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51. Bayesian approach to determining penetrance of pathogenic SDH variants

Author

Benn, Diana E, primary, Zhu, Ying, additional, Andrews, Katrina A, additional, Wilding, Mathilda, additional, Duncan, Emma L, additional, Dwight, Trisha, additional, Tothill, Richard W, additional, Burgess, John, additional, Crook, Ashley, additional, Gill, Anthony J, additional, Hicks, Rodney J, additional, Kim, Edward, additional, Luxford, Catherine, additional, Marfan, Helen, additional, Richardson, Anne Louise, additional, Robinson, Bruce, additional, Schlosberg, Arran, additional, Susman, Rachel, additional, Tacon, Lyndal, additional, Trainer, Alison, additional, Tucker, Katherine, additional, Maher, Eamonn R, additional, Field, Michael, additional, and Clifton-Bligh, Roderick J, additional

Published
2018
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52. CLAVATA Was a Genetic Novelty for the Morphological Innovation of 3D Growth in Land Plants

Author

Whitewoods, Chris D., primary, Cammarata, Joseph, additional, Nemec Venza, Zoe, additional, Sang, Stephanie, additional, Crook, Ashley D., additional, Aoyama, Tsuyoshi, additional, Wang, Xiao Y., additional, Waller, Manuel, additional, Kamisugi, Yasuko, additional, Cuming, Andrew C., additional, Szövényi, Péter, additional, Nimchuk, Zachary L., additional, Roeder, Adrienne H.K., additional, Scanlon, Michael J., additional, and Harrison, C. Jill, additional

Published
2018
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55. Annexin A1 expression in a pooled breast cancer series: Association with tumor subtypes and prognosis

Author

Sobral-Leite, Marcelo, Wesseling, Jelle, Smit, Vincent T H B M, Nevanlinna, Heli, van Miltenburg, Martine H., Sanders, Joyce, Hofland, Ingrid, Blows, Fiona M., Coulson, Penny, Patrycja, Gazinska, Schellens, Jan H M, Fagerholm, Rainer, Heikkilä, Päivi, Aittomäki, Kristiina, Blomqvist, Carl, Provenzano, Elena, Ali, Hamid Raza, Figueroa, Jonine, Sherman, Mark, Lissowska, Jolanta, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli Matti, Hartikainen, Jaana M., Phillips, Kelly Anne, Couch, Fergus J., Olson, Janet E., Vachon, Celine, Visscher, Daniel, Brenner, Hermann, Butterbach, Katja, Arndt, Volker, Holleczek, Bernd, Hooning, Maartje J., Hollestelle, Antoinette, Martens, John W M, van Deurzen, Carolien H M, van de Water, Bob, Broeks, Annegien, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Easton, Douglas F., Pharoah, Paul D P, García-Closas, Montserrat, de Graauw, Marjo, Schmidt, Marjanka K., Aghmesheh, Morteza, Amor, David, Andrews, Lesley, Antill, Yoland, Armitage, Shane, Arnold, Leanne, Balleine, Rosemary, Bankier, Agnes, Bastick, Patti, Beesley, Jonathan, Beilby, John, Bennett, Barbara, Bennett, Ian, Berry, Geoffrey, Blackburn, Anneke, Bogwitz, Michael, Brennan, Meagan, Brown, Melissa, Buckley, Michael, Burgess, Matthew, Burke, Jo, Butow, Phyllis, Byron, Keith, Callen, David, Campbell, Ian, Chauhan, Deepa, Chauhan, Manisha, Christian, Alice, Clarke, Christine, Colley, Alison, Cotton, Dick, Crook, Ashley, Cui, James, Culling, Bronwyn, Cummings, Margaret, Dawson, Sarah Jane, deFazio, Anna, Delatycki, Martin, Dickson, Rebecca, Dixon, Joanne, Dobrovic, Alexander, Dudding, Tracy, Edkins, Ted, Edwards, Stacey, Eisenbruch, Maurice, Farshid, Gelareh, Fawcett, Susan, Fellows, Andrew, Fenton, Georgina, Field, Michael, Firgaira, Frank, Flanagan, James, Fleming, Jean, Fong, Peter, Forbes, John, Fox, Stephen, French, Juliet, Friedlander, Michael, Gaff, Clara, Gardner, Mac, Gattas, Mike, George, Peter, Giles, Graham, Gill, Grantley, Goldblatt, Jack, Greening, Sian, Grist, Scott, Haan, Eric, Hardie, Kate, Harris, Marion, Hart, Stewart, Hayward, Nick, Healey, Sue, Heiniger, Louise, Hopper, John, Humphrey, Evelyn, Hunt, Clare, James, Paul, Jenkins, Mark, Jones, Alison, Kefford, Rick, Kidd, Alexa, Kiely, Belinda, Kirk, Judy, Koehler, Jessica, Kollias, James, Kovalenko, Serguei, Lakhani, Sunil, Leaming, Amanda, Leary, Jennifer, Lim, Jacqueline, Lindeman, Geoff, Lipton, Lara, Lobb, Liz, Mann, Graham, Marsh, Deborah, McLachlan, Sue Anne, Meiser, Bettina, Meldrum, Cliff, Milne, Roger, Mitchell, Gillian, Newman, Beth, Niedermayr, Eveline, Nightingale, Sophie, O'Connell, Shona, O'Loughlin, Imelda, Osborne, Richard, Pachter, Nick, Patterson, Briony, Peters, Lester, Phillips, Kelly, Price, Melanie, Purser, Lynne, Reeve, Tony, Reeve, Jeanne, Richards, Robert, Rickard, Edwina, Robinson, Bridget, Rudzki, Barney, Saleh, Mona, Salisbury, Elizabeth, Sambrook, Joe, Saunders, Christobel, Saunus, Jodi, Sayer, Robyn, Scott, Elizabeth, Scott, Rodney, Scott, Clare, Seshadri, Ram, Sexton, Adrienne, Sharma, Raghwa, Shelling, Andrew, Simpson, Peter, Southey, Melissa, Spurdle, Amanda, Suthers, Graeme, Sykes, Pamela, Tassell, Margaret, Taylor, Donna, Taylor, Jessica, Thierry, Benjamin, Thomas, Susan, Thompson, Ella, Thorne, Heather, Townshend, Sharron, Trainer, Alison, Tran, Lan, Tucker, Kathy, Tyler, Janet, Visvader, Jane, Walker, Logan, Walpole, Ian, Ward, Robin, Waring, Paul, Warner, Bev, Warren, Graham, Williams, Rachael, Wilson, Judy, Winship, Ingrid, Wu, Kathy, Young, Mary Ann, Bowtell, D., Green, A., Webb, P., de Fazio, A., Gertig, D., Pharmacoepidemiology and Clinical Pharmacology, Sub Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, and Sub Clinical Pharmacology

