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

Author

Kho, Pik Fang, Amant, Frederic, Annibali, Daniela, Ashton, Katie, Attia, John, Auer, Paul L., Beckmann, Matthias W., Black, Amanda, Brinton, Louise, Buchanan, Daniel D., Chanock, Stephen J., Chen, Chu, Chen, Maxine M., Cheng, Timothy H.T., Cook, Linda S., Crous-Bous, Marta, Czene, Kamila, De Vivo, Immaculata, Dennis, Joe, Dörk, Thilo, Dowdy, Sean C., Dunning, Alison M., Dürst, Matthias, Easton, Douglas F., Ekici, Arif B., Fasching, Peter A., Fridley, Brooke L., Friedenreich, Christine M., García-Closas, Montserrat, Gaudet, Mia M., Giles, Graham G., Goode, Ellen L., Gorman, Maggie, Haiman, Christopher A., Hall, Per, Hankinson, Susan E., Hein, Alexander, Hillemanns, Peter, Hodgson, Shirley, Hoivik, Erling A., Holliday, Elizabeth G., Hunter, David J., Jones, Angela M., Kraft, Peter, Krakstad, Camilla, Lambrechts, Diether, Le Marchand, Loic, Liang, Xiaolin, Lindblom, Annika, Lissowska, Jolanta, Long, Jirong, Lu, Lingeng, Magliocco, Anthony M., Martin, Lynn, McEvoy, Mark, Milne, Roger L., Mints, Miriam, Nassir, Rami, Otton, Geoffrey, Palles, Claire, Pooler, Loreall, Proietto, Tony, Rebbeck, Timothy R., Renner, Stefan P., Risch, Harvey A., Rübner, Matthias, Runnebaum, Ingo, Sacerdote, Carlotta, Sarto, Gloria E., Schumacher, Fredrick, Scott, Rodney J., Setiawan, V. Wendy, Shah, Mitul, Sheng, Xin, Shu, Xiao Ou, Southey, Melissa C., Tham, Emma, Tomlinson, Ian, Trovik, Jone, Turman, Constance, Tyrer, Jonathan P., Van Den Berg, David, Wang, Zhaoming, Wentzensen, Nicolas, Xia, Lucy, Xiang, Yong Bing, Yang, Hannah P., Yu, Herbert, Zheng, Wei, Webb, Penelope M., Thompson, Deborah J., Spurdle, Amanda B., Glubb, Dylan M., O'Mara, Tracy A., Kho, Pik Fang, Amant, Frederic, Annibali, Daniela, Ashton, Katie, Attia, John, Auer, Paul L., Beckmann, Matthias W., Black, Amanda, Brinton, Louise, Buchanan, Daniel D., Chanock, Stephen J., Chen, Chu, Chen, Maxine M., Cheng, Timothy H.T., Cook, Linda S., Crous-Bous, Marta, Czene, Kamila, De Vivo, Immaculata, Dennis, Joe, Dörk, Thilo, Dowdy, Sean C., Dunning, Alison M., Dürst, Matthias, Easton, Douglas F., Ekici, Arif B., Fasching, Peter A., Fridley, Brooke L., Friedenreich, Christine M., García-Closas, Montserrat, Gaudet, Mia M., Giles, Graham G., Goode, Ellen L., Gorman, Maggie, Haiman, Christopher A., Hall, Per, Hankinson, Susan E., Hein, Alexander, Hillemanns, Peter, Hodgson, Shirley, Hoivik, Erling A., Holliday, Elizabeth G., Hunter, David J., Jones, Angela M., Kraft, Peter, Krakstad, Camilla, Lambrechts, Diether, Le Marchand, Loic, Liang, Xiaolin, Lindblom, Annika, Lissowska, Jolanta, Long, Jirong, Lu, Lingeng, Magliocco, Anthony M., Martin, Lynn, McEvoy, Mark, Milne, Roger L., Mints, Miriam, Nassir, Rami, Otton, Geoffrey, Palles, Claire, Pooler, Loreall, Proietto, Tony, Rebbeck, Timothy R., Renner, Stefan P., Risch, Harvey A., Rübner, Matthias, Runnebaum, Ingo, Sacerdote, Carlotta, Sarto, Gloria E., Schumacher, Fredrick, Scott, Rodney J., Setiawan, V. Wendy, Shah, Mitul, Sheng, Xin, Shu, Xiao Ou, Southey, Melissa C., Tham, Emma, Tomlinson, Ian, Trovik, Jone, Turman, Constance, Tyrer, Jonathan P., Van Den Berg, David, Wang, Zhaoming, Wentzensen, Nicolas, Xia, Lucy, Xiang, Yong Bing, Yang, Hannah P., Yu, Herbert, Zheng, Wei, Webb, Penelope M., Thompson, Deborah J., Spurdle, Amanda B., Glubb, Dylan M., and O'Mara, Tracy A.

