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1. Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia

Author

McMaster, Mary L., Berndt, Sonja, I, Zhang, Jianqing, Slager, Susan L., Li, Shengchao Alfred, Vajdic, Claire M., Smedby, Karin E., Yan, Huihuang, Birmann, Brenda M., Brown, Elizabeth E., Smith, Alex, Kleinstern, Geffen, Fansler, Mervin M., Mayr, Christine, Zhu, Bin, Chung, Charles C., Park, Ju-Hyun, Burdette, Laurie, Hicks, Belynda D., Hutchinson, Amy, Teras, Lauren R., Adami, Hans-Olov, Bracci, Paige M., McKay, James, Monnereau, Alain, Link, Brian K., Vermeulen, Roel C. H., Ansell, Stephen M., Maria, Ann, Diver, W. Ryan, Melbye, Mads, Ojesina, Akinyemi, I, Kraft, Peter, Boffetta, Paolo, Clavel, Jacqueline, Giovannucci, Edward, Besson, Caroline M., Canzia, Federico, Travis, Ruth C., Vineis, Paolo, Weiderpass, Elisabete, Montalvan, Rebecca, Wang, Zhaoming, Yeager, Meredith, Becker, Nikolaus, Benavente, Yolanda, Brennan, Paul, Foretova, Lenka, Maynadie, Marc, Nieters, Alexandra, de Sanjose, Silvia, Staines, Anthony, Conde, Lucia, Riby, Jacques, Glimelius, Bengt, Hjalgrim, Henrik, Pradhan, Nisha, Feldman, Andrew L., Novak, Anne J., Lawrence, Charles, Bassig, Bryan A., Lan, Qing, Zheng, Tongzhang, North, Kari E., Tinker, Lesley F., Cozen, Wendy, Severson, Richard K., Hofmann, Jonathan N., Zhang, Yawei, Jackson, Rebecca D., Morton, Lindsay M., Purdue, Mark P., Chatterjee, Nilanjan, Offit, Kenneth, Cerhan, James R., Chanock, Stephen J., Rothman, Nathaniel, Vijai, Joseph, Goldin, Lynn R., Skibola, Christine F., Caporaso, Neil E., McMaster, Mary L., Berndt, Sonja, I, Zhang, Jianqing, Slager, Susan L., Li, Shengchao Alfred, Vajdic, Claire M., Smedby, Karin E., Yan, Huihuang, Birmann, Brenda M., Brown, Elizabeth E., Smith, Alex, Kleinstern, Geffen, Fansler, Mervin M., Mayr, Christine, Zhu, Bin, Chung, Charles C., Park, Ju-Hyun, Burdette, Laurie, Hicks, Belynda D., Hutchinson, Amy, Teras, Lauren R., Adami, Hans-Olov, Bracci, Paige M., McKay, James, Monnereau, Alain, Link, Brian K., Vermeulen, Roel C. H., Ansell, Stephen M., Maria, Ann, Diver, W. Ryan, Melbye, Mads, Ojesina, Akinyemi, I, Kraft, Peter, Boffetta, Paolo, Clavel, Jacqueline, Giovannucci, Edward, Besson, Caroline M., Canzia, Federico, Travis, Ruth C., Vineis, Paolo, Weiderpass, Elisabete, Montalvan, Rebecca, Wang, Zhaoming, Yeager, Meredith, Becker, Nikolaus, Benavente, Yolanda, Brennan, Paul, Foretova, Lenka, Maynadie, Marc, Nieters, Alexandra, de Sanjose, Silvia, Staines, Anthony, Conde, Lucia, Riby, Jacques, Glimelius, Bengt, Hjalgrim, Henrik, Pradhan, Nisha, Feldman, Andrew L., Novak, Anne J., Lawrence, Charles, Bassig, Bryan A., Lan, Qing, Zheng, Tongzhang, North, Kari E., Tinker, Lesley F., Cozen, Wendy, Severson, Richard K., Hofmann, Jonathan N., Zhang, Yawei, Jackson, Rebecca D., Morton, Lindsay M., Purdue, Mark P., Chatterjee, Nilanjan, Offit, Kenneth, Cerhan, James R., Chanock, Stephen J., Rothman, Nathaniel, Vijai, Joseph, Goldin, Lynn R., Skibola, Christine F., and Caporaso, Neil E.

Abstract

Waldenstrom macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare, chronic B-cell lymphoma with high heritability. We conduct a two-stage genome-wide association study of WM/LPL in 530 unrelated cases and 4362 controls of European ancestry and identify two high-risk loci associated with WM/LPL at 6p25.3 (rs116446171, near EXOC2 and IRF4; OR = 21.14, 95% CI: 14.40-31.03, P=1.36 x 10(-)(54)) and 14q32.13 (rs117410836, near TCL1; OR = 4.90, 95% CI: 3.45-6.96, P = 8.75 x 10(-)(19)) . Both risk alleles are observed at a low frequency among controls (similar to 2-3%) and occur in excess in affected cases within families. In silico data suggest that rs116446171 may have functional importance, and in functional studies, we demonstrate increased reporter transcription and proliferation in cells transduced with the 6p25.3 risk allele. Although further studies are needed to fully elucidate underlying biological mechanisms, together these loci explain 4% of the familial risk and provide insights into genetic susceptibility to this malignancy.