Subjects
Medicine(all), endocrine system, Breast cancer, skin and connective tissue diseases, Annexin A1, BRCA1 and BRCA2 mutations
Abstract

Background: Annexin A1 (ANXA1) is a protein related with the carcinogenesis process and metastasis formation in many tumors. However, little is known about the prognostic value of ANXA1 in breast cancer. The purpose of this study is to evaluate the association between ANXA1 expression, BRCA1/2 germline carriership, specific tumor subtypes and survival in breast cancer patients. Methods: Clinical-pathological information and follow-up data were collected from nine breast cancer studies from the Breast Cancer Association Consortium (BCAC) (n = 5,752) and from one study of familial breast cancer patients with BRCA1/2

Published
2015

56. Theme 13 Clinical management and support.

Author

Crook, Ashley, Hogden, Anne, Mumford, Virginia, Blair, Ian P., Williams, Kelly L., Rowe, Dominic B., Fell, Rosie, moura Campos, Cecilia Helena, Cruz, Fabiana Theodoro, Leico Oda, Adriana, O'Brien, Mary R., Oliver, David, Aoun, Samar, Mc Dermott, Christopher J., Kirton, Jennifer, Pearson, Emma, Lucia, Diana, McCombe, Pamela A., Henderson, Robert D., and Steyn, Frederik J.

Subjects
*SOCIAL surveys, *CAREER development
Abstract

2017; The 28th International Symposium on ALS/MND. 32 Costello J. (2012) Preserving legacy: A guide to Message Banking a patient's voice. A phase 1 study to evaluate bioequivalence between BHV-0223 40 mg zydis sublingual formulation and riluzole 50mg oral tablet in healthy volunteers. A phase 1 study to evaluate bioequivalence between BHV-0223 40 mg zydis sublingual formulation and riluzole 50mg oral tablet in healthy volunteers. https://www.biohavenpharma.com/sites/default/files/documents/bvh-0223-bioequivalence-aanem-2018.pdf. [Extracted from the article]

Published
2019
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58. Fumarate Hydratase–deficient Uterine Leiomyomas Occur in Both the Syndromic and Sporadic Settings

Author

Harrison, Wesley J., primary, Andrici, Juliana, additional, Maclean, Fiona, additional, Madadi-Ghahan, Raha, additional, Farzin, Mahtab, additional, Sioson, Loretta, additional, Toon, Christopher W., additional, Clarkson, Adele, additional, Watson, Nicole, additional, Pickett, Justine, additional, Field, Michael, additional, Crook, Ashley, additional, Tucker, Katherine, additional, Goodwin, Annabel, additional, Anderson, Lyndal, additional, Srinivasan, Bhuvana, additional, Grossmann, Petr, additional, Martinek, Petr, additional, Ondič, Ondrej, additional, Hes, Ondřej, additional, Trpkov, Kiril, additional, Clifton-Bligh, Roderick J., additional, Dwight, Trisha, additional, and Gill, Anthony J., additional

Published
2016
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59. Annexin A1 expression in a pooled breast cancer series: Association with tumor subtypes and prognosis