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

8. The clinical and functional effects of TERT variants in myelodysplastic syndrome

Author

Reilly, Christopher R., primary, Myllymäki, Mikko, additional, Redd, Robert, additional, Padmanaban, Shilpa, additional, Karunakaran, Druha, additional, Tesmer, Valerie, additional, Tsai, Frederick D., additional, Gibson, Christopher J., additional, Rana, Huma Q., additional, Zhong, Liang, additional, Saber, Wael, additional, Spellman, Stephen R., additional, Hu, Zhen-Huan, additional, Orr, Esther H., additional, Chen, Maxine M., additional, De Vivo, Immaculata, additional, DeAngelo, Daniel J., additional, Cutler, Corey, additional, Antin, Joseph H., additional, Neuberg, Donna, additional, Garber, Judy E., additional, Nandakumar, Jayakrishnan, additional, Agarwal, Suneet, additional, and Lindsley, R. Coleman, additional

Published
2021
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10. Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer

Author

Kho, Pik‐Fang, primary, Amant, Frederic, additional, Annibali, Daniela, additional, Ashton, Katie, additional, Attia, John, additional, Auer, Paul L., additional, Beckmann, Matthias W., additional, Black, Amanda, additional, Brinton, Louise, additional, Buchanan, Daniel D., additional, Chanock, Stephen J., additional, Chen, Chu, additional, Chen, Maxine M., additional, Cheng, Timothy H. T., additional, Cook, Linda S., additional, Crous‐Bous, Marta, additional, Czene, Kamila, additional, De Vivo, Immaculata, additional, Dennis, Joe, additional, Dörk, Thilo, additional, Dowdy, Sean C., additional, Dunning, Alison M., additional, Dürst, Matthias, additional, Easton, Douglas F., additional, Ekici, Arif B., additional, Fasching, Peter A., additional, Fridley, Brooke L., additional, Friedenreich, Christine M., additional, García‐Closas, Montserrat, additional, Gaudet, Mia M., additional, Giles, Graham G., additional, Goode, Ellen L., additional, Gorman, Maggie, additional, Haiman, Christopher A., additional, Hall, Per, additional, Hankinson, Susan E., additional, Hein, Alexander, additional, Hillemanns, Peter, additional, Hodgson, Shirley, additional, Hoivik, Erling A., additional, Holliday, Elizabeth G., additional, Hunter, David J., additional, Jones, Angela, additional, Kraft, Peter, additional, Krakstad, Camilla, additional, Lambrechts, Diether, additional, Le Marchand, Loic, additional, Liang, Xiaolin, additional, Lindblom, Annika, additional, Lissowska, Jolanta, additional, Long, Jirong, additional, Lu, Lingeng, additional, Magliocco, Anthony M., additional, Martin, Lynn, additional, McEvoy, Mark, additional, Milne, Roger L., additional, Mints, Miriam, additional, Nassir, Rami, additional, Otton, Geoffrey, additional, Palles, Claire, additional, Pooler, Loreall, additional, Proietto, Tony, additional, Rebbeck, Timothy R., additional, Renner, Stefan P., additional, Risch, Harvey A., additional, Rübner, Matthias, additional, Runnebaum, Ingo, additional, Sacerdote, Carlotta, additional, Sarto, Gloria E., additional, Schumacher, Fredrick, additional, Scott, Rodney J., additional, Setiawan, V. Wendy, additional, Shah, Mitul, additional, Sheng, Xin, additional, Shu, Xiao‐Ou, additional, Southey, Melissa C., additional, Tham, Emma, additional, Tomlinson, Ian, additional, Trovik, Jone, additional, Turman, Constance, additional, Tyrer, Jonathan P., additional, Van Den Berg, David, additional, Wang, Zhaoming, additional, Wentzensen, Nicolas, additional, Xia, Lucy, additional, Xiang, Yong‐Bing, additional, Yang, Hannah P., additional, Yu, Herbert, additional, Zheng, Wei, additional, Webb, Penelope M., additional, Thompson, Deborah J., additional, Spurdle, Amanda B., additional, Glubb, Dylan M., additional, and O'Mara, Tracy A., additional

Published
2020
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12. Genetic analyses of gynecological disease identify genetic relationships between uterine fibroids and endometrial cancer, and a novel endometrial cancer genetic risk region at the WNT4 1p36.12 locus.