Published
2018
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2. Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia

Author

One Health Chemisch, dIRAS RA-2, Sub Atmospheric physics and chemistry, McMaster, Mary L, Berndt, Sonja I, Zhang, Jianqing, Slager, Susan L, Li, Shengchao Alfred, Vajdic, Claire M, Smedby, Karin E, Yan, Huihuang, Birmann, Brenda M, Brown, Elizabeth E, Smith, Alex, Kleinstern, Geffen, Fansler, Mervin M, Mayr, Christine, Zhu, Bin, Chung, Charles C, Park, Ju-Hyun, Burdette, Laurie, Hicks, Belynda D, Hutchinson, Amy, Teras, Lauren R, Adami, Hans-Olov, Bracci, Paige M, McKay, James, Monnereau, Alain, Link, Brian K, Vermeulen, Roel C H, Ansell, Stephen M, Maria, Ann, Diver, W Ryan, Melbye, Mads, Ojesina, Akinyemi I, Kraft, Peter, Boffetta, Paolo, Clavel, Jacqueline, Giovannucci, Edward, Besson, Caroline M, Canzian, Federico, Travis, Ruth C, Vineis, Paolo, Weiderpass, Elisabete, Montalvan, Rebecca, Wang, Zhaoming, Yeager, Meredith, Becker, Nikolaus, Benavente, Yolanda, Brennan, Paul, Foretova, Lenka, Maynadie, Marc, Nieters, Alexandra, de Sanjose, Silvia, Staines, Anthony, Conde, Lucia, Riby, Jacques, Glimelius, Bengt, Hjalgrim, Henrik, Pradhan, Nisha, Feldman, Andrew L, Novak, Anne J, Lawrence, Charles, Bassig, Bryan A, Lan, Qing, Zheng, Tongzhang, North, Kari E, Tinker, Lesley F, Cozen, Wendy, Severson, Richard K, Hofmann, Jonathan N, Zhang, Yawei, Jackson, Rebecca D, Morton, Lindsay M, Purdue, Mark P, Chatterjee, Nilanjan, Offit, Kenneth, Cerhan, James R, Chanock, Stephen J, Rothman, Nathaniel, Vijai, Joseph, Goldin, Lynn R, Skibola, Christine F, Caporaso, Neil E, One Health Chemisch, dIRAS RA-2, Sub Atmospheric physics and chemistry, McMaster, Mary L, Berndt, Sonja I, Zhang, Jianqing, Slager, Susan L, Li, Shengchao Alfred, Vajdic, Claire M, Smedby, Karin E, Yan, Huihuang, Birmann, Brenda M, Brown, Elizabeth E, Smith, Alex, Kleinstern, Geffen, Fansler, Mervin M, Mayr, Christine, Zhu, Bin, Chung, Charles C, Park, Ju-Hyun, Burdette, Laurie, Hicks, Belynda D, Hutchinson, Amy, Teras, Lauren R, Adami, Hans-Olov, Bracci, Paige M, McKay, James, Monnereau, Alain, Link, Brian K, Vermeulen, Roel C H, Ansell, Stephen M, Maria, Ann, Diver, W Ryan, Melbye, Mads, Ojesina, Akinyemi I, Kraft, Peter, Boffetta, Paolo, Clavel, Jacqueline, Giovannucci, Edward, Besson, Caroline M, Canzian, Federico, Travis, Ruth C, Vineis, Paolo, Weiderpass, Elisabete, Montalvan, Rebecca, Wang, Zhaoming, Yeager, Meredith, Becker, Nikolaus, Benavente, Yolanda, Brennan, Paul, Foretova, Lenka, Maynadie, Marc, Nieters, Alexandra, de Sanjose, Silvia, Staines, Anthony, Conde, Lucia, Riby, Jacques, Glimelius, Bengt, Hjalgrim, Henrik, Pradhan, Nisha, Feldman, Andrew L, Novak, Anne J, Lawrence, Charles, Bassig, Bryan A, Lan, Qing, Zheng, Tongzhang, North, Kari E, Tinker, Lesley F, Cozen, Wendy, Severson, Richard K, Hofmann, Jonathan N, Zhang, Yawei, Jackson, Rebecca D, Morton, Lindsay M, Purdue, Mark P, Chatterjee, Nilanjan, Offit, Kenneth, Cerhan, James R, Chanock, Stephen J, Rothman, Nathaniel, Vijai, Joseph, Goldin, Lynn R, Skibola, Christine F, and Caporaso, Neil E