Author

Pharmacoepidemiology and Clinical Pharmacology, Sub Clinical Pharmacology, Sobral-Leite, Marcelo, Wesseling, Jelle, Smit, Vincent T H B M, Nevanlinna, Heli, van Miltenburg, Martine H., Sanders, Joyce, Hofland, Ingrid, Blows, Fiona M., Coulson, Penny, Patrycja, Gazinska, Schellens, Jan H M, Fagerholm, Rainer, Heikkilä, Päivi, Aittomäki, Kristiina, Blomqvist, Carl, Provenzano, Elena, Ali, Hamid Raza, Figueroa, Jonine, Sherman, Mark, Lissowska, Jolanta, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli Matti, Hartikainen, Jaana M., Phillips, Kelly Anne, Couch, Fergus J., Olson, Janet E., Vachon, Celine, Visscher, Daniel, Brenner, Hermann, Butterbach, Katja, Arndt, Volker, Holleczek, Bernd, Hooning, Maartje J., Hollestelle, Antoinette, Martens, John W M, van Deurzen, Carolien H M, van de Water, Bob, Broeks, Annegien, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Easton, Douglas F., Pharoah, Paul D P, García-Closas, Montserrat, de Graauw, Marjo, Schmidt, Marjanka K., Aghmesheh, Morteza, Amor, David, Andrews, Lesley, Antill, Yoland, Armitage, Shane, Arnold, Leanne, Balleine, Rosemary, Bankier, Agnes, Bastick, Patti, Beesley, Jonathan, Beilby, John, Bennett, Barbara, Bennett, Ian, Berry, Geoffrey, Blackburn, Anneke, Bogwitz, Michael, Brennan, Meagan, Brown, Melissa, Buckley, Michael, Burgess, Matthew, Burke, Jo, Butow, Phyllis, Byron, Keith, Callen, David, Campbell, Ian, Chauhan, Deepa, Chauhan, Manisha, Christian, Alice, Clarke, Christine, Colley, Alison, Cotton, Dick, Crook, Ashley, Cui, James, Culling, Bronwyn, Cummings, Margaret, Dawson, Sarah Jane, deFazio, Anna, Delatycki, Martin, Dickson, Rebecca, Dixon, Joanne, Dobrovic, Alexander, Dudding, Tracy, Edkins, Ted, Edwards, Stacey, Eisenbruch, Maurice, Farshid, Gelareh, Fawcett, Susan, Fellows, Andrew, Fenton, Georgina, Field, Michael, Firgaira, Frank, Flanagan, James, Fleming, Jean, Fong, Peter, Forbes, John, Fox, Stephen, French, Juliet, Friedlander, Michael, Gaff, Clara, Gardner, Mac, Gattas, Mike, George, Peter, Giles, Graham, Gill, Grantley, Goldblatt, Jack, Greening, Sian, Grist, Scott, Haan, Eric, Hardie, Kate, Harris, Marion, Hart, Stewart, Hayward, Nick, Healey, Sue, Heiniger, Louise, Hopper, John, Humphrey, Evelyn, Hunt, Clare, James, Paul, Jenkins, Mark, Jones, Alison, Kefford, Rick, Kidd, Alexa, Kiely, Belinda, Kirk, Judy, Koehler, Jessica, Kollias, James, Kovalenko, Serguei, Lakhani, Sunil, Leaming, Amanda, Leary, Jennifer, Lim, Jacqueline, Lindeman, Geoff, Lipton, Lara, Lobb, Liz, Mann, Graham, Marsh, Deborah, McLachlan, Sue Anne, Meiser, Bettina, Meldrum, Cliff, Milne, Roger, Mitchell, Gillian, Newman, Beth, Niedermayr, Eveline, Nightingale, Sophie, O'Connell, Shona, O'Loughlin, Imelda, Osborne, Richard, Pachter, Nick, Patterson, Briony, Peters, Lester, Phillips, Kelly, Price, Melanie, Purser, Lynne, Reeve, Tony, Reeve, Jeanne, Richards, Robert, Rickard, Edwina, Robinson, Bridget, Rudzki, Barney, Saleh, Mona, Salisbury, Elizabeth, Sambrook, Joe, Saunders, Christobel, Saunus, Jodi, Sayer, Robyn, Scott, Elizabeth, Scott, Rodney, Scott, Clare, Seshadri, Ram, Sexton, Adrienne, Sharma, Raghwa, Shelling, Andrew, Simpson, Peter, Southey, Melissa, Spurdle, Amanda, Suthers, Graeme, Sykes, Pamela, Tassell, Margaret, Taylor, Donna, Taylor, Jessica, Thierry, Benjamin, Thomas, Susan, Thompson, Ella, Thorne, Heather, Townshend, Sharron, Trainer, Alison, Tran, Lan, Tucker, Kathy, Tyler, Janet, Visvader, Jane, Walker, Logan, Walpole, Ian, Ward, Robin, Waring, Paul, Warner, Bev, Warren, Graham, Williams, Rachael, Wilson, Judy, Winship, Ingrid, Wu, Kathy, Young, Mary Ann, Bowtell, D., Green, A., Webb, P., de Fazio, A., Gertig, D., Pharmacoepidemiology and Clinical Pharmacology, Sub Clinical Pharmacology, Sobral-Leite, Marcelo, Wesseling, Jelle, Smit, Vincent T H B M, Nevanlinna, Heli, van Miltenburg, Martine H., Sanders, Joyce, Hofland, Ingrid, Blows, Fiona M., Coulson, Penny, Patrycja, Gazinska, Schellens, Jan H M, Fagerholm, Rainer, Heikkilä, Päivi, Aittomäki, Kristiina, Blomqvist, Carl, Provenzano, Elena, Ali, Hamid Raza, Figueroa, Jonine, Sherman, Mark, Lissowska, Jolanta, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli Matti, Hartikainen, Jaana M., Phillips, Kelly Anne, Couch, Fergus J., Olson, Janet E., Vachon, Celine, Visscher, Daniel, Brenner, Hermann, Butterbach, Katja, Arndt, Volker, Holleczek, Bernd, Hooning, Maartje J., Hollestelle, Antoinette, Martens, John W M, van Deurzen, Carolien H M, van de Water, Bob, Broeks, Annegien, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Easton, Douglas F., Pharoah, Paul D P, García-Closas, Montserrat, de Graauw, Marjo, Schmidt, Marjanka K., Aghmesheh, Morteza, Amor, David, Andrews, Lesley, Antill, Yoland, Armitage, Shane, Arnold, Leanne, Balleine, Rosemary, Bankier, Agnes, Bastick, Patti, Beesley, Jonathan, Beilby, John, Bennett, Barbara, Bennett, Ian, Berry, Geoffrey, Blackburn, Anneke, Bogwitz, Michael, Brennan, Meagan, Brown, Melissa, Buckley, Michael, Burgess, Matthew, Burke, Jo, Butow, Phyllis, Byron, Keith, Callen, David, Campbell, Ian, Chauhan, Deepa, Chauhan, Manisha, Christian, Alice, Clarke, Christine, Colley, Alison, Cotton, Dick, Crook, Ashley, Cui, James, Culling, Bronwyn, Cummings, Margaret, Dawson, Sarah Jane, deFazio, Anna, Delatycki, Martin, Dickson, Rebecca, Dixon, Joanne, Dobrovic, Alexander, Dudding, Tracy, Edkins, Ted, Edwards, Stacey, Eisenbruch, Maurice, Farshid, Gelareh, Fawcett, Susan, Fellows, Andrew, Fenton, Georgina, Field, Michael, Firgaira, Frank, Flanagan, James, Fleming, Jean, Fong, Peter, Forbes, John, Fox, Stephen, French, Juliet, Friedlander, Michael, Gaff, Clara, Gardner, Mac, Gattas, Mike, George, Peter, Giles, Graham, Gill, Grantley, Goldblatt, Jack, Greening, Sian, Grist, Scott, Haan, Eric, Hardie, Kate, Harris, Marion, Hart, Stewart, Hayward, Nick, Healey, Sue, Heiniger, Louise, Hopper, John, Humphrey, Evelyn, Hunt, Clare, James, Paul, Jenkins, Mark, Jones, Alison, Kefford, Rick, Kidd, Alexa, Kiely, Belinda, Kirk, Judy, Koehler, Jessica, Kollias, James, Kovalenko, Serguei, Lakhani, Sunil, Leaming, Amanda, Leary, Jennifer, Lim, Jacqueline, Lindeman, Geoff, Lipton, Lara, Lobb, Liz, Mann, Graham, Marsh, Deborah, McLachlan, Sue Anne, Meiser, Bettina, Meldrum, Cliff, Milne, Roger, Mitchell, Gillian, Newman, Beth, Niedermayr, Eveline, Nightingale, Sophie, O'Connell, Shona, O'Loughlin, Imelda, Osborne, Richard, Pachter, Nick, Patterson, Briony, Peters, Lester, Phillips, Kelly, Price, Melanie, Purser, Lynne, Reeve, Tony, Reeve, Jeanne, Richards, Robert, Rickard, Edwina, Robinson, Bridget, Rudzki, Barney, Saleh, Mona, Salisbury, Elizabeth, Sambrook, Joe, Saunders, Christobel, Saunus, Jodi, Sayer, Robyn, Scott, Elizabeth, Scott, Rodney, Scott, Clare, Seshadri, Ram, Sexton, Adrienne, Sharma, Raghwa, Shelling, Andrew, Simpson, Peter, Southey, Melissa, Spurdle, Amanda, Suthers, Graeme, Sykes, Pamela, Tassell, Margaret, Taylor, Donna, Taylor, Jessica, Thierry, Benjamin, Thomas, Susan, Thompson, Ella, Thorne, Heather, Townshend, Sharron, Trainer, Alison, Tran, Lan, Tucker, Kathy, Tyler, Janet, Visvader, Jane, Walker, Logan, Walpole, Ian, Ward, Robin, Waring, Paul, Warner, Bev, Warren, Graham, Williams, Rachael, Wilson, Judy, Winship, Ingrid, Wu, Kathy, Young, Mary Ann, Bowtell, D., Green, A., Webb, P., de Fazio, A., and Gertig, D.