Author

Kho, Pik Fang, Mortlock, Sally, Endometrial Cancer Association Consortium, Amant, Frederic, Annibali, Daniela, Ashton, Katie, Attia, John, Auer, Paul L., Beckmann, Matthias W., Black, Amanda, Brinton, Louise, Buchanan, Daniel D., Chanock, Stephen J., Chen, Chu, Chen, Maxine M., Cheng, Timothy H. T., Cook, Linda S., Crous-Bous, Marta, Czene, Kamila, and Vivo, Immaculata

Subjects
ENDOMETRIAL cancer, DISEASE risk factors, UTERINE fibroids, GENOME-wide association studies, GENETIC disorders, ENDOMETRIOSIS, UTERINE artery
Abstract

Endometriosis, polycystic ovary syndrome (PCOS) and uterine fibroids have been proposed as endometrial cancer risk factors; however, disentangling their relationships with endometrial cancer is complicated due to shared risk factors and comorbidities. Using genome-wide association study (GWAS) data, we explored the relationships between these non-cancerous gynecological diseases and endometrial cancer risk by assessing genetic correlation, causal relationships and shared risk loci. We found significant genetic correlation between endometrial cancer and PCOS, and uterine fibroids. Adjustment for genetically predicted body mass index (a risk factor for PCOS, uterine fibroids and endometrial cancer) substantially attenuated the genetic correlation between endometrial cancer and PCOS but did not affect the correlation with uterine fibroids. Mendelian randomization analyses suggested a causal relationship between only uterine fibroids and endometrial cancer. Gene-based analyses revealed risk regions shared between endometrial cancer and endometriosis, and uterine fibroids. Multi-trait GWAS analysis of endometrial cancer and the genetically correlated gynecological diseases identified a novel genome-wide significant endometrial cancer risk locus at 1p36.12, which replicated in an independent endometrial cancer dataset. Interrogation of functional genomic data at 1p36.12 revealed biologically relevant genes, including WNT4 which is necessary for the development of the female reproductive system. In summary, our study provides genetic evidence for a causal relationship between uterine fibroids and endometrial cancer. It further provides evidence that the comorbidity of endometrial cancer, PCOS and uterine fibroids may partly be due to shared genetic architecture. Notably, this shared architecture has revealed a novel genome-wide risk locus for endometrial cancer. [ABSTRACT FROM AUTHOR]