Published
2018

3. Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia

Author

LS IRAS EEPI GRA (Gezh.risico-analyse), dIRAS RA-2, Law, Philip J, Berndt, Sonja I., Speedy, Helen E, Camp, Nicola J, Sava, Georgina P, Skibola, Christine F., Holroyd, Amy, Joseph, Vijai, Sunter, Nicola J, Nieters, Alexandra, Bea, Silvia, Monnereau, Alain, Martin-Garcia, David, Goldin, Lynn R, Clot, Guillem, Teras, Lauren R., Quintela, Inés, Birmann, Brenda M., Jayne, Sandrine, Cozen, Wendy, Majid, Aneela, Smedby, Karin E, Lan, Qing, Dearden, Claire, Brooks-Wilson, Angela R., Hall, Andrew G, Purdue, Mark P., Mainou-Fowler, Tryfonia, Vajdic, Claire M., Jackson, Graham H, Cocco, Pierluigi, Marr, Helen, Zhang, Yawei, Zheng, Tongzhang, Giles, Graham G., Lawrence, Charles, Call, Timothy G., Liebow, Mark, Melbye, Mads, Glimelius, Bengt, Mansouri, Larry, Glenn, Martha, Curtin, Karen, Diver, W. Ryan, Link, Brian K., Conde, Lucia, Bracci, Paige M., Holly, Elizabeth A., Jackson, Rebecca D., Tinker, Lesley F., Benavente, Yolanda, Boffetta, Paolo, Brennan, Paul, Maynadie, Marc, McKay, James, Albanes, Demetrius, Weinstein, Stephanie, Wang, Zhaoming, Caporaso, Neil E, Morton, Lindsay M., Severson, Richard K., Riboli, Elio, Vineis, Paolo, Vermeulen, Roel C H, Southey, Melissa C., Milne, Roger L, Clavel, Jacqueline, Topka, Sabine, Spinelli, John, Kraft, Peter, Ennas, Maria Grazia, Summerfield, Geoffrey, Ferri, Giovanni M, Harris, Robert J, Miligi, Lucia, Pettitt, Andrew R, North, Kari E., Allsup, David J, Fraumeni, Joseph F., Bailey, James R, Offit, Kenneth, Pratt, Guy, Hjalgrim, Henrik, Pepper, Chris, Chanock, Stephen J., Fegan, Chris, Rosenquist, Richard, De Sanjose, Silvia, Carracedo, Angel, Dyer, Martin J S, Catovsky, Daniel, Campo, Elias, Cerhan, James R., Allan, James M, Rothman, Nathanial, Houlston, Richard S, Slager, Susan L., LS IRAS EEPI GRA (Gezh.risico-analyse), dIRAS RA-2, Law, Philip J, Berndt, Sonja I., Speedy, Helen E, Camp, Nicola J, Sava, Georgina P, Skibola, Christine F., Holroyd, Amy, Joseph, Vijai, Sunter, Nicola J, Nieters, Alexandra, Bea, Silvia, Monnereau, Alain, Martin-Garcia, David, Goldin, Lynn R, Clot, Guillem, Teras, Lauren R., Quintela, Inés, Birmann, Brenda M., Jayne, Sandrine, Cozen, Wendy, Majid, Aneela, Smedby, Karin E, Lan, Qing, Dearden, Claire, Brooks-Wilson, Angela R., Hall, Andrew G, Purdue, Mark P., Mainou-Fowler, Tryfonia, Vajdic, Claire M., Jackson, Graham H, Cocco, Pierluigi, Marr, Helen, Zhang, Yawei, Zheng, Tongzhang, Giles, Graham G., Lawrence, Charles, Call, Timothy G., Liebow, Mark, Melbye, Mads, Glimelius, Bengt, Mansouri, Larry, Glenn, Martha, Curtin, Karen, Diver, W. Ryan, Link, Brian K., Conde, Lucia, Bracci, Paige M., Holly, Elizabeth A., Jackson, Rebecca D., Tinker, Lesley F., Benavente, Yolanda, Boffetta, Paolo, Brennan, Paul, Maynadie, Marc, McKay, James, Albanes, Demetrius, Weinstein, Stephanie, Wang, Zhaoming, Caporaso, Neil E, Morton, Lindsay M., Severson, Richard K., Riboli, Elio, Vineis, Paolo, Vermeulen, Roel C H, Southey, Melissa C., Milne, Roger L, Clavel, Jacqueline, Topka, Sabine, Spinelli, John, Kraft, Peter, Ennas, Maria Grazia, Summerfield, Geoffrey, Ferri, Giovanni M, Harris, Robert J, Miligi, Lucia, Pettitt, Andrew R, North, Kari E., Allsup, David J, Fraumeni, Joseph F., Bailey, James R, Offit, Kenneth, Pratt, Guy, Hjalgrim, Henrik, Pepper, Chris, Chanock, Stephen J., Fegan, Chris, Rosenquist, Richard, De Sanjose, Silvia, Carracedo, Angel, Dyer, Martin J S, Catovsky, Daniel, Campo, Elias, Cerhan, James R., Allan, James M, Rothman, Nathanial, Houlston, Richard S, and Slager, Susan L.

