen, CJ, van den Ouweland, AMW, van Rensburg, EJ, Vega, A, Viel, A, Wang, Q, Wappenschmidt, B, Weitzel, JN, Wendt, C, Winqvist, R, Yang, XR, Yannoukakos, D, Ziogas, A, Kraft, P, Antoniou, AC, Zheng, W, Easton, DF, Milne, RL, Beesley, J, Chenevix-Trench, G, Arnold, N, Auber, B, Bogdanova-Markov, N, Borde, J, Caliebe, A, Ditsch, N, Dworniczak, B, Engert, S, Faust, U, Gehrig, A, Hahnen, E, Hauke, J, Hentschel, J, Herold, N, Honisch, E, Just, W, Kast, K, Larsen, M, Lemke, J, Huu, PN, Niederacher, D, Ott, C-E, Platzer, K, Pohl-Rescigno, E, Ramser, J, Rhiem, K, Steinemann, D, Sutter, C, Varon-Mateeva, R, Wang-Gohrke, S, Weber, BHF, Prieur, F, Pujol, P, Sagne, C, Sevenet, N, Sobol, H, Sokolowska, J, Stoppa-Lyonnet, D, Venat-Bouvet, L, Adlard, J, Ahmed, M, Barwell, J, Brady, A, Brewer, C, Cook, J, Davidson, R, Donaldson, A, Eason, J, Eeles, R, Evans, DG, Gregory, H, Hanson, H, Henderson, A, Hodgson, S, Izatt, L, Kennedy, MJ, Lalloo, F, Miller, C, Morrison, PJ, Ong, K-R, Perkins, J, Porteous, ME, Rogers, MT, Side, LE, Snape, K, Walker, L, Harrington, PA, Heemskerk-Gerritsen, BAM, Rookus, MA, Seynaeve, CM, van der Baan, FH, van der Hout, AH, van der Kolk, LE, van der Luijt, RB, van Deurzen, CHM, van Doorn, HC, van Engelen, K, van Hest, L, van Os, TAM, Verhoef, S, Vogel, MJ, Wijnen, JT, Miron, A, Kapuscinski, M, Bane, A, Ross, E, Buys, SS, Conner, TA, Balleine, R, Baxter, R, Braye, S, Carpenter, J, Dahlstrom, J, Forbes, J, Lee, SC, Marsh, D, Morey, A, Pathmanathan, N, Simpson, P, Spigelman, A, Wilcken, N, and Yip, D

Abstract

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.