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

Author

O'Mara, Tracy A, Glubb, Dylan M, Amant, Frederic, Annibali, Daniela, Ashton, Katie, Attia, John, Auer, Paul L, Beckmann, Matthias W, Black, Amanda, Bolla, Manjeet K, Brauch, Hiltrud, Brenner, Hermann, Brinton, Louise, Buchanan, Daniel D, Burwinkel, Barbara, Chang-Claude, Jenny, Chanock, Stephen J, Chen, Chu, Chen, Maxine M, Cheng, Timothy H T, Clarke, Christine L, Clendenning, Mark, Cook, Linda S, Couch, Fergus J, Cox, Angela, Crous-Bous, Marta, Czene, Kamila, Day, Felix, Dennis, Joe, Depreeuw, Jeroen, Doherty, Jennifer Anne, Dörk, Thilo, Dowdy, Sean C, Dürst, Matthias, Ekici, Arif B, Fasching, Peter A, Fridley, Brooke L, Friedenreich, Christine M, Fritschi, Lin, Fung, Jenny, García-Closas, Montserrat, Gaudet, Mia M, Giles, Graham G, Goode, Ellen L, Gorman, Maggie, Haiman, Christopher A, Hall, Per, Hankison, Susan E, Healey, Catherine S, Hein, Alexander, Hillemanns, Peter, Hodgson, Shirley, Hoivik, Erling A, Holliday, Elizabeth G, Hopper, John L, Hunter, David J, Jones, Angela, Krakstad, Camilla, Kristensen, Vessela N, Lambrechts, Diether, Marchand, Loic Le, Liang, Xiaolin, Lindblom, Annika, Lissowska, Jolanta, Long, Jirong, Lu, Lingeng, Magliocco, Anthony M, Martin, Lynn, McEvoy, Mark, Meindl, Alfons, Michailidou, Kyriaki, Milne, Roger L, Mints, Miriam, Montgomery, Grant W, Nassir, Rami, Olsson, Håkan, Orlow, Irene, Otton, Geoffrey, Palles, Claire, Perry, John R B, Peto, Julian, Pooler, Loreall, Prescott, Jennifer, Proietto, Tony, Rebbeck, Timothy R, Risch, Harvey A, Rogers, Peter A W, Rübner, Matthias, Runnebaum, Ingo, Sacerdote, Carlotta, Sarto, Gloria E, Schumacher, Fredrick, Scott, Rodney J, Setiawan, V Wendy, Shah, Mitul, Sheng, Xin, Shu, Xiao-Ou, Southey, Melissa C, Swerdlow, Anthony J, Tham, Emma, Trovik, Jone, Turman, Constance, Tyrer, Jonathan P, Vachon, Celine, VanDen Berg, David, Vanderstichele, Adriaan, Wang, Zhaoming, Webb, Penelope M, Wentzensen, Nicolas, Werner, Henrica M J, Winham, Stacey J, Wolk, Alicja, Xia, Lucy, Xiang, Yong-Bing, Yang, Hannah P, Yu, Herbert, Zheng, Wei, Pharoah, Paul D P, Dunning, Alison M, Kraft, Peter, De Vivo, Immaculata, Tomlinson, Ian, Easton, Douglas F, Spurdle, Amanda B, Thompson, Deborah J, O'Mara, Tracy A, Glubb, Dylan M, Amant, Frederic, Annibali, Daniela, Ashton, Katie, Attia, John, Auer, Paul L, Beckmann, Matthias W, Black, Amanda, Bolla, Manjeet K, Brauch, Hiltrud, Brenner, Hermann, Brinton, Louise, Buchanan, Daniel D, Burwinkel, Barbara, Chang-Claude, Jenny, Chanock, Stephen J, Chen, Chu, Chen, Maxine M, Cheng, Timothy H T, Clarke, Christine L, Clendenning, Mark, Cook, Linda S, Couch, Fergus J, Cox, Angela, Crous-Bous, Marta, Czene, Kamila, Day, Felix, Dennis, Joe, Depreeuw, Jeroen, Doherty, Jennifer Anne, Dörk, Thilo, Dowdy, Sean C, Dürst, Matthias, Ekici, Arif B, Fasching, Peter A, Fridley, Brooke L, Friedenreich, Christine M, Fritschi, Lin, Fung, Jenny, García-Closas, Montserrat, Gaudet, Mia M, Giles, Graham G, Goode, Ellen L, Gorman, Maggie, Haiman, Christopher A, Hall, Per, Hankison, Susan E, Healey, Catherine S, Hein, Alexander, Hillemanns, Peter, Hodgson, Shirley, Hoivik, Erling A, Holliday, Elizabeth G, Hopper, John L, Hunter, David J, Jones, Angela, Krakstad, Camilla, Kristensen, Vessela N, Lambrechts, Diether, Marchand, Loic Le, Liang, Xiaolin, Lindblom, Annika, Lissowska, Jolanta, Long, Jirong, Lu, Lingeng, Magliocco, Anthony M, Martin, Lynn, McEvoy, Mark, Meindl, Alfons, Michailidou, Kyriaki, Milne, Roger L, Mints, Miriam, Montgomery, Grant W, Nassir, Rami, Olsson, Håkan, Orlow, Irene, Otton, Geoffrey, Palles, Claire, Perry, John R B, Peto, Julian, Pooler, Loreall, Prescott, Jennifer, Proietto, Tony, Rebbeck, Timothy R, Risch, Harvey A, Rogers, Peter A W, Rübner, Matthias, Runnebaum, Ingo, Sacerdote, Carlotta, Sarto, Gloria E, Schumacher, Fredrick, Scott, Rodney J, Setiawan, V Wendy, Shah, Mitul, Sheng, Xin, Shu, Xiao-Ou, Southey, Melissa C, Swerdlow, Anthony J, Tham, Emma, Trovik, Jone, Turman, Constance, Tyrer, Jonathan P, Vachon, Celine, VanDen Berg, David, Vanderstichele, Adriaan, Wang, Zhaoming, Webb, Penelope M, Wentzensen, Nicolas, Werner, Henrica M J, Winham, Stacey J, Wolk, Alicja, Xia, Lucy, Xiang, Yong-Bing, Yang, Hannah P, Yu, Herbert, Zheng, Wei, Pharoah, Paul D P, Dunning, Alison M, Kraft, Peter, De Vivo, Immaculata, Tomlinson, Ian, Easton, Douglas F, Spurdle, Amanda B, and Thompson, Deborah J

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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14. The clinical and functional effects of TERTvariants in myelodysplastic syndrome

