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1. Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer

Author

Kho, P-F, Amant, F, Annibali, D, Ashton, K, Attia, J, Auer, PL, Beckmann, MW, Black, A, Brinton, L, Buchanan, DD, Chen, C, Chen, MM, Cheng, THT, Cook, LS, Crous-Bous, M, Czene, K, De Vivo, I, Dennis, J, Dörk, T, Dowdy, SC, Dunning, AM, Dürst, M, Easton, DF, Ekici, AB, Fasching, PA, Fridley, BL, Friedenreich, CM, García-Closas, M, Gaudet, MM, Giles, GG, Goode, EL, Gorman, M, Haiman, CA, Hall, P, Hankison, SE, Hein, A, Hillemanns, P, Hodgson, S, Hoivik, EA, Holliday, EG, Hunter, DJ, Jones, A, Kraft, P, Krakstad, C, Lambrechts, D, Le Marchand, L, Liang, X, Lindblom, A, Lissowska, J, Long, J, Lu, L, Magliocco, AM, Martin, L, McEvoy, M, Milne, RL, Mints, M, Nassir, R, Otton, G, Palles, C, Pooler, L, Proietto, T, Rebbeck, TR, Renner, SP, Risch, HA, Rübner, M, Runnebaum, I, Sacerdote, C, Sarto, GE, Schumacher, F, Scott, RJ, Setiawan, VW, Shah, M, Sheng, X, Shu, X-O, Southey, MC, Tham, E, Tomlinson, I, Trovik, J, Turman, C, Tyrer, JP, Van Den Berg, D, Wang, Z, Wentzensen, N, Xia, L, Xiang, Y-B, Yang, HP, Yu, H, Zheng, W, Webb, PM, Thompson, DJ, Spurdle, AB, Glubb, DM, and O'Mara, TA

Subjects
lipids (amino acids, peptides, and proteins)
Abstract

Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two‐sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low‐density lipoprotein [LDL] and high‐density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels (P

Published
2020

2. Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer.

Author

Hodgson S., De Vivo I., Dennis J., Dork T., Dowdy S.C., Dunning A.M., Durst M., Easton D.F., Ekici A.B., Fasching P.A., Fridley B.L., Friedenreich C.M., Garcia-Closas M., Gaudet M.M., Giles G.G., Goode E.L., Gorman M., Haiman C.A., Hall P., Hankinson S.E., Hein A., Hillemanns P., Hoivik E.A., Holliday E.G., Hunter D.J., Kraft P., Krakstad C., Lambrechts D., Le Marchand L., Liang X., Lindblom A., Lissowska J., Long J., Lu L., Magliocco A.M., Martin L., McEvoy M., Milne R.L., Mints M., Nassir R., Otton G., Palles C., Pooler L., Proietto T., Rebbeck T.R., Renner S.P., Risch H.A., Rubner M., Runnebaum I., Sacerdote C., Sarto G.E., Schumacher F., Scott R.J., Setiawan V.W., Shah M., Sheng X., Shu X.-O., Southey M.C., Tham E., Tomlinson I., Trovik J., Turman C., Tyrer J.P., Van Den Berg D., Wang Z., Wentzensen N., Xia L., Xiang Y.-B., Yang H.P., Yu H., Zheng W., Webb P.M., Thompson D.J., Spurdle A.B., Glubb D.M., O'Mara T.A., Chen C., Jones A., Kho P.-F., Amant F., Annibali D., Ashton K., Attia J., Auer P.L., Beckmann M.W., Black A., Brinton L., Buchanan D.D., Chanock S.J., Chen M.M., Cheng T.H.T., Cook L.S., Crous-Bous M., Czene K., Hodgson S., De Vivo I., Dennis J., Dork T., Dowdy S.C., Dunning A.M., Durst M., Easton D.F., Ekici A.B., Fasching P.A., Fridley B.L., Friedenreich C.M., Garcia-Closas M., Gaudet M.M., Giles G.G., Goode E.L., Gorman M., Haiman C.A., Hall P., Hankinson S.E., Hein A., Hillemanns P., Hoivik E.A., Holliday E.G., Hunter D.J., Kraft P., Krakstad C., Lambrechts D., Le Marchand L., Liang X., Lindblom A., Lissowska J., Long J., Lu L., Magliocco A.M., Martin L., McEvoy M., Milne R.L., Mints M., Nassir R., Otton G., Palles C., Pooler L., Proietto T., Rebbeck T.R., Renner S.P., Risch H.A., Rubner M., Runnebaum I., Sacerdote C., Sarto G.E., Schumacher F., Scott R.J., Setiawan V.W., Shah M., Sheng X., Shu X.-O., Southey M.C., Tham E., Tomlinson I., Trovik J., Turman C., Tyrer J.P., Van Den Berg D., Wang Z., Wentzensen N., Xia L., Xiang Y.-B., Yang H.P., Yu H., Zheng W., Webb P.M., Thompson D.J., Spurdle A.B., Glubb D.M., O'Mara T.A., Chen C., Jones A., Kho P.-F., Amant F., Annibali D., Ashton K., Attia J., Auer P.L., Beckmann M.W., Black A., Brinton L., Buchanan D.D., Chanock S.J., Chen M.M., Cheng T.H.T., Cook L.S., Crous-Bous M., and Czene K.