Published
2019

31. Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer

Author

Ferreira, M. A. (Manuel A.), Gamazon, E. R. (Eric R.), Al-Ejeh, F. (Fares), Aittomaki, K. (Kristiina), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Arason, A. (Adalgeir), Arndt, V. (Volker), Aronson, K. J. (Kristan J.), Arun, B. K. (Banu K.), Asseryanis, E. (Ella), Azzollini, J. (Jacopo), Balmana, J. (Judith), Barnes, D. R. (Daniel R.), Barrowdale, D. (Daniel), Beckmann, M. W. (Matthias W.), Behrens, S. (Sabine), Benitez, J. (Javier), Bermisheva, M. (Marina), Bialkowska, K. (Katarzyna), Blomqvist, C. (Carl), Bogdanova, N. V. (Natalia, V), Bojesen, S. E. (Stig E.), Bolla, M. K. (Manjeet K.), Borg, A. (Ake), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Broeks, A. (Annegien), Burwinkel, B. (Barbara), Caldes, T. (Trinidad), Caligo, M. A. (Maria A.), Campa, D. (Daniele), Campbell, I. (Ian), Canzian, F. (Federico), Carter, J. (Jonathan), Carter, B. D. (Brian D.), Castelao, J. E. (Jose E.), Chang-Claude, J. (Jenny), Chanock, S. J. (Stephen J.), Christiansen, H. (Hans), Chung, W. K. (Wendy K.), Claes, K. B. (Kathleen B. M.), Clarke, C. L. (Christine L.), Couch, F. J. (Fergus J.), Cox, A. (Angela), Cross, S. S. (Simon S.), Czene, K. (Kamila), Daly, M. B. (Mary B.), de la Hoya, M. (Miguel), Dennis, J. (Joe), Devilee, P. (Peter), Diez, O. (Orland), Doerk, T. (Thilo), Dunning, A. M. (Alison M.), Dwek, M. (Miriam), Eccles, D. M. (Diana M.), Ejlertsen, B. (Bent), Ellberg, C. (Carolina), Engel, C. (Christoph), Eriksson, M. (Mikael), Fasching, P. A. (Peter A.), Fletcher, O. (Olivia), Flyger, H. (Henrik), Friedman, E. (Eitan), Frost, D. (Debra), Gabrielson, M. (Marike), Gago-Dominguez, M. (Manuela), Ganz, P. A. (Patricia A.), Gapstur, S. M. (Susan M.), Garber, J. (Judy), Garcia-Closas, M. (Montserrat), Garcia-Saenz, J. A. (Jose A.), Gaudet, M. M. (Mia M.), Giles, G. G. (Graham G.), Glendon, G. (Gord), Godwin, A. K. (Andrew K.), Goldberg, M. S. (Mark S.), Goldgar, D. E. (David E.), Gonzalez-Neira, A. (Anna), Greene, M. H. (Mark H.), Gronwald, J. (Jacek), Guenel, P. (Pascal), Haiman, C. A. (Christopher A.), Hall, P. (Per), Hamann, U. (Ute), He, W. (Wei), Heyworth, J. (Jane), Hogervorst, F. B. (Frans B. L.), Hollestelle, A. (Antoinette), Hoover, R. N. (Robert N.), Hopper, J. L. (John L.), Hulick, P. J. (Peter J.), Humphreys, K. (Keith), Imyanitov, E. N. (Evgeny N.), Isaacs, C. (Claudine), Jakimovska, M. (Milena), Jakubowska, A. (Anna), James, P. A. (Paul A.), Janavicius, R. (Ramunas), Jankowitz, R. C. (Rachel C.), John, E. M. (Esther M.), Johnson, N. (Nichola), Joseph, V. (Vijai), Karlan, B. Y. (Beth Y.), Khusnutdinova, E. (Elza), Kiiski, J. I. (Johanna, I), Ko, Y.-D. (Yon-Dschun), Jones, M. E. (Michael E.), Konstantopoulou, I. (Irene), Kristensen, V. N. (Vessela N.), Laitman, Y. (Yael), Lambrechts, D. (Diether), Lazaro, C. (Conxi), Leslie, G. (Goska), Lester, J. (Jenny), Lesueur, F. (Fabienne), Lindstrom, S. (Sara), Long, J. (Jirong), Loud, J. T. (Jennifer T.), Lubinski, J. (Jan), Makalic, E. (Enes), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Margolin, S. (Sara), Maurer, T. (Tabea), Mavroudis, D. (Dimitrios), McGuffog, L. (Lesley), Meindl, A. (Alfons), Menon, U. (Usha), Michailidou, K. (Kyriaki), Miller, A. (Austin), Montagna, M. (Marco), Moreno, F. (Fernando), Moserle, L. (Lidia), Mulligan, A. M. (Anna Marie), Nathanson, K. L. (Katherine L.), Neuhausen, S. L. (Susan L.), Nevanlinna, H. (Heli), Nevelsteen, I. (Ines), Nielsen, F. C. (Finn C.), Nikitina-Zake, L. (Liene), Nussbaum, R. L. (Robert L.), Offit, K. (Kenneth), Olah, E. (Edith), Olopade, O. I. (Olufunmilayo, I), Olsson, H. (Hakan), Osorio, A. (Ana), Papp, J. (Janos), Park-Simon, T.