Author

Reilly, Christopher R., Myllymäki, Mikko, Redd, Robert, Padmanaban, Shilpa, Karunakaran, Druha, Tesmer, Valerie, Tsai, Frederick D., Gibson, Christopher J., Rana, Huma Q., Zhong, Liang, Saber, Wael, Spellman, Stephen R., Hu, Zhen-Huan, Orr, Esther H., Chen, Maxine M., De Vivo, Immaculata, DeAngelo, Daniel J., Cutler, Corey, Antin, Joseph H., Neuberg, Donna, Garber, Judy E., Nandakumar, Jayakrishnan, Agarwal, Suneet, and Lindsley, R. Coleman

Abstract

Germline pathogenic TERTvariants are associated with short telomeres and an increased risk of developing myelodysplastic syndrome (MDS) among patients with a telomere biology disorder. We identified TERTrare variants in 41 of 1514 MDS patients (2.7%) without a clinical diagnosis of a telomere biology disorder who underwent allogeneic transplantation. Patients with a TERTrare variant had shorter telomere length (P< .001) and younger age at MDS diagnosis (52 vs 59 years, P= .03) than patients without a TERTrare variant. In multivariable models, TERTrare variants were associated with inferior overall survival (P= .034) driven by an increased incidence of nonrelapse mortality (NRM; P= .015). Death from a noninfectious pulmonary cause was more frequent among patients with a TERTrare variant. Most variants were missense substitutions and classified as variants of unknown significance. Therefore, we cloned all rare missense variants and quantified their impact on telomere elongation in a cell-based assay. We found that 90% of TERTrare variants had severe or intermediate impairment in their capacity to elongate telomeres. Using a homology model of human TERTbound to the shelterin protein TPP1, we inferred that TERTrare variants disrupt domain-specific functions, including catalysis, protein–RNA interactions, and recruitment to telomeres. Our results indicate that the contribution of TERTrare variants to MDS pathogenesis and NRM risk is underrecognized. Routine screening for TERTrare variants in MDS patients regardless of age or clinical suspicion may identify clinically inapparent telomere biology disorders and improve transplant outcomes through risk-adapted approaches.

Published
2021
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15. Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer.

Author

Kho, Pik‐Fang, Amant, Frederic, Annibali, Daniela, Ashton, Katie, Attia, John, Auer, Paul L., Beckmann, Matthias W., Black, Amanda, Brinton, Louise, Buchanan, Daniel D., Chanock, Stephen J., Chen, Chu, Chen, Maxine M., Cheng, Timothy H. T., Cook, Linda S., Crous‐Bous, Marta, Czene, Kamila, De Vivo, Immaculata, Dennis, Joe, and Dörk, Thilo

Subjects
BLOOD lipids, ENDOMETRIAL cancer, CHOLESTERYL ester transfer protein, DYSLIPIDEMIA, CHOLESTEROL, BODY mass index, HEMATOLOGIC malignancies, HIGH density lipoproteins
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. What's new? Some studies have suggested that serum lipids may correlate with endometrial cancer (EC) risk, but results have been inconsistent. In our study, the authors used genetic markers to predict LDL and HDL cholesterol levels and analyze EC risk. They found that when lower LDL or higher HDL levels were predicted, EC risk was increased. These results support a role for LDL and HDL cholesterol in the development of EC, and lipid levels may represent a risk factor for EC. Further studies are required to assess the biological and clinical significance of these associations. [ABSTRACT FROM AUTHOR]

Published
2021
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16. Telomere Length and Telomerase Complex Mutations Predict Fatal Treatment Toxicity after Stem Cell Transplantation in Patients with Myelodysplastic Syndrome

Author

Myllymaki, Mikko, primary, Redd, Robert A., additional, Cutler, Corey S., additional, Saber, Wael, additional, Hu, Zhen-Huan, additional, Wang, Tao, additional, Spellman, Stephen R., additional, Gibson, Christopher J., additional, Chen, Maxine M, additional, Orr, Esther, additional, Steensma, David P., additional, Antin, Joseph H., additional, De Vivo, Immaculata, additional, Neuberg, Donna S, additional, Agarwal, Suneet, additional, and Lindsley, R. Coleman, additional

Published
2018
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17. Identification of nine new susceptibility loci for endometrial cancer