Published
2015

60. BRAFV600E Immunohistochemistry Facilitates Universal Screening of Colorectal Cancers for Lynch Syndrome

Author

Toon, Christopher W., primary, Walsh, Michael D., additional, Chou, Angela, additional, Capper, David, additional, Clarkson, Adele, additional, Sioson, Loretta, additional, Clarke, Stephen, additional, Mead, Scott, additional, Walters, Rhiannon J., additional, Clendenning, Mark, additional, Rosty, Christophe, additional, Young, Joanne P., additional, Win, Aung Ko, additional, Hopper, John L., additional, Crook, Ashley, additional, von Deimling, Andreas, additional, Jenkins, Mark A., additional, Buchanan, Daniel D., additional, and Gill, Anthony J., additional

Published
2013
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62. The systemic nodule number regulation kinase SUNN in Medicago truncatula interacts with Mt CLV2 and Mt CRN.

Author

Crook, Ashley D., Schnabel, Elise L., and Frugoli, Julia A.

Subjects
*MEDICAGO truncatula, *CELLULAR signal transduction, *ROOT-tubercles, *PHENOTYPES, *PLANT mutation
Abstract

Autoregulation of nodulation ( AON), a systemic signaling pathway in legumes, limits the number of nodules formed by the legume in its symbiosis with rhizobia. Recent research suggests a model for the systemic regulation in Medicago truncatula in which root signaling peptides are translocated to the shoot where they bind to a shoot receptor complex containing the leucine-rich repeat receptor-like kinase SUNN, triggering signal transduction which terminates nodule formation in roots. Here we show that a tagged SUNN protein capable of rescuing the sunn-4 phenotype is localized to the plasma membrane and is associated with the plasmodesmata. Using bimolecular fluorescence complementation analysis we show that, like its sequence ortholog Arabidopsis CLV1, SUNN interacts with homologous CLV1-interacting proteins Mt CLAVATA2 and Mt CORYNE. All three proteins were also able to form homomers and Mt CRN and Mt CLV2 also interact with each other. A crn Tnt1 insertion mutant of M. truncatula displayed a shoot controlled increased nodulation phenotype, similar to the clv2 mutants of pea and Lotus japonicus. Together these data suggest that legume AON signaling could occur through a multi-protein complex and that both Mt CRN and Mt CLV2 may play roles in AON together with SUNN. [ABSTRACT FROM AUTHOR]

Published
2016
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63. Connecting patients, researchers and clinical genetics services: the experiences of participants in the Australian Ovarian Cancer Study (AOCS).

Author

Crook, Ashley, Plunkett, Loren, Forrest, Laura E, Hallowell, Nina, Wake, Samantha, Alsop, Kathryn, Gleeson, Margaret, Bowtell, David, Mitchell, Gillian, and Young, Mary-Anne

Subjects
*OVARIAN cancer, *GENETIC research, *MEDICAL genetics, *CANCER research
Abstract

Population-based genetic research may produce information that has clinical implications for participants and their family. Researchers notify participants or their next of kin (NoK) about the availability of genetic information via a notification letter; however, many subsequently do not contact a family cancer centre (FCC) to clarify their genetic status. Therefore, the purpose of this study was to examine research participants' experience of receiving a notification letter and the factors that influenced contact with an FCC. Twenty-five semi-structured interviews were conducted with research participants (n=10) or their NoK (n=15) who had received a notification letter following participation in the Australian Ovarian Cancer Study. There were a number of factors which impacted participants' access to genetic counselling at an FCC. Some participants had unmet information and support needs, which were addressed by their participation in this psychosocial interview study. Recruitment and participation in this study therefore inadvertently increased a number of participants' intention to contact an FCC. For others, participation in this study facilitated access to an FCC. Recommendations are proposed regarding future notification as well as implications for clinical practice. An approach that also provides opportunity to address research participants' support and informational needs before contacting a clinical genetics service as well as practical guidance for accessing genetic services would facilitate timely and smooth access for research participants who are interested in following up clinically relevant genetic test results. [ABSTRACT FROM AUTHOR]

Published
2015
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64. CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers

Author

Johnson, Nichola, Maguire, Sarah, Morra, Anna, Kapoor, Pooja Middha, Tomczyk, Katarzyna, Jones, Michael E., Schoemaker, Minouk J., Gilham, Clare, Bolla, Manjeet K., Wang, Qin, Dennis, Joe, Ahearn, Thomas U., Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Arndt, Volker, Aronson, Kristan J., Augustinsson, Annelie, Baynes, Caroline, Freeman, Laura E. Beane, Beckmann, Matthias W., Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Boeckx, Bram, Bogdanova, Natalia V., Bojesen, Stig E., Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Campa, Daniele, Canzian, Federico, Castelao, Jose E., Chanock, Stephen J., Chenevix-Trench, Georgia, Clarke, Christine L., Conroy, Don M., Couch, Fergus J., Cox, Angela, Cross, Simon S., Czene, Kamila, Dörk, Thilo, Eliassen, A. Heather, Engel, Christoph, Evans, D. Gareth, Fasching, Peter A., Figueroa, Jonine, Floris, Giuseppe, Flyger, Henrik, Gago-Dominguez, Manuela, Gapstur, Susan M., García-Closas, Montserrat, Gaudet, Mia M., Giles, Graham G., Goldberg, Mark S., González-Neira, Anna, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A., Håkansson, Niclas, Hall, Per, Hamann, Ute, Harrington, Patricia A., Hart, Steven N., Hooning, Maartje J., Hopper, John L., Howell, Anthony, Hunter, David J., Jager, Agnes, Jakubowska, Anna, John, Esther M., Kaaks, Rudolf, Keeman, Renske, Khusnutdinova, Elza, Kitahara, Cari M., Kosma, Veli-Matti, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N., Kurian, Allison W., Lambrechts, Diether, Le Marchand, Loic, Linet, Martha, Lubiński, Jan, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Martens, John W. M., Mavroudis, Dimitrios, Mayes, Rebecca, Meindl, Alfons, Milne, Roger L., Neuhausen, Susan L., Nevanlinna, Heli, Newman, William G., Nielsen, Sune F., Nordestgaard, Børge G., Obi, Nadia, Olshan, Andrew F., Olson, Janet E., Olsson, Håkan, Orban, Ester, Park-Simon, Tjoung-Won, Peterlongo, Paolo, Plaseska-Karanfilska, Dijana, Pylkäs, Katri, Rennert, Gad, Rennert, Hedy S., Ruddy, Kathryn J., Saloustros, Emmanouil, Sandler, Dale P., Sawyer, Elinor J., Schmutzler, Rita K., Scott, Christopher, Shu, Xiao-Ou, Simard, Jacques, Smichkoska, Snezhana, Sohn, Christof, Southey, Melissa C., Spinelli, John J., Stone, Jennifer, Tamimi, Rulla M., Taylor, Jack A., Tollenaar, Rob A. E. M., Tomlinson, Ian, Troester, Melissa A., Truong, Thérèse, Vachon, Celine M., Van Veen, Elke M., Wang, Sophia S., Weinberg, Clarice R., Wendt, Camilla, Wildiers, Hans, Winqvist, Robert, Wolk, Alicja, Zheng, Wei, Ziogas, Argyrios, Dunning, Alison M., Pharoah, Paul D. P., Easton, Douglas F., Howie, A. Forbes, Peto, Julian, Dos-Santos-Silva, Isabel, Swerdlow, Anthony J., Chang-Claude, Jenny, Schmidt, Marjanka K., Orr, Nick, Fletcher, Olivia, Børresen-Dale, Anne-Lise, Alnæs, Grethe I. Grenaker, Sahlberg, Kristine K., Ottestad, Lars, Kåresen, Rolf, Schlichting, Ellen, Holmen, Marit Muri, Sauer, Toril, Haakensen, Vilde, Engebråten, Olav, Naume, Bjørn, Fosså, Alexander, Kiserud, Cecile E., Reinertsen, Kristin V., Helland, Åslaug, Riis, Margit, Geisler, Jürgen, Bowtell, David D. L., DeFazio, Anna, Webb, Penelope M., Clarke, Christine, Marsh, Deborah, Scott, Rodney, Baxter, Robert, Yip, Desmond, Carpenter, Jane, Davis, Alison, Pathmanathan, Nirmala, Simpson, Peter, Graham, Dinny, Sachchithananthan, Mythily, Amor, David, Andrews, Lesley, Antill, Yoland, Balleine, Rosemary, Beesley, Jonathan, Bennett, Ian, Bogwitz, Michael, Botes, Leon, Brennan, Meagan, Brown, Melissa, Buckley, Michael, Burke, Jo, Butow, Phyllis, Caldon, Liz, Campbell, Ian, Chauhan, Deepa, Chauhan, Manisha, Christian, Alice, Cohen, Paul, Colley, Alison, Crook, Ashley, Cui, James, Cummings, Margaret, Dawson, Sarah-Jane, Delatycki, Martin, Dickson, Rebecca, Dixon, Joanne, Edkins, Ted, Edwards, Stacey, Farshid, Gelareh, Fellows, Andrew, Fenton, Georgina, Field, Michael, Flanagan, James, Fong, Peter, Forrest, Laura, Fox, Stephen, French, Juliet, Friedlander, Michael, Gaff, Clara, Gattas, Mike, George, Peter, Greening, Sian, Harris, Marion, Hart, Stewart, Hayward, Nick, Hopper, John, Hoskins, Cass, Hunt, Clare, James, Paul, Jenkins, Mark, Kidd, Alexa, Kirk, Judy, Koehler, Jessica, Kollias, James, Lakhani, Sunil, Lawrence, Mitchell, Lindeman, Geoff, Lipton, Lara, Lobb, Liz, Mann, Graham, McLachlan, Sue Anne, Meiser, Bettina, Milne, Roger, Nightingale, Sophie, O’Connell, Shona, O’Sullivan, Sarah, Ortega, David Gallego, Pachter, Nick, Patterson, Briony, Pearn, Amy, Phillips, Kelly, Pieper, Ellen, Rickard, Edwina, Robinson, Bridget, Saleh, Mona, Salisbury, Elizabeth, Saunders, Christobel, Saunus, Jodi, Scott, Clare, Sexton, Adrienne, Shelling, Andrew, Southey, Melissa, Spurdle, Amanda, Taylor, Jessica, Taylor, Renea, Thorne, Heather, Trainer, Alison, Tucker, Kathy, Visvader, Jane, Walker, Logan, Williams, Rachael, Winship, Ingrid, and Young, Mary Ann