Abstract

Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two-sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels (P < 5 x 10-8) were identified as instrumental variables, and assessed using genome-wide association study data from the Endometrial Cancer Association Consortium (12 906 cases and 108 979 controls) and the Global Lipids Genetic Consortium (n = 188 578). Mendelian randomization analyses found genetically raised LDL cholesterol levels to be associated with lower risks of endometrial cancer of all histologies combined, and of endometrioid and non-endometrioid subtypes. Conversely, higher genetically predicted HDL cholesterol levels were associated with increased risk of non-endometrioid endometrial cancer. After accounting for the potential confounding role of obesity (as measured by genetic variants associated with body mass index), the association between genetically predicted increased LDL cholesterol levels and lower endometrial cancer risk remained significant, especially for non-endometrioid endometrial cancer. There was no evidence to support a role for triglycerides in endometrial cancer development. Our study supports a role for LDL and HDL cholesterol in the development of non-endometrioid endometrial cancer. Further studies are required to understand the mechanisms underlying these findings.Copyright © 2020 Union for International Cancer Control

Published
2021

3. Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer

Author

Kho, P-F, Amant, F, Annibali, D, Ashton, K, Attia, J, Auer, PL, Beckmann, MW, Black, A, Brinton, L, Buchanan, DD, Chanock, SJ, Chen, C, Chen, MM, Cheng, THT, Cook, LS, Crous-Bous, M, Czene, K, De Vivo, I, Dennis, J, Doerk, T, Dowdy, SC, Dunning, AM, Duerst, M, Easton, DF, Ekici, AB, Fasching, PA, Fridley, BL, Friedenreich, CM, Garcia-Closas, M, Gaudet, MM, Giles, GG, Goode, EL, Gorman, M, Haiman, CA, Hall, P, Hankinson, SE, Hein, A, Hillemanns, P, Hodgson, S, Hoivik, EA, Holliday, EG, Hunter, DJ, Jones, A, Kraft, P, Krakstad, C, Lambrechts, D, Le Marchand, L, Liang, X, Lindblom, A, Lissowska, J, Long, J, Lu, L, Magliocco, AM, Martin, L, McEvoy, M, Milne, RL, Mints, M, Nassir, R, Otton, G, Palles, C, Pooler, L, Proietto, T, Rebbeck, TR, Renner, SP, Risch, HA, Ruebner, M, Runnebaum, I, Sacerdote, C, Sarto, GE, Schumacher, F, Scott, RJ, Setiawan, VW, Shah, M, Sheng, X, Shu, X-O, Southey, MC, Tham, E, Tomlinson, I, Trovik, J, Turman, C, Tyrer, JP, van den Berg, D, Wang, Z, Wentzensen, N, Xia, L, Xiang, Y-B, Yang, HP, Yu, H, Zheng, W, Webb, PM, Thompson, DJ, Spurdle, AB, Glubb, DM, O'Mara, TA, Kho, P-F, Amant, F, Annibali, D, Ashton, K, Attia, J, Auer, PL, Beckmann, MW, Black, A, Brinton, L, Buchanan, DD, Chanock, SJ, Chen, C, Chen, MM, Cheng, THT, Cook, LS, Crous-Bous, M, Czene, K, De Vivo, I, Dennis, J, Doerk, T, Dowdy, SC, Dunning, AM, Duerst, M, Easton, DF, Ekici, AB, Fasching, PA, Fridley, BL, Friedenreich, CM, Garcia-Closas, M, Gaudet, MM, Giles, GG, Goode, EL, Gorman, M, Haiman, CA, Hall, P, Hankinson, SE, Hein, A, Hillemanns, P, Hodgson, S, Hoivik, EA, Holliday, EG, Hunter, DJ, Jones, A, Kraft, P, Krakstad, C, Lambrechts, D, Le Marchand, L, Liang, X, Lindblom, A, Lissowska, J, Long, J, Lu, L, Magliocco, AM, Martin, L, McEvoy, M, Milne, RL, Mints, M, Nassir, R, Otton, G, Palles, C, Pooler, L, Proietto, T, Rebbeck, TR, Renner, SP, Risch, HA, Ruebner, M, Runnebaum, I, Sacerdote, C, Sarto, GE, Schumacher, F, Scott, RJ, Setiawan, VW, Shah, M, Sheng, X, Shu, X-O, Southey, MC, Tham, E, Tomlinson, I, Trovik, J, Turman, C, Tyrer, JP, van den Berg, D, Wang, Z, Wentzensen, N, Xia, L, Xiang, Y-B, Yang, HP, Yu, H, Zheng, W, Webb, PM, Thompson, DJ, Spurdle, AB, Glubb, DM, and O'Mara, TA