Author

O’Mara, Tracy A., primary, Glubb, Dylan M., additional, Amant, Frederic, additional, Annibali, Daniela, additional, Ashton, Katie, additional, Attia, John, additional, Auer, Paul L., additional, Beckmann, Matthias W., additional, Black, Amanda, additional, Bolla, Manjeet K., additional, Brauch, Hiltrud, additional, Brenner, Hermann, additional, Brinton, Louise, additional, Buchanan, Daniel D., additional, Burwinkel, Barbara, additional, Chang-Claude, Jenny, additional, Chanock, Stephen J., additional, Chen, Chu, additional, Chen, Maxine M., additional, Cheng, Timothy H. T., additional, Clarke, Christine L., additional, Clendenning, Mark, additional, Cook, Linda S., additional, Couch, Fergus J., additional, Cox, Angela, additional, Crous-Bous, Marta, additional, Czene, Kamila, additional, Day, Felix, additional, Dennis, Joe, additional, Depreeuw, Jeroen, additional, Doherty, Jennifer Anne, additional, Dörk, Thilo, additional, Dowdy, Sean C., additional, Dürst, Matthias, additional, Ekici, Arif B., additional, Fasching, Peter A., additional, Fridley, Brooke L., additional, Friedenreich, Christine M., additional, Fritschi, Lin, additional, Fung, Jenny, additional, García-Closas, Montserrat, additional, Gaudet, Mia M., additional, Giles, Graham G., additional, Goode, Ellen L., additional, Gorman, Maggie, additional, Haiman, Christopher A., additional, Hall, Per, additional, Hankison, Susan E., additional, Healey, Catherine S., additional, Hein, Alexander, additional, Hillemanns, Peter, additional, Hodgson, Shirley, additional, Hoivik, Erling A., additional, Holliday, Elizabeth G., additional, Hopper, John L., additional, Hunter, David J., additional, Jones, Angela, additional, Krakstad, Camilla, additional, Kristensen, Vessela N., additional, Lambrechts, Diether, additional, Marchand, Loic Le, additional, Liang, Xiaolin, additional, Lindblom, Annika, additional, Lissowska, Jolanta, additional, Long, Jirong, additional, Lu, Lingeng, additional, Magliocco, Anthony M., additional, Martin, Lynn, additional, McEvoy, Mark, additional, Meindl, Alfons, additional, Michailidou, Kyriaki, additional, Milne, Roger L., additional, Mints, Miriam, additional, Montgomery, Grant W., additional, Nassir, Rami, additional, Olsson, Håkan, additional, Orlow, Irene, additional, Otton, Geoffrey, additional, Palles, Claire, additional, Perry, John R. B., additional, Peto, Julian, additional, Pooler, Loreall, additional, Prescott, Jennifer, additional, Proietto, Tony, additional, Rebbeck, Timothy R., additional, Risch, Harvey A., additional, Rogers, Peter A. W., additional, Rübner, Matthias, additional, Runnebaum, Ingo, additional, Sacerdote, Carlotta, additional, Sarto, Gloria E., additional, Schumacher, Fredrick, additional, Scott, Rodney J., additional, Setiawan, V. Wendy, additional, Shah, Mitul, additional, Sheng, Xin, additional, Shu, Xiao-Ou, additional, Southey, Melissa C., additional, Swerdlow, Anthony J., additional, Tham, Emma, additional, Trovik, Jone, additional, Turman, Constance, additional, Tyrer, Jonathan P., additional, Vachon, Celine, additional, VanDen Berg, David, additional, Vanderstichele, Adriaan, additional, Wang, Zhaoming, additional, Webb, Penelope M., additional, Wentzensen, Nicolas, additional, Werner, Henrica M. J., additional, Winham, Stacey J., additional, Wolk, Alicja, additional, Xia, Lucy, additional, Xiang, Yong-Bing, additional, Yang, Hannah P., additional, Yu, Herbert, additional, Zheng, Wei, additional, Pharoah, Paul D. P., additional, Dunning, Alison M., additional, Kraft, Peter, additional, De Vivo, Immaculata, additional, Tomlinson, Ian, additional, Easton, Douglas F., additional, Spurdle, Amanda B., additional, and Thompson, Deborah J., additional

Published
2018
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18. GWAS meta-analysis of 16 852 women identifies new susceptibility locus for endometrial cancer