Subjects
631/67/68, article, 631/67/2324, 631/67/1347, 3. Good health
Abstract

Funder: Breast Cancer Now (BCN); doi: https://doi.org/10.13039/100009794, Funder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289, Funder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265, Funder: U.S. Department of Health & Human Services | National Institutes of Health (NIH), Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440, Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): HEALTH-F2-2009-223175, HEALTH-F2-2009-223175, Funder: Genome Canada (Génome Canada); doi: https://doi.org/10.13039/100008762, Funder: Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada); doi: https://doi.org/10.13039/501100000024, Funder: Quebec Breast cancer Foundation Genome Quebec, Funder: U.S. Department of Health & Human Services | NIH | U.S. National Library of Medicine (NLM); doi: https://doi.org/10.13039/100000092, Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)), Funder: European Union’s Horizon 2020, Funder: Deutsche Krebshilfe (German Cancer Aid); doi: https://doi.org/10.13039/501100005972, Funder: BCAST - European Union’s Horizon 2020, Funder: Breast Cancer Now; doi: https://doi.org/10.13039/501100007913, Background: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. Methods: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. Results: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (−49.2%, 95% CI −56.1% to −41.1%, P = 3.1 × 10–18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (−26.7%, 95% CI −39.4% to −11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82–0.91, P = 6.9 × 10–8). Conclusions: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.

65. Homologous recombination DNA repair defects in PALB2- associated breast cancers

Author

Li, Anqi, Geyer, Felipe C., Blecua, Pedro, Lee, Ju Youn, Selenica, Pier, Brown, David N., Pareja, Fresia, Lee, Simon S. K., Kumar, Rahul, Rivera, Barbara, Bi, Rui, Piscuoglio, Salvatore, Wen, Hannah Y., Lozada, John R., Gularte-Mérida, Rodrigo, Cavallone, Luca, Rezoug, Zoulikha, Nguyen-Dumont, Tu, Peterlongo, Paolo, Tondini, Carlo, Terkelsen, Thorkild, Rønlund, Karina, Boonen, Susanne E., Mannerma, Arto, Winqvist, Robert, Janatova, Marketa, Rajadurai, Pathmanathan, Xia, Bing, Norton, Larry, Robson, Mark E., Ng, Pei-Sze, Looi, Lai-Meng, Southey, Melissa C., Weigelt, Britta, Soo-Hwang, Teo, Tischkowitz, Marc, Foulkes, William D., Reis-Filho, Jorge S., Aghmesheh, Morteza, Amor, David, Andrews, Leslie, Antill, Yoland, Balleine, Rosemary, Beesley, Jonathan, Blackburn, Anneke, Bogwitz, Michael, Brown, Melissa, Burgess, Matthew, Burke, Jo, Butow, Phyllis, Caldon, Liz, Campbell, Ian, Christian, Alice, Clarke, Christine, Cohen, Paul, Crook, Ashley, Cui, James, Cummings, Margaret, Dawson, Sarah-Jane, De Fazio, Anna, Delatycki, Martin, Dobrovic, Alex, Dudding, Tracy, Duijf, Pascal, Edkins, Edward, Edwards, Stacey, Farshid, Gelareh, Fellows, Andrew, Field, Michael, Flanagan, James, Fong, Peter, Forbes, John, Forrest, Laura, Fox, Stephen, French, Juliet, Friedlander, Michael, Ortega, David Gallego, Gattas, Michael, Giles, Graham, Gill, Grantley, Gleeson, Margaret, Greening, Sian, Haan, Eric, Harris, Marion, Hayward, Nick, Hickie, Ian, Hopper, John, Hunt, Clare, James, Paul, Jenkins, Mark, Kefford, Rick, Kentwell, Maira, Kirk, Judy, Kollias, James, Lakhani, Sunil, Lindeman, Geoff, Lipton, Lara, Lobb, Lizz, Lok, Sheau, Macrea, Finlay, Mann, Graham, Marsh, Deb, McLachlan, Sue-Anne, Meiser, Bettina, Milne, Roger, Nightingale, Sophie, O’Connell, Shona, Pachter, Nick, Patterson, Briony, Phillips, Kelly, Saleh, Mona, Salisbury, Elizabeth, Saunders, Christobel, Saunus, Jodi, Scott, Clare, Scott, Rodney, Sexton, Adrienne, Shelling, Andrew, Simpson, Peter, Spigelman, Allan, Spurdle, Mandy, Stone, Jennifer, Taylor, Jessica, Thorne, Heather, Trainer, Alison, Trench, Georgia, Tucker, Kathy, Visvader, Jane, Walker, Logan, Wallis, Mathew, Williams, Rachael, Winship, Ingrid, Wu, Kathy, and Young, Mary Anne

Subjects
631/67/68, article, 631/67/1347, 692/699/67/69, 3. Good health
Abstract

Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD.