-W. (Tjoung-Won), Parsons, M. T. (Michael T.), Pedersen, I. S. (Inge Sokilde), Peixoto, A. (Ana), Peterlongo, P. (Paolo), Pharoah, P. D. (Paul D. P.), Plaseska-Karanfilska, D. (Dijana), Poppe, B. (Bruce), Presneau, N. (Nadege), Radice, P. (Paolo), Rantala, J. (Johanna), Rennert, G. (Gad), Risch, H. A. (Harvey A.), Saloustros, E. (Emmanouil), Sanden, K. (Kristin), Sawyer, E. J. (Elinor J.), Schmidt, M. K. (Marjanka K.), Schmutzler, R. K. (Rita K.), Sharma, P. (Priyanka), Shu, X.-O. (Xiao-Ou), Simard, J. (Jacques), Singer, C. F. (Christian F.), Soucy, P. (Penny), Southey, M. C. (Melissa C.), Spinelli, J. J. (John J.), Spurdle, A. B. (Amanda B.), Stone, J. (Jennifer), Swerdlow, A. J. (Anthony J.), Tapper, W. J. (William J.), Taylor, J. A. (Jack A.), Teixeira, M. R. (Manuel R.), Terry, M. B. (Mary Beth), Teule, A. (Alex), Thomassen, M. (Mads), Thoene, K. (Kathrin), Thull, D. L. (Darcy L.), Tischkowitz, M. (Marc), Toland, A. E. (Amanda E.), Torres, D. (Diana), Truong, T. (Therese), Tung, N. (Nadine), Vachon, C. M. (Celine M.), van Asperen, C. J. (Christi J.), van den Ouweland, A. M. (Ans M. W.), van Rensburg, E. J. (Elizabeth J.), Vega, A. (Ana), Viel, A. (Alessandra), Wang, Q. (Qin), Wappenschmidt, B. (Barbara), Weitzel, J. N. (Jeffrey N.), Wendt, C. (Camilla), Winqvist, R. (Robert), Yang, X. R. (Xiaohong R.), Yannoukakos, D. (Drakoulis), Ziogas, A. (Argyrios), Kraft, P. (Peter), Antoniou, A. C. (Antonis C.), Zheng, W. (Wei), Easton, D. F. (Douglas F.), Milne, R. L. (Roger L.), Beesley, J. (Jonathan), Chenevix-Trench, G. (Georgia), Arnold, N. (Norbert), Auber, B. (Bernd), Bogdanova-Markov, N. (Nadja), Borde, J. (Julika), Caliebe, A. (Almuth), Ditsch, N. (Nina), Dworniczak, B. (Bernd), Engert, S. (Stefanie), Faust, U. (Ulrike), Gehrig, A. (Andrea), Hahnen, E. (Eric), Hauke, J. (Jan), Hentschel, J. (Julia), Herold, N. (Natalie), Honisch, E. (Ellen), Just, W. (Walter), Kast, K. (Karin), Larsen, M. (Mirjam), Lemke, J. (Johannes), . (), Niederacher, D. (Dieter), Ott, C.-E. (Claus-Eric), Platzer, K. (Konrad), Pohl-Rescigno, E. (Esther), Ramser, J. (Juliane), Rhiem, K. (Kerstin), Steinemann, D. (Doris), Sutter, C. (Christian), Varon-Mateeva, R. (Raymonda), Wang-Gohrke, S. (Shan), Weber, B. H. (Bernhard H. F.), Prieur, F. (Fabienne), Pujol, P. (Pascal), Sagne, C. (Charlotte), Sevenet, N. (Nicolas), Sobol, H. (Hagay), Sokolowska, J. (Johanna), Stoppa-Lyonnet, D. (Dominique), Venat-Bouvet, L. (Laurence), Adlard, J. (Julian), Ahmed, M. (Munaza), Barwell, J. (Julian), Brady, A. (Angela), Brewer, C. (Carole), Cook, J. (Jackie), Davidson, R. (Rosemarie), Donaldson, A. (Alan), Eason, J. (Jacqueline), Eeles, R. (Ros), Evans, D. G. (D. Gareth), Gregory, H. (Helen), Hanson, H. (Helen), Henderson, A. (Alex), Hodgson, S. (Shirley), Izatt, L. (Louise), Kennedy, M. J. (M. John), Lalloo, F. (Fiona), Miller, C. (Clare), Morrison, P. J. (Patrick J.), Ong, K.-r. (Kai-ren), Perkins, J. (Jo), Porteous, M. E. (Mary E.), Rogers, M. T. (Mark T.), Side, L. E. (Lucy E.), Snape, K. (Katie), Walker, L. (Lisa), Harrington, P. A. (Patricia A.), Heemskerk-Gerritsen, B. A. (Bernadette A. M.), Rookus, M. A. (Matti A.), Seynaeve, C. M. (Caroline M.), van der Baan, F. H. (Frederieke H.), van der Hout, A. H. (Annemieke H.), van der Kolk, L. E. (Lizet E.), van der Luijt, R. B. (Rob B.), van Deurzen, C. H. (Carolien H. M.), van Doorn, H. C. (Helena C.), van Engelen, K. (Klaartje), van Hest, L. (Liselotte), van Os, T. A. (Theo A. M.), Verhoef, S. (Senno), Vogel, M. J. (Maartje J.), Wijnen, J. T. (Juul T.), Miron, A. (Alexander), Kapuscinski, M. (Miroslav), Bane, A. (Anita), Ross, E. (Eric), Buys, S. S. (Saundra S.), Conner, T. A. (Thomas A.), Balleine, R. (Rosemary), Baxter, R. (Robert), Braye, S. (Stephen), Carpenter, J. (Jane), Dahlstrom, J. (Jane), Forbes, J. (John), Lee, S. C. (Soon C.), Marsh, D. (Deborah), Morey, A. (Adrienne), Pathmanathan, N. (Nirmala), Simpson, P. (Peter), Spigelman, A. (Allan), Wilcken, N. (Nicholas), Yip, D. (Desmond), Ferreira, M. A. (Manuel