Abstract

Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two-sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels (P < 5 × 10-8 ) were identified as instrumental variables, and assessed using genome-wide association study data from the Endometrial Cancer Association Consortium (12 906 cases and 108 979 controls) and the Global Lipids Genetic Consortium (n = 188 578). Mendelian randomization analyses found genetically raised LDL cholesterol levels to be associated with lower risks of endometrial cancer of all histologies combined, and of endometrioid and non-endometrioid subtypes. Conversely, higher genetically predicted HDL cholesterol levels were associated with increased risk of non-endometrioid endometrial cancer. After accounting for the potential confounding role of obesity (as measured by genetic variants associated with body mass index), the association between genetically predicted increased LDL cholesterol levels and lower endometrial cancer risk remained significant, especially for non-endometrioid endometrial cancer. There was no evidence to support a role for triglycerides in endometrial cancer development. Our study supports a role for LDL and HDL cholesterol in the development of non-endometrioid endometrial cancer. Further studies are required to understand the mechanisms underlying these findings.

Published
2021

4. Identification of nine new susceptibility loci for endometrial cancer.

Author

Fung J., Chanock S.J., Chen C., Chen M.M., Ashton K., Milne R.L., Mints M., Montgomery G.W., Nassir R., Olsson H., Orlow I., Otton G., Palles C., Perry J.R.B., Peto J., Pooler L., Prescott J., Proietto T., Rebbeck T.R., Risch H.A., Rogers P.A.W., Rubner M., Runnebaum I., Sacerdote C., Sarto G.E., Schumacher F., Scott R.J., Setiawan V.W., Shah M., Sheng X., Shu X.-O., Southey M.C., Swerdlow A.J., Tham E., Trovik J., Turman C., Tyrer J.P., Vachon C., VanDen Berg D., Vanderstichele A., Wang Z., Webb P.M., Wentzensen N., Werner H.M.J., Winham S.J., Wolk A., Xia L., Xiang Y.-B., Yang H.P., Yu H., Zheng W., Pharoah P.D.P., Dunning A.M., Kraft P., De Vivo I., Tomlinson I., Easton D.F., Spurdle A.B., Thompson D.J., Jones A., O'Mara T.A., Glubb D.M., Amant F., Annibali D., Attia J., Auer P.L., Beckmann M.W., Black A., Bolla M.K., Brauch H., Brenner H., Brinton L., Buchanan D.D., Burwinkel B., Cheng T.H.T., Clarke C.L., Clendenning