Author

Chen, Maxine M, O'Mara, Tracy A, Thompson, Deborah J, Painter, Jodie N, Australian National Endometrial Cancer Study Group (ANECS), Attia, John, Black, Amanda, Brinton, Louise, Chanock, Stephen, Chen, Chu, Cheng, Timothy Ht, Cook, Linda S, Crous-Bou, Marta, Doherty, Jennifer, Friedenreich, Christine M, Garcia-Closas, Montserrat, Gaudet, Mia M, Gorman, Maggie, Haiman, Christopher, Hankinson, Susan E, Hartge, Patricia, Henderson, Brian E, Hodgson, Shirley, Holliday, Elizabeth G, Horn-Ross, Pamela L, Hunter, David J, Le Marchand, Loic, Liang, Xiaolin, Lissowska, Jolanta, Long, Jirong, Lu, Lingeng, Magliocco, Anthony M, Martin, Lynn, McEvoy, Mark, National Study Of Endometrial Cancer Genetics Group (NSECG), Olson, Sara H, Orlow, Irene, Pooler, Loreall, Prescott, Jennifer, Rastogi, Radhai, Rebbeck, Timothy R, Risch, Harvey, Sacerdote, Carlotta, Schumacher, Frederick, Wendy Setiawan, Veronica, Scott, Rodney J, Sheng, Xin, Shu, Xiao-Ou, Turman, Constance, Van Den Berg, David, Wang, Zhaoming, Weiss, Noel S, Wentzensen, Nicholas, Xia, Lucy, Xiang, Yong-Bing, Yang, Hannah P, Yu, Herbert, Zheng, Wei, Pharoah, Paul DP, Dunning, Alison M, Tomlinson, Ian, Easton, Douglas F, Kraft, Peter, Spurdle, Amanda B, De Vivo, Immaculata, Thompson, Deborah [0000-0003-1465-5799], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository

Subjects
Genotype, Humans, Chromosomes, Human, Pair 6, Female, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, White People, Endometrial Neoplasms, Genome-Wide Association Study
Abstract

Endometrial cancer is the most common gynecological malignancy in the developed world. Although there is evidence of genetic predisposition to the disease, most of the genetic risk remains unexplained. We present the meta-analysis results of four genome-wide association studies (4907 cases and 11 945 controls total) in women of European ancestry. We describe one new locus reaching genome-wide significance (P < 5 × 10 -8) at 6p22.3 (rs1740828; P = 2.29 × 10 -8, OR = 1.20), providing evidence of an additional region of interest for genetic susceptibility to endometrial cancer.

Published
2016

20. Shorter telomere length in Europeans than in Africans due to polygenetic adaptation

Author

Hansen, Matthew E.B., primary, Hunt, Steven C., additional, Stone, Rivka C., additional, Horvath, Kent, additional, Herbig, Utz, additional, Ranciaro, Alessia, additional, Hirbo, Jibril, additional, Beggs, William, additional, Reiner, Alexander P., additional, Wilson, James G., additional, Kimura, Masayuki, additional, De Vivo, Immaculata, additional, Chen, Maxine M., additional, Kark, Jeremy D., additional, Levy, Daniel, additional, Nyambo, Thomas, additional, Tishkoff, Sarah A., additional, and Aviv, Abraham, additional

Published
2016
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21. Exome-Wide Association Study of Endometrial Cancer in a Multiethnic Population

Author

Chen, Maxine M., primary, Crous-Bou, Marta, additional, Setiawan, Veronica W., additional, Prescott, Jennifer, additional, Olson, Sara H., additional, Wentzensen, Nicolas, additional, Black, Amanda, additional, Brinton, Louise, additional, Chen, Chu, additional, Chen, Constance, additional, Cook, Linda S., additional, Doherty, Jennifer, additional, Friedenreich, Christine M., additional, Hankinson, Susan E., additional, Hartge, Patricia, additional, Henderson, Brian E., additional, Hunter, David J., additional, Le Marchand, Loic, additional, Liang, Xiaolin, additional, Lissowska, Jolanta, additional, Lu, Lingeng, additional, Orlow, Irene, additional, Petruzella, Stacey, additional, Polidoro, Silvia, additional, Pooler, Loreall, additional, Rebbeck, Timothy R., additional, Risch, Harvey, additional, Sacerdote, Carlotta, additional, Schumacher, Frederick, additional, Sheng, Xin, additional, Shu, Xiao-ou, additional, Weiss, Noel S., additional, Xia, Lucy, additional, Van Den Berg, David, additional, Yang, Hannah P., additional, Yu, Herbert, additional, Chanock, Stephen, additional, Haiman, Christopher, additional, Kraft, Peter, additional, and De Vivo, Immaculata, additional

Published
2014
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26. Genetics and Genomics of Endometrial Cancer