Published
2017

4. Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia

Author

LS IRAS EEPI GRA (Gezh.risico-analyse), Sub Atmospheric physics and chemistry, dIRAS RA-I&I RA, dIRAS RA-2, Berndt, Sonja I, Camp, Nicola J, Skibola, Christine F, Vijai, Joseph, Wang, Zhaoming, Gu, Jian, Nieters, Alexandra, Kelly, Rachel S, Smedby, Karin E, Monnereau, Alain, Cozen, Wendy, Cox, Angela, Wang, Sophia S, Lan, Qing, Teras, Lauren R, Machado, Moara, Yeager, Meredith, Brooks-Wilson, Angela R, Hartge, Patricia, Purdue, Mark P, Birmann, Brenda M, Vajdic, Claire M, Cocco, Pierluigi, Zhang, Yawei, Giles, Graham G, Zeleniuch-Jacquotte, Anne, Lawrence, Charles, Montalvan, Rebecca, Burdett, Laurie, Hutchinson, Amy, Ye, Yuanqing, Call, Timothy G, Shanafelt, Tait D, Novak, Anne J, Kay, Neil E, Liebow, Mark, Cunningham, Julie M, Allmer, Cristine, Hjalgrim, Henrik, Adami, Hans-Olov, Melbye, Mads, Glimelius, Bengt, Chang, Ellen T, Glenn, Martha, Curtin, Karen, Cannon-Albright, Lisa A, Diver, W Ryan, Link, Brian K, Weiner, George J, Conde, Lucia, Bracci, Paige M, Riby, Jacques, Arnett, Donna K, Zhi, Degui, Leach, Justin M, Holly, Elizabeth A, Jackson, Rebecca D, Tinker, Lesley F, Benavente, Yolanda, Sala, Núria, Casabonne, Delphine, Becker, Nikolaus, Boffetta, Paolo, Brennan, Paul, Foretova, Lenka, Maynadie, Marc, McKay, James, Staines, Anthony, Chaffee, Kari G, Achenbach, Sara J, Vachon, Celine M, Goldin, Lynn R, Strom, Sara S, Leis, Jose F, Weinberg, J Brice, Caporaso, Neil E, Norman, Aaron D, De Roos, Anneclaire J, Morton, Lindsay M, Severson, Richard K, Riboli, Elio, Vineis, Paolo, Kaaks, Rudolph, Masala, Giovanna, Weiderpass, Elisabete, Chirlaque, María-Dolores, Vermeulen, Roel C H, Travis, Ruth C, Southey, Melissa C, Milne, Roger L, Albanes, Demetrius, Virtamo, Jarmo, Weinstein, Stephanie, Clavel, Jacqueline, Zheng, Tongzhang, Holford, Theodore R, Villano, Danylo J, Maria, Ann, Spinelli, John J, Gascoyne, Randy D, Connors, Joseph M, Bertrand, Kimberly A, Giovannucci, Edward, Kraft, Peter, Kricker, Anne, Turner, Jenny, Ennas, Maria Grazia, Ferri, Giovanni M, Miligi, Lucia, Liang, Liming, Ma, Baoshan, Huang, Jinyan, Crouch, Simon, Park, Ju-Hyun, Chatterjee, Nilanjan, North, Kari E, Snowden, John A, Wright, Josh, Fraumeni, Joseph F, Offit, Kenneth, Wu, Xifeng, de Sanjose, Silvia, Cerhan, James R, Chanock, Stephen J, Rothman, Nathaniel, Slager, Susan L, LS IRAS EEPI GRA (Gezh.risico-analyse), Sub Atmospheric physics and chemistry, dIRAS RA-I&I RA, dIRAS RA-2, Berndt, Sonja I, Camp, Nicola J, Skibola, Christine F, Vijai, Joseph, Wang, Zhaoming, Gu, Jian, Nieters, Alexandra, Kelly, Rachel S, Smedby, Karin E, Monnereau, Alain, Cozen, Wendy, Cox, Angela, Wang, Sophia S, Lan, Qing, Teras, Lauren R, Machado, Moara, Yeager, Meredith, Brooks-Wilson, Angela R, Hartge, Patricia, Purdue, Mark P, Birmann, Brenda M, Vajdic, Claire M, Cocco, Pierluigi, Zhang, Yawei, Giles, Graham G, Zeleniuch-Jacquotte, Anne, Lawrence, Charles, Montalvan, Rebecca, Burdett, Laurie, Hutchinson, Amy, Ye, Yuanqing, Call, Timothy G, Shanafelt, Tait D, Novak, Anne J, Kay, Neil E, Liebow, Mark, Cunningham, Julie M, Allmer, Cristine, Hjalgrim, Henrik, Adami, Hans-Olov, Melbye, Mads, Glimelius, Bengt, Chang, Ellen T, Glenn, Martha, Curtin, Karen, Cannon-Albright, Lisa A, Diver, W Ryan, Link, Brian K, Weiner, George J, Conde, Lucia, Bracci, Paige M, Riby, Jacques, Arnett, Donna K, Zhi, Degui, Leach, Justin M, Holly, Elizabeth A, Jackson, Rebecca D, Tinker, Lesley F, Benavente, Yolanda, Sala, Núria, Casabonne, Delphine, Becker, Nikolaus, Boffetta, Paolo, Brennan, Paul, Foretova, Lenka, Maynadie, Marc, McKay, James, Staines, Anthony, Chaffee, Kari G, Achenbach, Sara J, Vachon, Celine M, Goldin, Lynn R, Strom, Sara S, Leis, Jose F, Weinberg, J Brice, Caporaso, Neil E, Norman, Aaron D, De Roos, Anneclaire J, Morton, Lindsay M, Severson, Richard K, Riboli, Elio, Vineis, Paolo, Kaaks, Rudolph, Masala, Giovanna, Weiderpass, Elisabete, Chirlaque, María-Dolores, Vermeulen, Roel C H, Travis, Ruth C, Southey, Melissa C, Milne, Roger L, Albanes, Demetrius, Virtamo, Jarmo, Weinstein, Stephanie, Clavel, Jacqueline, Zheng, Tongzhang, Holford, Theodore R, Villano, Danylo J, Maria, Ann, Spinelli, John J, Gascoyne, Randy D, Connors, Joseph M, Bertrand, Kimberly A, Giovannucci, Edward, Kraft, Peter, Kricker, Anne, Turner, Jenny, Ennas, Maria Grazia, Ferri, Giovanni M, Miligi, Lucia, Liang, Liming, Ma, Baoshan, Huang, Jinyan, Crouch, Simon, Park, Ju-Hyun, Chatterjee, Nilanjan, North, Kari E, Snowden, John A, Wright, Josh, Fraumeni, Joseph F, Offit, Kenneth, Wu, Xifeng, de Sanjose, Silvia, Cerhan, James R, Chanock, Stephen J, Rothman, Nathaniel, and Slager, Susan L