M., Cook L.S., Couch F.J., Cox A., Crous-Bous M., Czene K., Day F., Dennis J., Depreeuw J., Doherty J.A., Dork T., Dowdy S.C., Durst M., Ekici A.B., Fasching P.A., Fridley B.L., Friedenreich C.M., Fritschi L., Chang-Claude J., Garcia-Closas M., Gaudet M.M., Giles G.G., Goode E.L., Gorman M., Haiman C.A., Hall P., Hankison S.E., Healey C.S., Hein A., Hillemanns P., Hodgson S., Hoivik E.A., Holliday E.G., Hopper J.L., Hunter D.J., Krakstad C., Kristensen V.N., Lambrechts D., Marchand L.L., Liang X., Lindblom A., Lissowska J., Long J., Lu L., Magliocco A.M., Martin L., McEvoy M., Meindl A., Michailidou K., Fung J., Chanock S.J., Chen C., Chen M.M., Ashton K., Milne R.L., Mints M., Montgomery G.W., Nassir R., Olsson H., Orlow I., Otton G., Palles C., Perry J.R.B., Peto J., Pooler L., Prescott J., Proietto T., Rebbeck T.R., Risch H.A., Rogers P.A.W., Rubner M., Runnebaum I., Sacerdote C., Sarto G.E., Schumacher F., Scott R.J., Setiawan V.W., Shah M., Sheng X., Shu X.-O., Southey M.C., Swerdlow A.J., Tham E., Trovik J., Turman C., Tyrer J.P., Vachon C., VanDen Berg D., Vanderstichele A., Wang Z., Webb P.M., Wentzensen N., Werner H.M.J., Winham S.J., Wolk A., Xia L., Xiang Y.-B., Yang H.P., Yu H., Zheng W., Pharoah P.D.P., Dunning A.M., Kraft P., De Vivo I., Tomlinson I., Easton D.F., Spurdle A.B., Thompson D.J., Jones A., O'Mara T.A., Glubb D.M., Amant F., Annibali D., Attia J., Auer P.L., Beckmann M.W., Black A., Bolla M.K., Brauch H., Brenner H., Brinton L., Buchanan D.D., Burwinkel B., Cheng T.H.T., Clarke C.L., Clendenning M., Cook L.S., Couch F.J., Cox A., Crous-Bous M., Czene K., Day F., Dennis J., Depreeuw J., Doherty J.A., Dork T., Dowdy S.C., Durst M., Ekici A.B., Fasching P.A., Fridley B.L., Friedenreich C.M., Fritschi L., Chang-Claude J., Garcia-Closas M., Gaudet M.M., Giles G.G., Goode E.L., Gorman M., Haiman C.A., Hall P., Hankison S.E., Healey C.S., Hein A., Hillemanns P., Hodgson S., Hoivik E.A., Holliday E.G., Hopper J.L., Hunter D.J., Krakstad C., Kristensen V.N., Lambrechts D., Marchand L.L., Liang X., Lindblom A., Lissowska J., Long J., Lu L., Magliocco A.M., Martin L., McEvoy M., Meindl A., and Michailidou K.

Abstract

Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes; risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins (SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study.Copyright © 2018, The Author(s).