66. The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Author

Figlioli, Gisella, Bogliolo, Massimo, Catucci, Irene, Caleca, Laura, Lasheras, Sandra Viz, Pujol, Roser, Kiiski, Johanna I., Muranen, Taru A., Barnes, Daniel R., Dennis, Joe, Michailidou, Kyriaki, Bolla, Manjeet K., Leslie, Goska, Aalfs, Cora M., Adank, Muriel A., Adlard, Julian, Agata, Simona, Cadoo, Karen, Agnarsson, Bjarni A., Ahearn, Thomas, Aittomäki, Kristiina, Ambrosone, Christine B., Andrews, Lesley, Anton-Culver, Hoda, Antonenkova, Natalia N., Arndt, Volker, Arnold, Norbert, Aronson, Kristan J., Arun, Banu K., Asseryanis, Ella, Auber, Bernd, Auvinen, Päivi, Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B., Barrowdale, Daniel, Barwell, Julian, Beane Freeman, Laura E., Beauparlant, Charles Joly, Beckmann, Matthias W., Behrens, Sabine, Benitez, Javier, Berger, Raanan, Bermisheva, Marina, Blanco, Amie M., Blomqvist, Carl, Bogdanova, Natalia V., Bojesen, Anders, Bojesen, Stig E., Bonanni, Bernardo, Borg, Ake, Brady, Angela F., Brauch, Hiltrud, Brenner, Hermann, Brüning, Thomas, Burwinkel, Barbara, Buys, Saundra S., Caldés, Trinidad, Caliebe, Almuth, Caligo, Maria A., Campa, Daniele, Campbell, Ian G., Canzian, Federico, Castelao, Jose E., Chang-Claude, Jenny, Chanock, Stephen J., Claes, Kathleen B. M., Clarke, Christine L., Collavoli, Anita, Conner, Thomas A., Cox, David G., Cybulski, Cezary, Czene, Kamila, Daly, Mary B., De La Hoya, Miguel, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Dite, Gillian S., Ditsch, Nina, Domchek, Susan M., Dorfling, Cecilia M., Dos-Santos-Silva, Isabel, Durda, Katarzyna, Dwek, Miriam, Eccles, Diana M., Ekici, Arif B., Eliassen, A. Heather, Ellberg, Carolina, Eriksson, Mikael, Evans, D. Gareth, Fasching, Peter A., Figueroa, Jonine, Flyger, Henrik, Foulkes, William D., Friebel, Tara M., Friedman, Eitan, Gabrielson, Marike, Gaddam, Pragna, Gago-Dominguez, Manuela, Gao, Chi, Gapstur, Susan M., Garber, Judy, García-Closas, Montserrat, García-Sáenz, José A., Gaudet, Mia M., Gayther, Simon A., Giles, Graham G., Glendon, Gord, Godwin, Andrew K., Goldberg, Mark S., Goldgar, David E., Guénel, Pascal, Gutierrez-Barrera, Angelica M., Haeberle, Lothar, Haiman, Christopher A., Håkansson, Niclas, Hall, Per, Hamann, Ute, Harrington, Patricia A., Hein, Alexander, Heyworth, Jane, Hillemanns, Peter, Hollestelle, Antoinette, Hopper, John L., Hosgood, H. Dean, Howell, Anthony, Hu, Chunling, Hulick, Peter J., Hunter, David J., Imyanitov, Evgeny N., Isaacs, Claudine, Jakimovska, Milena, Jakubowska, Anna, James, Paul, Janavicius, Ramunas, Janni, Wolfgang, John, Esther M., Jones, Michael E., Jung, Audrey, Kaaks, Rudolf, Karlan, Beth Y., Khusnutdinova, Elza, Kitahara, Cari M., Konstantopoulou, Irene, Koutros, Stella, Kraft, Peter, Lambrechts, Diether, Lazaro, Conxi, Le Marchand, Loic, Lester, Jenny, Lesueur, Fabienne, Lilyquist, Jenna, Loud, Jennifer T., Lu, Karen H., Luben, Robert N., Lubinski, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martens, John W. M., Maurer, Tabea, Mavroudis, Dimitrios, Mebirouk, Noura, Meindl, Alfons, Menon, Usha, Miller, Austin, Montagna, Marco, Nathanson, Katherine L., Neuhausen, Susan L., Newman, William G., Nguyen-Dumont, Tu, Nielsen, Finn Cilius, Nielsen, Sarah, Nikitina-Zake, Liene, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I., Olshan, Andrew F., Olson, Janet E., Olsson, Håkan, Osorio, Ana, Ottini, Laura, Peissel, Bernard, Peixoto, Ana, Peto, Julian, Plaseska-Karanfilska, Dijana, Pocza, Timea, Presneau, Nadege, Pujana, Miquel Angel, Punie, Kevin, Rack, Brigitte, Rantala, Johanna, Rashid, Muhammad U., Rau-Murthy, Rohini, Rennert, Gad, Lejbkowicz, Flavio, Rhenius, Valerie, Romero, Atocha, Rookus, Matti A., Ross, Eric A., Rossing, Maria, Rudaitis, Vilius, Ruebner, Matthias, Saloustros, Emmanouil, Sanden, Kristin, Santamariña, Marta, Scheuner, Maren T., Schmutzler, Rita K., Schneider, Michael, Scott, Christopher, Senter, Leigha, Shah, Mitul, Sharma, Priyanka, Shu, Xiao-Ou, Simard, Jacques, Singer, Christian F., Sohn, Christof, Soucy, Penny, Southey, Melissa C., Spinelli, John J., Steele, Linda, Stoppa-Lyonnet, Dominique, Tapper, William J., Teixeira, Manuel R., Terry, Mary Beth, Thomassen, Mads, Thompson, Jennifer, Thull, Darcy L., Tischkowitz, Marc, Tollenaar, Rob A.E.M., Torres, Diana, Troester, Melissa A., Truong, Thérèse, Tung, Nadine, Untch, Michael, Vachon, Celine M., Van Rensburg, Elizabeth J., Van Veen, Elke M., Vega, Ana, Viel, Alessandra, Wappenschmidt, Barbara, Weitzel, Jeffrey N., Wendt, Camilla, Wieme, Greet, Wolk, Alicja, Yang, Xiaohong R., Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K., Dunning, Alison