Published
2016

5. Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia

Author

Law, Philip J., Berndt, Sonja I., Speedy, Helen E., Camp, Nicola J., Sava, Georgina P., Skibola, Christine F., Holroyd, Amy, Joseph, Vijai, Sunter, Nicola J., Nieters, Alexandra, Bea, Silvia, Monnereau, Alain, Martin-Garcia, David, Goldin, Lynn R., Clot, Guillem, Teras, Lauren R., Quintela, Inés, Birmann, Brenda M., Jayne, Sandrine, Cozen, Wendy, Majid, Aneela, Smedby, Karin E., Lan, Qing, Dearden, Claire, Brooks-Wilson, Angela R., Hall, Andrew G., Purdue, Mark P., Mainou-Fowler, Tryfonia, Vajdic, Claire M., Jackson, Graham H., Cocco, Pierluigi, Marr, Helen, Zhang, Yawei, Zheng, Tongzhang, Giles, Graham G., Lawrence, Charles, Call, Timothy G., Liebow, Mark, Melbye, Mads, Glimelius, Bengt, Mansouri, Larry, Glenn, Martha, Curtin, Karen, Diver, W Ryan, Link, Brian K., Conde, Lucia, Bracci, Paige M., Holly, Elizabeth A., Jackson, Rebecca D., Tinker, Lesley F., Benavente, Yolanda, Boffetta, Paolo, Brennan, Paul, Maynadie, Marc, McKay, James, Albanes, Demetrius, Weinstein, Stephanie, Wang, Zhaoming, Caporaso, Neil E., Morton, Lindsay M., Severson, Richard K., Riboli, Elio, Vineis, Paolo, Vermeulen, Roel C. H., Southey, Melissa C., Milne, Roger L., Clavel, Jacqueline, Topka, Sabine, Spinelli, John J., Kraft, Peter, Ennas, Maria Grazia, Summerfield, Geoffrey, Ferri, Giovanni M., Harris, Robert J., Miligi, Lucia, Pettitt, Andrew R., North, Kari E., Allsup, David J., Fraumeni, Joseph F., Bailey, James R., Offit, Kenneth, Pratt, Guy, Hjalgrim, Henrik, Pepper, Chris, Chanock, Stephen J., Fegan, Chris, Rosenquist, Richard, de Sanjose, Silvia, Carracedo, Angel, Dyer, Martin J. S., Catovsky, Daniel, Campo, Elias, Cerhan, James R., Allan, James M., Rothman, Nathanial, Houlston, Richard, and Slager, Susan

Abstract

Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P=5.04 × 10−13), 1q42.13 (rs41271473, P=1.06 × 10−10), 4q24 (rs71597109, P=1.37 × 10−10), 4q35.1 (rs57214277, P=3.69 × 10−8), 6p21.31 (rs3800461, P=1.97 × 10−8), 11q23.2 (rs61904987, P=2.64 × 10−11), 18q21.1 (rs1036935, P=3.27 × 10−8), 19p13.3 (rs7254272, P=4.67 × 10−8) and 22q13.33 (rs140522, P=2.70 × 10−9). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response.

Published
2017
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6. Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome

Author

Machiela, Mitchell J., Zhou, Weiyin, Karlins, Eric, Sampson, Joshua N., Freedman, Neal D., Yang, Qi, Hicks, Belynda, Dagnall, Casey, Hautman, Christopher, Jacobs, Kevin B., Abnet, Christian C., Aldrich, Melinda C., Amos, Christopher, Amundadottir, Laufey T., Arslan, Alan A., Beane-Freeman, Laura E., Berndt, Sonja I., Black, Amanda, Blot, William J., Bock, Cathryn H., Bracci, Paige M., Brinton, Louise A., Bueno-de-Mesquita, H Bas, Burdett, Laurie, Buring, Julie E., Butler, Mary A., Canzian, Federico, Carreón, Tania, Chaffee, Kari G., Chang, I-Shou, Chatterjee, Nilanjan, Chen, Chu, Chen, Constance, Chen, Kexin, Chung, Charles C., Cook, Linda S., Crous Bou, Marta, Cullen, Michael, Davis, Faith G., De Vivo, Immaculata, Ding, Ti, Doherty, Jennifer, Duell, Eric J., Epstein, Caroline G., Fan, Jin-Hu, Figueroa, Jonine D., Fraumeni, Joseph F., Friedenreich, Christine M., Fuchs, Charles S., Gallinger, Steven, Gao, Yu-Tang, Gapstur, Susan M., Garcia-Closas, Montserrat, Gaudet, Mia M., Gaziano, J. Michael, Giles, Graham G., Gillanders, Elizabeth M., Giovannucci, Edward L., Goldin, Lynn, Goldstein, Alisa M., Haiman, Christopher A., Hallmans, Goran, Hankinson, Susan E., Harris, Curtis C., Henriksson, Roger, Holly, Elizabeth A., Hong, Yun-Chul, Hoover, Robert N., Hsiung, Chao A., Hu, Nan, Hu, Wei, Hunter, David J., Hutchinson, Amy, Jenab, Mazda, Johansen, Christoffer, Khaw, Kay-Tee, Kim, Hee Nam, Kim, Yeul Hong, Kim, Young Tae, Klein, Alison P., Klein, Robert, Koh, Woon-Puay, Kolonel, Laurence N., Kooperberg, Charles, Kraft, Peter, Krogh, Vittorio, Kurtz, Robert C., LaCroix, Andrea, Lan, Qing, Landi, Maria Teresa, Marchand, Loic Le, Li, Donghui, Liang, Xiaolin, Liao, Linda M., Lin, Dongxin, Liu, Jianjun, Lissowska, Jolanta, Lu, Lingeng, Magliocco, Anthony M., Malats, Nuria, Matsuo, Keitaro, McNeill, Lorna H., McWilliams, Robert R., Melin, Beatrice S., Mirabello, Lisa, Moore, Lee, Olson, Sara H., Orlow, Irene, Park, Jae Yong, Patiño-Garcia, Ana, Peplonska, Beata, Peters, Ulrike, Petersen, Gloria M., Pooler, Loreall, Prescott, Jennifer, Prokunina-Olsson, Ludmila, Purdue, Mark P., Qiao, You-Lin, Rajaraman, Preetha, Real, Francisco X., Riboli, Elio, Risch, Harvey A., Rodriguez-Santiago, Benjamin, Ruder, Avima M., Savage, Sharon A., Schumacher, Fredrick, Schwartz, Ann G., Schwartz, Kendra L., Seow, Adeline, Wendy Setiawan, Veronica, Severi, Gianluca, Shen, Hongbing, Sheng, Xin, Shin, Min-Ho, Shu, Xiao-Ou, Silverman, Debra T., Spitz, Margaret R., Stevens, Victoria L., Stolzenberg-Solomon, Rachael, Stram, Daniel, Tang, Ze-Zhong, Taylor, Philip R., Teras, Lauren R., Tobias, Geoffrey S., Van Den Berg, David, Visvanathan, Kala, Wacholder, Sholom, Wang, Jiu-Cun, Wang, Zhaoming, Wentzensen, Nicolas, Wheeler, William, White, Emily, Wiencke, John K., Wolpin, Brian M., Wong, Maria Pik, Wu, Chen, Wu, Tangchun, Wu, Xifeng, Wu, Yi-Long, Wunder, Jay S., Xia, Lucy, Yang, Hannah P., Yang, Pan-Chyr, Yu, Kai, Zanetti, Krista A., Zeleniuch-Jacquotte, Anne, Zheng, Wei, Zhou, Baosen, Ziegler, Regina G., Perez-Jurado, Luis A., Caporaso, Neil E., Rothman, Nathaniel, Tucker, Margaret, Dean, Michael C., Yeager, Meredith, and Chanock, Stephen J.

Abstract

To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.

Published
2016
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7. Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia

Author

Berndt, Sonja I., Camp, Nicola J., Skibola, Christine F., Vijai, Joseph, Wang, Zhaoming, Gu, Jian, Nieters, Alexandra, Kelly, Rachel S., Smedby, Karin E., Monnereau, Alain, Cozen, Wendy, Cox, Angela, Wang, Sophia S., Lan, Qing, Teras, Lauren R., Machado, Moara, Yeager, Meredith, Brooks-Wilson, Angela R., Hartge, Patricia, Purdue, Mark P., Birmann, Brenda M., Vajdic, Claire M., Cocco, Pierluigi, Zhang, Yawei, Giles, Graham G., Zeleniuch-Jacquotte, Anne, Lawrence, Charles, Montalvan, Rebecca, Burdett, Laurie, Hutchinson, Amy, Ye, Yuanqing, Call, Timothy G., Shanafelt, Tait D., Novak, Anne J., Kay, Neil E., Liebow, Mark, Cunningham, Julie M., Allmer, Cristine, Hjalgrim, Henrik, Adami, Hans-Olov, Melbye, Mads, Glimelius, Bengt, Chang, Ellen T., Glenn, Martha, Curtin, Karen, Cannon-Albright, Lisa A., Diver, W Ryan, Link, Brian K., Weiner, George J., Conde, Lucia, Bracci, Paige M., Riby, Jacques, Arnett, Donna K., Zhi, Degui, Leach, Justin M., Holly, Elizabeth A., Jackson, Rebecca D., Tinker, Lesley F., Benavente, Yolanda, Sala, Núria, Casabonne, Delphine, Becker, Nikolaus, Boffetta, Paolo, Brennan, Paul, Foretova, Lenka, Maynadie, Marc, McKay, James, Staines, Anthony, Chaffee, Kari G., Achenbach, Sara J., Vachon, Celine M., Goldin, Lynn R., Strom, Sara S., Leis, Jose F., Weinberg, J. Brice, Caporaso, Neil E., Norman, Aaron D., De Roos, Anneclaire J., Morton, Lindsay M., Severson, Richard K., Riboli, Elio, Vineis, Paolo, Kaaks, Rudolph, Masala, Giovanna, Weiderpass, Elisabete, Chirlaque, María- Dolores, Vermeulen, Roel C. H., Travis, Ruth C., Southey, Melissa C., Milne, Roger L., Albanes, Demetrius, Virtamo, Jarmo, Weinstein, Stephanie, Clavel, Jacqueline, Zheng, Tongzhang, Holford, Theodore R., Villano, Danylo J., Maria, Ann, Spinelli, John J., Gascoyne, Randy D., Connors, Joseph M., Bertrand, Kimberly A., Giovannucci, Edward, Kraft, Peter, Kricker, Anne, Turner, Jenny, Ennas, Maria Grazia, Ferri, Giovanni M., Miligi, Lucia, Liang, Liming, Ma, Baoshan, Huang, Jinyan, Crouch, Simon, Park, Ju-Hyun, Chatterjee, Nilanjan, North, Kari E., Snowden, John A., Wright, Josh, Fraumeni, Joseph F., Offit, Kenneth, Wu, Xifeng, de Sanjose, Silvia, Cerhan, James R., Chanock, Stephen J., Rothman, Nathaniel, and Slager, Susan L.

Abstract

Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P=2.55 × 10−11), 6p25.2 (rs73718779, SERPINB6, P=1.97 × 10−8) and 3q28 (rs9815073, LPP, P=3.62 × 10−8), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P=1.00 × 10−11) in the combined analysis. We find suggestive evidence (P<5 × 10−7) for two additional new loci at 4q24 (rs10028805, BANK1, P=7.19 × 10−8) and 3p22.2 (rs1274963, CSRNP1, P=2.12 × 10−7). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility.

Published
2016
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8. Detectable Clonal Mosaicism from Birth to Old Age and its Relationship to Cancer

Author

Laurie, Cathy C., Laurie, Cecelia A., Doheny, Kimberly F., Zelnick, Leila R., McHugh, Caitlin P., Ling, Hua, Hetrick, Kurt N., Amos, Chris, Wei, Qingyi, Wang, Li-e, Hansel, Nadia N., Mathias, Rasika, Daley, Denise, Beaty, Terri H., Scott, Alan F., Ruczinski, Ingo, Scharpf, Rob B., Bierut, Laura J., Hartz, Sarah M., Landi, Maria Teresa, Freedman, Neal D., Goldin, Lynn R., Ginsburg, David, Desch, Karl C., Strom, Sara S., Blot, William J., Ingles, Sue A., Chanock, Stephen J., Berndt, Sonja I., Le Marchand, Loic, Monroe, Kristine R, Heit, John A., de Andrade, Mariza, Armasu, Sebastian M., Regnier, Cynthia, Lowe, William L., Marazita, Mary L., Feingold, Eleanor, Murray, Jeffrey C., Melbye, Mads, Feenstra, Bjarke, Jarvik, Gail P., McDavid, Andrew N., Seshan, Venkatraman E., Mirel, Daniel B., Crenshaw, Andrew, Sharopova, Nataliya, Wise, Anastasia, Shen, Jess, Crosslin, David R., Zheng, Xiuwen, Udren, Jenna I, Bennett, Siiri, Gogarten, Stephanie M., Conomos, Matthew P., Heagerty, Patrick, Manolio, Teri, Haiman, Christopher A., Caporaso, Neil, Weir, Bruce S., Rice, Kenneth, Kang, Jae Hee, Pugh, Elizabeth W., Lee, Jeffrey E., Barnes, Kathleen C., Li, Jun, Signorello, Lisa B, Henderson, Brian E., Hayes, M. Geoffrey, Wiggs, Janey Lee, Levine, David M., Nelson, Sarah C., and Pasquale, Louis

Abstract

Clonal mosaicism for large chromosomal anomalies (duplications, deletions and uniparental disomy) was detected using SNP microarray data from over 50,000 subjects recruited for genome-wide association studies. This detection method requires a relatively high frequency of cells (>5–10%) with the same abnormal karyotype (presumably of clonal origin) in the presence of normal cells. The frequency of detectable clonal mosaicism in peripheral blood is low (<0.5%) from birth until 50 years of age, after which it rises rapidly to 2–3% in the elderly. Many of the mosaic anomalies are characteristic of those found in hematological cancers and identify common deleted regions that pinpoint the locations of genes previously associated with hematological cancers. Although only 3% of subjects with detectable clonal mosaicism had any record of hematological cancer prior to DNA sampling, those without a prior diagnosis have an estimated 10-fold higher risk of a subsequent hematological cancer (95% confidence interval = 6–18).