Author

Chen, Maxine M. and De Vivo, Immaculata

Subjects
Health Sciences, Epidemiology
Abstract

Endometrial cancer (EC) is the most common gynecological cancer among women in the developed world and is hypothesized to arise from excess estrogen exposure from established risk factors like estrogen-only hormone therapy and obesity. EC is divided into the common “estrogen-dependent” endometrioid subtype and the rare “estrogen-independent” non- endometrioid subtype. However, this broad categorization of EC is not sufficient based on evidence for EC heterogeneity. Furthermore, family history and hereditary syndromes also increase risk, suggesting a genetic component. This dissertation examines the genetic and genomic architecture of EC to provide insight into its etiology and heterogeneity. In Chapter 1, a four-study EC meta-analysis of 4,907 cases and 11,645 controls in women of European ancestry is presented. Four loci reached genome-wide significance. One novel susceptibility locus at 6p22.3 was identified and two previously discovered loci at 6q22.31 and 13q22.1 were confirmed. Genes near the 6p22.3 locus are implicated in malignancy and poor prognosis in many cancers, highlighting the potential importance of this region to general cancer susceptibility. In Chapter 2, we conduct an exome-wide association study of EC. Using a new, commercially-developed exome array comprising ~260,000 putative functional exonic variants, we genotyped a multiethnic population of 3,067 women (1,169 EC cases and 1,898 controls) from the Epidemiology of Endometrial Cancer Consortium to test whether rare variants in coding regions are associated with endometrial cancer risk. No variants reached global significance in this study. Larger studies are needed to detect associations between rare exonic variants and EC. In Chapter 3, we combined targeted next-generation sequencing from archival EC tissue with clinical, immunohistochemical, and epidemiologic data for a comprehensive characterization of EC in 37 women from the Nurses’ Health Study. Mutations most frequently occurred in TP53, PTEN, and PIK3CA. TP53 mutations were seen in the majority of tumors that were p53 abnormal. Low grade correlated with frequency of PTEN and PIK3CA mutation. The archival EC tissue had mutation profiles consistent with previous studies, supporting use of targeted sequencing panels on archival tissue for mutation detection. Our comprehensive annotation of EC tumors demonstrates the utility of integrating many data types to reveal differences between tumors.

Published
2016

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

Author

Kho, Pik-Fang, Amant, Frederic, Annibali, Daniela, Ashton, Katie, Attia, John, Auer, Paul L, Beckmann, Matthias W, Black, Amanda, Brinton, Louise, Buchanan, Daniel D, Chanock, Stephen J, Chen, Chu, Chen, Maxine M, Cheng, Timothy HT, Cook, Linda S, Crous-Bous, Marta, Czene, Kamila, De Vivo, Immaculata, Dennis, Joe, Dörk, Thilo, Dowdy, Sean C, Dunning, Alison M, Dürst, Matthias, Easton, Douglas F, Ekici, Arif B, Fasching, Peter A, Fridley, Brooke L, Friedenreich, Christine M, García-Closas, Montserrat, Gaudet, Mia M, Giles, Graham G, Goode, Ellen L, Gorman, Maggie, Haiman, Christopher A, Hall, Per, Hankinson, Susan E, Hein, Alexander, Hillemanns, Peter, Hodgson, Shirley, Hoivik, Erling A, Holliday, Elizabeth G, Hunter, David J, Jones, Angela, Kraft, Peter, Krakstad, Camilla, Lambrechts, Diether, Le Marchand, Loic, Liang, Xiaolin, Lindblom, Annika, Lissowska, Jolanta, Long, Jirong, Lu, Lingeng, Magliocco, Anthony M, Martin, Lynn, McEvoy, Mark, Milne, Roger L, Mints, Miriam, Nassir, Rami, Otton, Geoffrey, Palles, Claire, Pooler, Loreall, Proietto, Tony, Rebbeck, Timothy R, Renner, Stefan P, Risch, Harvey A, Rübner, Matthias, Runnebaum, Ingo, Sacerdote, Carlotta, Sarto, Gloria E, Schumacher, Fredrick, Scott, Rodney J, Setiawan, V Wendy, Shah, Mitul, Sheng, Xin, Shu, Xiao-Ou, Southey, Melissa C, Tham, Emma, Tomlinson, Ian, Trovik, Jone, Turman, Constance, Tyrer, Jonathan P, Van Den Berg, David, Wang, Zhaoming, Wentzensen, Nicolas, Xia, Lucy, Xiang, Yong-Bing, Yang, Hannah P, Yu, Herbert, Zheng, Wei, Webb, Penelope M, Thompson, Deborah J, Spurdle, Amanda B, Glubb, Dylan M, and O'Mara, Tracy A

Subjects
2. Zero hunger, Risk, Cholesterol, HDL, endometrial cancer risk, Cholesterol, LDL, Mendelian Randomization Analysis, 3. Good health, Endometrial Neoplasms, HDL cholesterol, Case-Control Studies, LDL cholesterol, Mendelian randomization, Humans, lipids (amino acids, peptides, and proteins), Female, triglycerides, Genome-Wide Association Study
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.

28. 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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