Published
2018

5. Identification of nine new susceptibility loci for endometrial cancer

Author

O'Mara, TA, Glubb, DM, Amant, F, Annibali, D, Ashton, K, Attia, J, Auer, PL, Beckmann, MW, Black, A, Bolla, MK, Brauch, H, Brenner, H, Brinton, L, Buchanan, DD, Burwinkel, B, Chang-Claude, J, Chanock, SJ, Chen, C, Chen, MM, Cheng, THT, Clarke, CL, Clendenning, M, Cook, LS, Couch, FJ, Cox, A, Crous-Bous, M, Czene, K, Day, F, Dennis, J, Depreeuw, J, Doherty, JA, Dork, T, Dowdy, SC, Duerst, M, Ekici, AB, Fasching, PA, Fridley, BL, Friedenreich, CM, Fritschi, L, Fung, J, Garcia-Closas, M, Gaudet, MM, Giles, GG, Goode, EL, Gorman, M, Haiman, CA, Hall, P, Hankison, SE, Healey, CS, Hein, A, Hillemanns, P, Hodgson, S, Hoivik, EA, Holliday, EG, Hopper, JL, Hunter, DJ, Jones, A, Krakstad, C, Kristensen, VN, Lambrechts, D, Le Marchand, L, Liang, X, Lindblom, A, Lissowska, J, Long, J, Lu, L, Magliocco, AM, Martin, L, McEvoy, M, Meindl, A, Michailidou, K, Milne, RL, Mints, M, Montgomery, GW, Nassir, R, Olsson, H, Orlow, I, Otton, G, Palles, C, Perry, JRB, Peto, J, Pooler, L, Prescott, J, Proietto, T, Rebbeck, TR, Risch, HA, Rogers, PAW, Ruebner, M, Runnebaum, I, Sacerdote, C, Sarto, GE, Schumacher, F, Scott, RJ, Setiawan, VW, Shah, M, Sheng, X, Shu, X-O, Southey, MC, Swerdlow, AJ, Tham, E, Trovik, J, Turman, C, Tyrer, JP, Vachon, C, Vanden Berg, D, Vanderstichele, A, Wang, Z, Webb, PM, Wentzensen, N, Werner, HMJ, Winham, SJ, Wolk, A, Xia, L, Xiang, Y-B, Yang, HP, Yu, H, Zheng, W, Pharoah, PDP, Dunning, AM, Kraft, P, De Vivo, I, Tomlinson, I, Easton, DF, Spurdle, AB, Thompson, DJ, O'Mara, TA, Glubb, DM, Amant, F, Annibali, D, Ashton, K, Attia, J, Auer, PL, Beckmann, MW, Black, A, Bolla, MK, Brauch, H, Brenner, H, Brinton, L, Buchanan, DD, Burwinkel, B, Chang-Claude, J, Chanock, SJ, Chen, C, Chen, MM, Cheng, THT, Clarke, CL, Clendenning, M, Cook, LS, Couch, FJ, Cox, A, Crous-Bous, M, Czene, K, Day, F, Dennis, J, Depreeuw, J, Doherty, JA, Dork, T, Dowdy, SC, Duerst, M, Ekici, AB, Fasching, PA, Fridley, BL, Friedenreich, CM, Fritschi, L, Fung, J, Garcia-Closas, M, Gaudet, MM, Giles, GG, Goode, EL, Gorman, M, Haiman, CA, Hall, P, Hankison, SE, Healey, CS, Hein, A, Hillemanns, P, Hodgson, S, Hoivik, EA, Holliday, EG, Hopper, JL, Hunter, DJ, Jones, A, Krakstad, C, Kristensen, VN, Lambrechts, D, Le Marchand, L, Liang, X, Lindblom, A, Lissowska, J, Long, J, Lu, L, Magliocco, AM, Martin, L, McEvoy, M, Meindl, A, Michailidou, K, Milne, RL, Mints, M, Montgomery, GW, Nassir, R, Olsson, H, Orlow, I, Otton, G, Palles, C, Perry, JRB, Peto, J, Pooler, L, Prescott, J, Proietto, T, Rebbeck, TR, Risch, HA, Rogers, PAW, Ruebner, M, Runnebaum, I, Sacerdote, C, Sarto, GE, Schumacher, F, Scott, RJ, Setiawan, VW, Shah, M, Sheng, X, Shu, X-O, Southey, MC, Swerdlow, AJ, Tham, E, Trovik, J, Turman, C, Tyrer, JP, Vachon, C, Vanden Berg, D, Vanderstichele, A, Wang, Z, Webb, PM, Wentzensen, N, Werner, HMJ, Winham, SJ, Wolk, A, Xia, L, Xiang, Y-B, Yang, HP, Yu, H, Zheng, W, Pharoah, PDP, Dunning, AM, Kraft, P, De Vivo, I, Tomlinson, I, Easton, DF, Spurdle, AB, and Thompson, DJ

Abstract

Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes; risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins (SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study.