A.), Gamazon, E. R. (Eric R.), Al-Ejeh, F. (Fares), Aittomaki, K. (Kristiina), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Arason, A. (Adalgeir), Arndt, V. (Volker), Aronson, K. J. (Kristan J.), Arun, B. K. (Banu K.), Asseryanis, E. (Ella), Azzollini, J. (Jacopo), Balmana, J. (Judith), Barnes, D. R. (Daniel R.), Barrowdale, D. (Daniel), Beckmann, M. W. (Matthias W.), Behrens, S. (Sabine), Benitez, J. (Javier), Bermisheva, M. (Marina), Bialkowska, K. (Katarzyna), Blomqvist, C. (Carl), Bogdanova, N. V. (Natalia, V), Bojesen, S. E. (Stig E.), Bolla, M. K. (Manjeet K.), Borg, A. (Ake), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Broeks, A. (Annegien), Burwinkel, B. (Barbara), Caldes, T. (Trinidad), Caligo, M. A. (Maria A.), Campa, D. (Daniele), Campbell, I. (Ian), Canzian, F. (Federico), Carter, J. (Jonathan), Carter, B. D. (Brian D.), Castelao, J. E. (Jose E.), Chang-Claude, J. (Jenny), Chanock, S. J. (Stephen J.), Christiansen, H. (Hans), Chung, W. K. (Wendy K.), Claes, K. B. (Kathleen B. M.), Clarke, C. L. (Christine L.), Couch, F. J. (Fergus J.), Cox, A. (Angela), Cross, S. S. (Simon S.), Czene, K. (Kamila), Daly, M. B. (Mary B.), de la Hoya, M. (Miguel), Dennis, J. (Joe), Devilee, P. (Peter), Diez, O. (Orland), Doerk, T. (Thilo), Dunning, A. M. (Alison M.), Dwek, M. (Miriam), Eccles, D. M. (Diana M.), Ejlertsen, B. (Bent), Ellberg, C. (Carolina), Engel, C. (Christoph), Eriksson, M. (Mikael), Fasching, P. A. (Peter A.), Fletcher, O. (Olivia), Flyger, H. (Henrik), Friedman, E. (Eitan), Frost, D. (Debra), Gabrielson, M. (Marike), Gago-Dominguez, M. (Manuela), Ganz, P. A. (Patricia A.), Gapstur, S. M. (Susan M.), Garber, J. (Judy), Garcia-Closas, M. (Montserrat), Garcia-Saenz, J. A. (Jose A.), Gaudet, M. M. (Mia M.), Giles, G. G. (Graham G.), Glendon, G. (Gord), Godwin, A. K. (Andrew K.), Goldberg, M. S. (Mark S.), Goldgar, D. E. (David E.), Gonzalez-Neira, A. (Anna), Greene, M. H. (Mark H.), Gronwald, J. (Jacek), Guenel, P. (Pascal), Haiman, C. A. (Christopher A.), Hall, P. (Per), Hamann, U. (Ute), He, W. (Wei), Heyworth, J. (Jane), Hogervorst, F. B. (Frans B. L.), Hollestelle, A. (Antoinette), Hoover, R. N. (Robert N.), Hopper, J. L. (John L.), Hulick, P. J. (Peter J.), Humphreys, K. (Keith), Imyanitov, E. N. (Evgeny N.), Isaacs, C. (Claudine), Jakimovska, M. (Milena), Jakubowska, A. (Anna), James, P. A. (Paul A.), Janavicius, R. (Ramunas), Jankowitz, R. C. (Rachel C.), John, E. M. (Esther M.), Johnson, N. (Nichola), Joseph, V. (Vijai), Karlan, B. Y. (Beth Y.), Khusnutdinova, E. (Elza), Kiiski, J. I. (Johanna, I), Ko, Y.-D. (Yon-Dschun), Jones, M. E. (Michael E.), Konstantopoulou, I. (Irene), Kristensen, V. N. (Vessela N.), Laitman, Y. (Yael), Lambrechts, D. (Diether), Lazaro, C. (Conxi), Leslie, G. (Goska), Lester, J. (Jenny), Lesueur, F. (Fabienne), Lindstrom, S. (Sara), Long, J. (Jirong), Loud, J. T. (Jennifer T.), Lubinski, J. (Jan), Makalic, E. (Enes), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Margolin, S. (Sara), Maurer, T. (Tabea), Mavroudis, D. (Dimitrios), McGuffog, L. (Lesley), Meindl, A. (Alfons), Menon, U. (Usha), Michailidou, K. (Kyriaki), Miller, A. (Austin), Montagna, M. (Marco), Moreno, F. (Fernando), Moserle, L. (Lidia), Mulligan, A. M. (Anna Marie), Nathanson, K. L. (Katherine L.), Neuhausen, S. L. (Susan L.), Nevanlinna, H. (Heli), Nevelsteen, I. (Ines), Nielsen, F. C. (Finn C.), Nikitina-Zake, L. (Liene), Nussbaum, R. L. (Robert L.), Offit, K. (Kenneth), Olah, E. (Edith), Olopade, O. I. (Olufunmilayo, I), Olsson, H. (Hakan), Osorio, A. (Ana), Papp, J. (Janos), Park-Simon, T.