Published
2012
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9. Detectable clonal mosaicism and its relationship to aging and cancer

Author

Jacobs, Kevin B., Yeager, Meredith, Zhou, Weiyin, Wacholder, Sholom, Wang, Zhaoming, Rodriguez-Santiago, Benjamin, Hutchinson, Amy, Deng, Xiang, Liu, Chenwei, Horner, Marie-Josephe, Cullen, Michael, Liao, Linda, Schwartz, Ann G., McNeill, Lorna H., Schwenn, Molly, Figueroa, Jonine D., Henderson, Brian E., Shu, Xiao-Ou, Zeleniuch-Jacquotte, Anne, Wiencke, John K., Gonzalez, Juan R., Gallinger, Steven, Fan, Jin-Hu, Thomas, Gilles, Wrensch, Margaret, Savage, Sharon A., Silverman, Debra T., Amos, Christopher I., Tang, Ze-Zhong, Sierrasesúmaga, Luis, Consonni, Dario, Albanes, Demetrius, Trichopoulos, Dimitrios, Olson, Sara H., Chow, Wong-Ho, Krogh, Vittorio, Beane Freeman, Laura, Kratz, Christian P., Holly, Elizabeth A., Blot, William J., Hallmans, Göran, Peters, Ulrike, Duell, Eric J., Brinton, Louise A., Yu, Herbert, Hoover, Robert N., Caporaso, Neil E ., Bertazzi, Pier Alberto, Chanock, Stephen J., Erickson, Ralph L., Elena, Joanne W., Visvanathan, Kala, Tobias, Geoffrey S., Rothman, Nathaniel, Gross, Myron D., Hassan, Manal, Chang, Kenneth, Cotterchio, Michelle, Johnson, Alison, Moore, Lee E., Rajaraman, Preetha, Purdue, Mark, Klein, Alison P., Wheeler, William, Wentzensen, Nicolas, Tjønneland, Anne, Arslan, Alan A., Petersen, Gloria, Chatterjee, Nilanjan, Canzian, Federico, Goggins, Michael, Landi, Maria Teresa, Kurtz, Robert C., Graubard, Barry I., Kovaks, Joseph, Marenne, Gaelle, Dean, Michael C., Giovannucci, Edward L., Wunder, Jay S., Andrulis, Irene L., Butler, Mary A., Jenab, Mazda, Bueno de Mesquita, H. Bas, Marchand, Loic Le, Carreon, Tania, Goldin, Lynn, Virtamo, Jarmo, Ruder, Avima M., Peplonska, Beata, Burdett, Laurie, Sampson, Joshua, Gorlick, Richard G., Fuchs, Charles S., Chung, Charles C., Barkauskas, Donald A., Taylor, Philip R., Haiman, Christopher A., Hunter, David J., Gapstur, Susan M., Giles, Graham G., White, Emily, Mendelsohn, Julie B., Zheng, Wei, Lissowska, Jolanta, Amundadottir, Laufey, Andersson, Ulrika, Davis, Faith G., Freedman, Neal D., Boutron-Ruault, Marie-Christine, LaCroix, Andrea, Rabe, Kari G., Hankinson, Susan E., Bracci, Paige M., McKean-Cowdin, Roberta, Weinstein, Stephanie J., Mandelson, Margaret T., Gao, Yu-Tang, Kolonel, Laurence N., Harris, Curtis C., Teras, Lauren T., Fraumeni Jr., Joseph F., Greene, Mark H., Sesso, Howard D., Mirabello, Lisa, Schwartz, Kendra L., Risch, Harvey A., Abnet, Christian C., Prokunina-Olsson, Ludmila, Garcia Closas, Montserrat, Michaud, Dominique S., Stevens, Victoria L., Signorello, Lisa B., Tucker, Margaret, Ding, Ti, Aldrich, Melinda C., Stram, Daniel, Kraft, Peter, Pérez Jurado, Luis A., Berg, Christine D., Hoffman Bolton, Judith A., Koh, Woon-Puay, Buring, Julie E., Ziegler, Regina G., Bock, Cathryn H., McWilliams, Robert R., Feychting, Maria, Goldstein, Alisa M., Hartge, Patricia, Johansen, Christoffer, Hu, Nan, Patiño García, Ana, Rotunno, Melissa, Gillanders, Elizabeth M., Rybicki, Benjamin A., Spitz, Margaret R., Riboli, Elio, Gaziano, J. Michael, Epstein, Caroline G., Khaw, Kay-Tee, Inskip, Peter D., Melin, Beatrice S., Severi, Gianluca, McGlynn, Katherine A., Wolpin, Brian M., Henriksson, Roger, Stolzenberg-Solomon, Rachael Z., Qiao, You-Lin, Gaudet, Mia M., Wu, Xifeng, Berndt, Sonja I., Yu, Kai, Hsing, Ann W., Landgren, Annelie, Wolk, Alicja, Xiang, Yong-Bing, Ahlbom, Anders, Cook, Michael B., Black, Amanda, Baris, Dalsu, Yuan, Jian-Min, Li, Donghui, Malats, Núria, Jiao, Li, Kogevinas, Manolis, Kooperberg, Charles, Villa, Olaya, Real, Francisco X., Zanetti, Krista A., and Schumacher, Fredrick

Subjects
Aging, Envelliment, Càncer, Cancer
Abstract

In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of > 2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 x 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 x 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.

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