Published
2018

6. Identification of nine new susceptibility loci for endometrial cancer

Author

O Mara, T., Glubb, D., Amant, F., Annibali, D., Ashton, K., Attia, J., Auer, P., Beckmann, M., Black, A., Bolla, M., Brauch, H., Brenner, H., Brinton, L., Buchanan, D., Burwinkel, B., Chang-Claude, J., Chanock, S., Chen, C., Chen, M., Cheng, T., Clarke, C., Clendenning, M., Cook, L., Couch, F., Cox, A., Crous-Bous, M., Czene, K., Day, F., Dennis, J., Depreeuw, J., Doherty, J., Dörk, T., Dowdy, S., Dürst, M., Ekici, A., Fasching, P., Fridley, B., Friedenreich, C., Fritschi, Lin, Fung, J., García-Closas, M., Gaudet, M., Giles, G., Goode, E., Gorman, M., Haiman, C., Hall, P., Hankison, S., Healey, C., Hein, A., Hillemanns, P., Hodgson, S., Hoivik, E., Holliday, E., Hopper, J., Hunter, D., Jones, A., Krakstad, C., Kristensen, V., Lambrechts, D., Marchand, L., Liang, X., Lindblom, A., Lissowska, J., Long, J., Lu, L., Magliocco, A., Martin, L., McEvoy, M., O Mara, T., Glubb, D., Amant, F., Annibali, D., Ashton, K., Attia, J., Auer, P., Beckmann, M., Black, A., Bolla, M., Brauch, H., Brenner, H., Brinton, L., Buchanan, D., Burwinkel, B., Chang-Claude, J., Chanock, S., Chen, C., Chen, M., Cheng, T., Clarke, C., Clendenning, M., Cook, L., Couch, F., Cox, A., Crous-Bous, M., Czene, K., Day, F., Dennis, J., Depreeuw, J., Doherty, J., Dörk, T., Dowdy, S., Dürst, M., Ekici, A., Fasching, P., Fridley, B., Friedenreich, C., Fritschi, Lin, Fung, J., García-Closas, M., Gaudet, M., Giles, G., Goode, E., Gorman, M., Haiman, C., Hall, P., Hankison, S., Healey, C., Hein, A., Hillemanns, P., Hodgson, S., Hoivik, E., Holliday, E., Hopper, J., Hunter, D., Jones, A., Krakstad, C., Kristensen, V., Lambrechts, D., Marchand, L., Liang, X., Lindblom, A., Lissowska, J., Long, J., Lu, L., Magliocco, A., Martin, L., and McEvoy, M.

Abstract

Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes; risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins (SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study.

Published
2018

7. Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer.

Author

Kho PF, Amant F, Annibali D, Ashton K, Attia J, Auer PL, Beckmann MW, Black A, Brinton L, Buchanan DD, Chanock SJ, Chen C, Chen MM, Cheng THT, Cook LS, Crous-Bous M, Czene K, De Vivo I, Dennis J, Dörk T, Dowdy SC, Dunning AM, Dürst M, Easton DF, Ekici AB, Fasching PA, Fridley BL, Friedenreich CM, García-Closas M, Gaudet MM, Giles GG, Goode EL, Gorman M, Haiman CA, Hall P, Hankinson SE, Hein A, Hillemanns P, Hodgson S, Hoivik EA, Holliday EG, Hunter DJ, Jones A, Kraft P, Krakstad C, Lambrechts D, Le Marchand L, Liang X, Lindblom A, Lissowska J, Long J, Lu L, Magliocco AM, Martin L, McEvoy M, Milne RL, Mints M, Nassir R, Otton G, Palles C, Pooler L, Proietto T, Rebbeck TR, Renner SP, Risch HA, Rübner M, Runnebaum I, Sacerdote C, Sarto GE, Schumacher F, Scott RJ, Setiawan VW, Shah M, Sheng X, Shu XO, Southey MC, Tham E, Tomlinson I, Trovik J, Turman C, Tyrer JP, Van Den Berg D, Wang Z, Wentzensen N, Xia L, Xiang YB, Yang HP, Yu H, Zheng W, Webb PM, Thompson DJ, Spurdle AB, Glubb DM, and O'Mara TA