-W. (Tjoung-Won), Parsons, M. T. (Michael T.), Pedersen, I. S. (Inge Sokilde), Peixoto, A. (Ana), Peterlongo, P. (Paolo), Pharoah, P. D. (Paul D. P.), Plaseska-Karanfilska, D. (Dijana), Poppe, B. (Bruce), Presneau, N. (Nadege), Radice, P. (Paolo), Rantala, J. (Johanna), Rennert, G. (Gad), Risch, H. A. (Harvey A.), Saloustros, E. (Emmanouil), Sanden, K. (Kristin), Sawyer, E. J. (Elinor J.), Schmidt, M. K. (Marjanka K.), Schmutzler, R. K. (Rita K.), Sharma, P. (Priyanka), Shu, X.-O. (Xiao-Ou), Simard, J. (Jacques), Singer, C. F. (Christian F.), Soucy, P. (Penny), Southey, M. C. (Melissa C.), Spinelli, J. J. (John J.), Spurdle, A. B. (Amanda B.), Stone, J. (Jennifer), Swerdlow, A. J. (Anthony J.), Tapper, W. J. (William J.), Taylor, J. A. (Jack A.), Teixeira, M. R. (Manuel R.), Terry, M. B. (Mary Beth), Teule, A. (Alex), Thomassen, M. (Mads), Thoene, K. (Kathrin), Thull, D. L. (Darcy L.), Tischkowitz, M. (Marc), Toland, A. E. (Amanda E.), Torres, D. (Diana), Truong, T. (Therese), Tung, N. (Nadine), Vachon, C. M. (Celine M.), van Asperen, C. J. (Christi J.), van den Ouweland, A. M. (Ans M. W.), van Rensburg, E. J. (Elizabeth J.), Vega, A. (Ana), Viel, A. (Alessandra), Wang, Q. (Qin), Wappenschmidt, B. (Barbara), Weitzel, J. N. (Jeffrey N.), Wendt, C. (Camilla), Winqvist, R. (Robert), Yang, X. R. (Xiaohong R.), Yannoukakos, D. (Drakoulis), Ziogas, A. (Argyrios), Kraft, P. (Peter), Antoniou, A. C. (Antonis C.), Zheng, W. (Wei), Easton, D. F. (Douglas F.), Milne, R. L. (Roger L.), Beesley, J. (Jonathan), Chenevix-Trench, G. (Georgia), Arnold, N. (Norbert), Auber, B. (Bernd), Bogdanova-Markov, N. (Nadja), Borde, J. (Julika), Caliebe, A. (Almuth), Ditsch, N. (Nina), Dworniczak, B. (Bernd), Engert, S. (Stefanie), Faust, U. (Ulrike), Gehrig, A. (Andrea), Hahnen, E. (Eric), Hauke, J. (Jan), Hentschel, J. (Julia), Herold, N. (Natalie), Honisch, E. (Ellen), Just, W. (Walter), Kast, K. (Karin), Larsen, M. (Mirjam), Lemke, J. (Johannes), . (), Niederacher, D. (Dieter), Ott, C.-E. (Claus-Eric), Platzer, K. (Konrad), Pohl-Rescigno, E. (Esther), Ramser, J. (Juliane), Rhiem, K. (Kerstin), Steinemann, D. (Doris), Sutter, C. (Christian), Varon-Mateeva, R. (Raymonda), Wang-Gohrke, S. (Shan), Weber, B. H. (Bernhard H. F.), Prieur, F. (Fabienne), Pujol, P. (Pascal), Sagne, C. (Charlotte), Sevenet, N. (Nicolas), Sobol, H. (Hagay), Sokolowska, J. (Johanna), Stoppa-Lyonnet, D. (Dominique), Venat-Bouvet, L. (Laurence), Adlard, J. (Julian), Ahmed, M. (Munaza), Barwell, J. (Julian), Brady, A. (Angela), Brewer, C. (Carole), Cook, J. (Jackie), Davidson, R. (Rosemarie), Donaldson, A. (Alan), Eason, J. (Jacqueline), Eeles, R. (Ros), Evans, D. G. (D. Gareth), Gregory, H. (Helen), Hanson, H. (Helen), Henderson, A. (Alex), Hodgson, S. (Shirley), Izatt, L. (Louise), Kennedy, M. J. (M. John), Lalloo, F. (Fiona), Miller, C. (Clare), Morrison, P. J. (Patrick J.), Ong, K.-r. (Kai-ren), Perkins, J. (Jo), Porteous, M. E. (Mary E.), Rogers, M. T. (Mark T.), Side, L. E. (Lucy E.), Snape, K. (Katie), Walker, L. (Lisa), Harrington, P. A. (Patricia A.), Heemskerk-Gerritsen, B. A. (Bernadette A. M.), Rookus, M. A. (Matti A.), Seynaeve, C. M. (Caroline M.), van der Baan, F. H. (Frederieke H.), van der Hout, A. H. (Annemieke H.), van der Kolk, L. E. (Lizet E.), van der Luijt, R. B. (Rob B.), van Deurzen, C. H. (Carolien H. M.), van Doorn, H. C. (Helena C.), van Engelen, K. (Klaartje), van Hest, L. (Liselotte), van Os, T. A. (Theo A. M.), Verhoef, S. (Senno), Vogel, M. J. (Maartje J.), Wijnen, J. T. (Juul T.), Miron, A. (Alexander), Kapuscinski, M. (Miroslav), Bane, A. (Anita), Ross, E. (Eric), Buys, S. S. (Saundra S.), Conner, T. A. (Thomas A.), Balleine, R. (Rosemary), Baxter, R. (Robert), Braye, S. (Stephen), Carpenter, J. (Jane), Dahlstrom, J. (Jane), Forbes, J. (John), Lee, S. C. (Soon C.), Marsh, D. (Deborah), Morey, A. (Adrienne), Pathmanathan, N. (Nirmala), Simpson, P. (Peter), Spigelman, A. (Allan), Wilcken, N. (Nicholas), and Yip, D. (Desmond)