Subjects
Case-Control Studies, Cholesterol, HDL genetics, Cholesterol, LDL genetics, Endometrial Neoplasms genetics, Female, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Risk, Triglycerides genetics, Cholesterol, HDL blood, Cholesterol, LDL blood, Endometrial Neoplasms blood, Triglycerides blood
Abstract

Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two-sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels (P < 5 × 10 -8 ) were identified as instrumental variables, and assessed using genome-wide association study data from the Endometrial Cancer Association Consortium (12 906 cases and 108 979 controls) and the Global Lipids Genetic Consortium (n = 188 578). Mendelian randomization analyses found genetically raised LDL cholesterol levels to be associated with lower risks of endometrial cancer of all histologies combined, and of endometrioid and non-endometrioid subtypes. Conversely, higher genetically predicted HDL cholesterol levels were associated with increased risk of non-endometrioid endometrial cancer. After accounting for the potential confounding role of obesity (as measured by genetic variants associated with body mass index), the association between genetically predicted increased LDL cholesterol levels and lower endometrial cancer risk remained significant, especially for non-endometrioid endometrial cancer. There was no evidence to support a role for triglycerides in endometrial cancer development. Our study supports a role for LDL and HDL cholesterol in the development of non-endometrioid endometrial cancer. Further studies are required to understand the mechanisms underlying these findings., (© 2020 Union for International Cancer Control.)

Published
2021
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8. Identification of nine new susceptibility loci for endometrial cancer.

Author

O'Mara TA, Glubb DM, Amant F, Annibali D, Ashton K, Attia J, Auer PL, Beckmann MW, Black A, Bolla MK, Brauch H, Brenner H, Brinton L, Buchanan DD, Burwinkel B, Chang-Claude J, Chanock SJ, Chen C, Chen MM, Cheng THT, Clarke CL, Clendenning M, Cook LS, Couch FJ, Cox A, Crous-Bous M, Czene K, Day F, Dennis J, Depreeuw J, Doherty JA, Dörk T, Dowdy SC, Dürst M, Ekici AB, Fasching PA, Fridley BL, Friedenreich CM, Fritschi L, Fung J, García-Closas M, Gaudet MM, Giles GG, Goode EL, Gorman M, Haiman CA, Hall P, Hankison SE, Healey CS, Hein A, Hillemanns P, Hodgson S, Hoivik EA, Holliday EG, Hopper JL, Hunter DJ, Jones A, Krakstad C, Kristensen VN, Lambrechts D, Marchand LL, Liang X, Lindblom A, Lissowska J, Long J, Lu L, Magliocco AM, Martin L, McEvoy M, Meindl A, Michailidou K, Milne RL, Mints M, Montgomery GW, Nassir R, Olsson H, Orlow I, Otton G, Palles C, Perry JRB, Peto J, Pooler L, Prescott J, Proietto T, Rebbeck TR, Risch HA, Rogers PAW, Rübner M, Runnebaum I, Sacerdote C, Sarto GE, Schumacher F, Scott RJ, Setiawan VW, Shah M, Sheng X, Shu XO, Southey MC, Swerdlow AJ, Tham E, Trovik J, Turman C, Tyrer JP, Vachon C, VanDen Berg D, Vanderstichele A, Wang Z, Webb PM, Wentzensen N, Werner HMJ, Winham SJ, Wolk A, Xia L, Xiang YB, Yang HP, Yu H, Zheng W, Pharoah PDP, Dunning AM, Kraft P, De Vivo I, Tomlinson I, Easton DF, Spurdle AB, and Thompson DJ

Subjects
Alleles, Chromatin chemistry, Female, Gene Frequency, Genome-Wide Association Study, Genotype, Humans, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, Signal Transduction, Biomarkers, Tumor genetics, Endometrial Neoplasms genetics, Genetic Predisposition to Disease
Abstract

Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes; risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins (SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study.

Published
2018
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