Abstract

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.

Published
2019

33. Abstract P1-15-04: Breast cancer recurrence and predictors for recurrence despite pathologic complete response following neoadjuvant chemotherapy

Author

Borremans, K, primary, Berteloot, P, additional, Van Nieuwenhuysen, E, additional, Han, S, additional, Hoste, G, additional, Wildiers, H, additional, Punie, K, additional, Smeets, A, additional, Nevelsteen, I, additional, Floris, G, additional, Van Ongeval, C, additional, Keupers, M, additional, Prevos, R, additional, Van Limbergen, E, additional, Menten, J, additional, Weltens, C, additional, Janssen, H, additional, Vergote, I, additional, and Neven, P, additional

Published
2019
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34. Abstract P4-02-07: Comparison of breast cancer molecular subtyping by Immunohistochemistry and by BluePrint® next generation RNA sequencing-based test at University Hospitals Leuven and Curie Institute Paris

Author

Darrigues, L, primary, Slembrouck, L, additional, Mittempergher, L, additional, Delahaye, LJ, additional, Vanden Bempt, I, additional, Vander Borght, S, additional, Vliegen, L, additional, Sintubin, P, additional, Raynal, V, additional, Bohec, M, additional, Reyes, C, additional, Rapinat, A, additional, Helsmoortel, C, additional, Jongen, L, additional, Hoste, G, additional, Neven, P, additional, Wildiers, H, additional, Smeets, A, additional, Nevelsteen, I, additional, Punie, K, additional, Van Nieuwenhuysen, E, additional, Han, S, additional, Laurent, C, additional, Vincent-Salomon, A, additional, Laas-Faron, E, additional, Witteveen, AT, additional, Neijenhuis, S, additional, Glas, AM, additional, Floris, G, additional, and Reyal, F, additional

Published
2019
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35. Abstract P3-08-20: Clinical next-generation sequencing analysis in ER-positive HER2-negative metastatic breast cancer patients: Mutation frequency & clinical correlations

Author

Goyens, J, primary, Punie, K, additional, Wildiers, H, additional, Smeets, A, additional, Vander Borght, S, additional, Floris, G, additional, Vergote, I, additional, Van Nieuwenhuysen, E, additional, Han, S, additional, Nevelsteen, I, additional, Neven, P, additional, and Vanden Bempt, I, additional

Published
2019
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37. Abstract P5-09-05: Hereditary breast cancer beyond BRCA: Clinical and histopathological characteristics in patients with germline CHEK2, ATM, PALB2 and TP53-mutations

Author

Hoste, G, primary, D'Hoore, P, additional, Legius, E, additional, Van Buggenhout, G, additional, Floris, G, additional, Wildiers, H, additional, Han, SN, additional, Van Nieuwenhuysen, E, additional, Berteloot, P, additional, Smeets, A, additional, Nevelsteen, I, additional, Weltens, C, additional, Janssen, H, additional, Van Limbergen, E, additional, Neven, P, additional, and Punie, K, additional

Published
2019
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38. Abstract P3-03-32: Monocentric experience with the sentinel lymph node biopsy prior to neoadjuvant chemotherapy in clinically lymph node negative early breast cancer

Author

Delameilleure, M, primary, Smeets, A, additional, Nevelsteen, I, additional, Han, S, additional, Van Nieuwenhuysen, E, additional, Berteloot, P, additional, Hoste, G, additional, Salihi, R, additional, Van Ongeval, C, additional, Keupers, M, additional, Prevos, R, additional, Wildiers, H, additional, Punie, K, additional, Van Limbergen, E, additional, Weltens, C, additional, Janssen, H, additional, Floris, G, additional, Vergote, I, additional, and Neven, P, additional

Published
2019
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39. Abstract P4-08-25: Decentralized beta testing of MammaPrint and BluePrint NGS kit at University Hospitals Leuven and Curie Institute Paris

Author

Slembrouck, L, primary, Laurent, C, additional, Delahaye, LJ, additional, Mittempergher, L, additional, Vanden Bempt, I, additional, Vander Borght, S, additional, Darrigues, L, additional, Vliegen, L, additional, Sintubin, P, additional, Raynal, V, additional, Bohec, M, additional, Reyes, C, additional, Rapinat, A, additional, Helsmoortel, C, additional, Jongen, L, additional, Hoste, G, additional, Neven, P, additional, Wildiers, H, additional, Smeets, A, additional, Nevelsteen, I, additional, Punie, K, additional, Van Nieuwenhuysen, E, additional, Han, S, additional, Salomon, AV, additional, Faron, EL, additional, Cynober, T, additional, Witteveen, AT, additional, Neijenhuis, S, additional, Glas, AM, additional, Reyal, F, additional, and Floris, G, additional

Published
2019
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41. Genetic testing for breast cancer: Optimizing care for patients and their healthcare workers Development of a theoretical framework

Author

Vandezande, L., primary, Reymen, M., additional, Coppens, L., additional, Plasschaert, E., additional, Skevee, A., additional, Cusumano, P., additional, Leunen, K., additional, Vanhoudt, R., additional, Bossuyt, H., additional, Dehasque, E., additional, Christiaens, M.R., additional, Legius, E., additional, and Nevelsteen, I., additional

Published
2018
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43. Efficacy of CDK 4/6 inhibition after fulvestrant in metastatic breast cancer

Author

Hoste, G., primary, Punie, K., additional, Wildiers, H., additional, Neven, P., additional, Vergote, I., additional, Beuselinck, B., additional, Concin, N., additional, Han, S., additional, Van Nieuwenhuysen, E., additional, Salihi, R., additional, Smeets, A., additional, Berteloot, P., additional, Lefever, I., additional, Nevelsteen, I., additional, Van Limbergen, E., additional, Weltens, C., additional, and Janssen, H., additional

Published
2018
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45. Breast cancer subtype and survival by parity and time since last birth

Author

De Mulder, H., primary, Laenen, A., additional, Wildiers, H., additional, Punie, K., additional, Poppe, A., additional, Remmerie, C., additional, Lefrère, H., additional, Nevelsteen, I., additional, Smeets, A., additional, Van Nieuwenhuysen, E., additional, Han, S., additional, Van Limbergen, E., additional, Floris, G., additional, Vergote, I., additional, and Neven, P., additional

Published
2018
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48. Abstract P6-09-32: The association of breast cancer subtype and breast cancer survival with parity and time since last birth

Author

De Mulder, H, primary, Laenen, A, additional, Wildiers, H, additional, Punie, K, additional, Poppe, A, additional, Remmerie, C, additional, Nevelsteen, I, additional, Smeets, A, additional, Van Nieuwenhuysen, E, additional, Van Limbergen, E, additional, Floris, G, additional, Vergote, I, additional, and Neven, P, additional

Published
2017
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50. SNP-SNP interaction analysis of NF-kappa B signaling pathway on breast cancer survival

Author

Jamshidi, M., Fagerholm, R., Khan, S., Aittomaki, K., Czene, K., Darabi, H., Li, J.M., Andrulis, I.L., Chang-Claude, J., Devilee, P., Fasching, P.A., Michailidou, K., Bolla, M.K., Dennis, J., Wang, Q., Guo, Q., Rhenius, V., Cornelissen, S., Rudolph, A., Knight, J.A., Loehberg, C.R., Burwinkel, B., Marme, F., Hopper, J.L., Southey, M.C., Bojesen, S.E., Flyger, H., Brenner, H., Holleczek, B., Margolin, S., Mannermaa, A., Kosma, V.M., Dyck, L. van, Nevelsteen, I., Couch, F.J., Olson, J.E., Giles, G.G., McLean, C., Haiman, C.A., Henderson, B.E., Winqvist, R., Pylkas, K., Tollenaar, R.A.E.M., Garcia-Closas, M., Figueroa, J., Hooning, M.J., Martens, J.W.M., Cox, A., Cross, S.S., Simard, J., Dunning, A.M., Easton, D.F., Pharoah, P.D.P., Hall, P., Blomqvist, C., Schmidt, M.K., Nevanlinna, H., kConFab Investigators, Department of Obstetrics and Gynecology, Clinicum, Medicum, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, and Department of Oncology

Subjects
Oncology, medicine.medical_specialty, GENES, In silico, 3122 Cancers, Single-nucleotide polymorphism, Breast Neoplasms, Biology, Bioinformatics, ANNOTATION, Polymorphism, Single Nucleotide, survival analysis, ACTIVATION, Breast cancer, breast cancer, 3123 Gynaecology and paediatrics, Internal medicine, Genetic variation, medicine, Biomarkers, Tumor, SNP, Humans, Neoplasm Invasiveness, TRANSCRIPTION, Allele, Survival rate, Survival analysis, POLYMORPHISMS, Neoplasm Staging, NF-κB pathway, IDENTIFICATION, NF-kappa B, NF-kappa B pathway, CHEMOTHERAPY, medicine.disease, Prognosis, 3. Good health, FALSE DISCOVERY RATE, Survival Rate, SNP-SNP interaction, CELLS, Female, Neoplasm Grading, Research Paper, Signal Transduction
Abstract

In breast cancer, constitutive activation of NF-κB has been reported, however, the impact of genetic variation of the pathway on patient prognosis has been little studied. Furthermore, a combination of genetic variants, rather than single polymorphisms, may affect disease prognosis. Here, in an extensive dataset (n = 30,431) from the Breast Cancer Association Consortium, we investigated the association of 917 SNPs in 75 genes in the NF-κB pathway with breast cancer prognosis. We explored SNP-SNP interactions on survival using the likelihood-ratio test comparing multivariate Cox’ egression models of SNP pairs without and with an interaction term. We found two interacting pairs associating with prognosis: patients simultaneously homozygous for the rare alleles of rs5996080 and rs7973914 had worse survival (HRinteraction 6.98, 95% CI=3.3-14.4, P=1.42E-07), and patients carrying at least one rare allele for rs17243893 and rs57890595 had better survival (HRinteraction 0.51, 95% CI=0.3-0.6, P = 2.19E-05). Based on in silico functional analyses and literature, we speculate that the rs5996080 and rs7973914 loci may affect the BAFFR and TNFR1/TNFR3 receptors and breast cancer survival, possibly by disturbing both the canonical and non-canonical NF-κB pathways or their dynamics, whereas, rs17243893-rs57890595 interaction on survival may be mediated through TRAF2-TRAIL-R4 interplay. These results warrant further validation and functional analyses. ispartof: Oncotarget vol:6 issue:35 pages:37979-94 ispartof: location:United States status: published

Published
2015

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