M., Lush, Michael, Wang, Qin, McGuffog, Lesley, Parsons, Michael T., Pharoah, Paul D. P., Fostira, Florentia, Toland, Amanda E., Andrulis, Irene L., Ramus, Susan J., Swerdlow, Anthony J., Greene, Mark H., Chung, Wendy K., Milne, Roger L., Chenevix-Trench, Georgia, Dörk, Thilo, Schmidt, Marjanka K., Easton, Douglas F., Radice, Paolo, Hahnen, Eric, Antoniou, Antonis C., Couch, Fergus J., Nevanlinna, Heli, Surrallés, Jordi, Peterlongo, Paolo, Balleine, Rosemary, Baxter, Robert, Braye, Stephen, Carpenter, Jane, Dahlstrom, Jane, Forbes, John, Lee, C. Soon, Marsh, Deborah, Morey, Adrienne, Pathmanathan, Nirmala, Scott, Rodney, Simpson, Peter, Spigelman, Allan, Wilcken, Nicholas, Yip, Desmond, Zeps, Nikolajs, Belotti, Muriel, Bertrand, Ophélie, Birot, Anne-Marie, Buecher, Bruno, Caputo, Sandrine, Dupré, Anaïs, Fourme, Emmanuelle, Gauthier-Villars, Marion, Golmard, Lisa, Le Mentec, Marine, Moncoutier, Virginie, De Pauw, Antoine, Saule, Claire, Boutry-Kryza, Nadia, Calender, Alain, Giraud, Sophie, Léone, Mélanie, Bressac-De-Paillerets, Brigitte, Caron, Olivier, Guillaud-Bataille, Marine, Bignon, Yves-Jean, Uhrhammer, Nancy, Bonadona, Valérie, Lasset, Christine, Berthet, Pascaline, Castera, Laurent, Vaur, Dominique, Bourdon, Violaine, Noguès, Catherine, Noguchi, Tetsuro, Popovici, Cornel, Remenieras, Audrey, Sobol, Hagay, Coupier, Isabelle, Pujol, Pascal, Adenis, Claude, Dumont, Aurélie, Révillion, Françoise, Muller, Danièle, Barouk-Simonet, Emmanuelle, Bonnet, Françoise, Bubien, Virginie, Longy, Michel, Sevenet, Nicolas, Gladieff, Laurence, Guimbaud, Rosine, Feillel, Viviane, Toulas, Christine, Dreyfus, Hélène, Leroux, Christine Dominique, Peysselon, Magalie, Rebischung, Christine, Legrand, Clémentine, Baurand, Amandine, Bertolone, Geoffrey, Coron, Fanny, Faivre, Laurence, Jacquot, Caroline, Lizard, Sarab, Kientz, Caroline, Lebrun, Marine, Prieur, Fabienne, Fert-Ferrer, Sandra, Mari, Véronique, Vénat-Bouvet, Laurence, Bézieau, Stéphane, Delnatte, Capucine, Mortemousque, Isabelle, Colas, Chrystelle, Coulet, Florence, Soubrier, Florent, Warcoin, Mathilde, Bronner, Myriam, Sokolowska, Johanna, Collonge-Rame, Marie-Agnès, Damette, Alexandre, Gesta, Paul, Lallaoui, Hakima, Chiesa, Jean, Molina-Gomes, Denise, Ingster, Olivier, Manouvrier-Hanu, Sylvie, Lejeune, Sophie, Aghmesheh, Morteza, Greening, Sian, Amor, David, Gattas, Mike, Botes, Leon, Buckley, Michael, Friedlander, Michael, Koehler, Jessica, Meiser, Bettina, Saleh, Mona, Salisbury, Elizabeth, Trainer, Alison, Tucker, Kathy, Antill, Yoland, Dobrovic, Alexander, Fellows, Andrew, Fox, Stephen, Harris, Marion, Nightingale, Sophie, Phillips, Kelly, Sambrook, Joe, Thorne, Heather, Armitage, Shane, Arnold, Leanne, Kefford, Rick, Kirk, Judy, Rickard, Edwina, Bastick, Patti, Beesley, Jonathan, Hayward, Nick, Spurdle, Amanda, Walker, Logan, Beilby, John, Saunders, Christobel, Bennett, Ian, Blackburn, Anneke, Bogwitz, Michael, Gaff, Clara, Lindeman, Geoff, Pachter, Nick, Scott, Clare, Sexton, Adrienne, Visvader, Jane, Taylor, Jessica, Winship, Ingrid, Brennan, Meagan, Brown, Melissa, French, Juliet, Edwards, Stacey, Burgess, Matthew, Burke, Jo, Patterson, Briony, Butow, Phyllis, Culling, Bronwyn, Caldon, Liz, Callen, David, Chauhan, Deepa, Eisenbruch, Maurice, Heiniger, Louise, Chauhan, Manisha, Christian, Alice, Dixon, Joanne, Kidd, Alexa, Cohen, Paul, Colley, Alison, Fenton, Georgina, Crook, Ashley, Dickson, Rebecca, Field, Michael, Cui, James, Cummings, Margaret, Dawson, Sarah-Jane, DeFazio, Anna, Delatycki, Martin, Dudding, Tracy, Edkins, Ted, Farshid, Gelareh, Flanagan, James, Fong, Peter, Forrest, Laura, Gallego-Ortega, David, George, Peter, Gill, Grantley, Kollias, James, Haan, Eric, Hart, Stewart, Jenkins, Mark, Hunt, Clare, Lakhani, Sunil, Lipton, Lara, Lobb, Liz, Mann, Graham, McLachlan, Sue Anne, O’Connell, Shona, O’Sullivan, Sarah, Pieper, Ellen, Robinson, Bridget, Saunus, Jodi, Scott, Elizabeth, Shelling, Andrew, Williams, Rachael, and Young, Mary Ann

Subjects
692/4028/67/68, 631/67/68, article, nutritional and metabolic diseases, 631/208/68, skin and connective tissue diseases, 3. Good health
Abstract

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.

67. Bayesian approach to determining penetrance of pathogenic SDH variants

Author

Benn, Diana E, Zhu, Ying, Andrews, Katrina A, Wilding, Mathilda, Duncan, Emma L, Dwight, Trisha, Tothill, Richard W, Burgess, John, Crook, Ashley, Gill, Anthony J, Hicks, Rodney J, Kim, Edward, Luxford, Catherine, Marfan, Helen, Richardson, Anne Louise, Robinson, Bruce, Schlosberg, Arran, Susman, Rachel, Tacon, Lyndal, Trainer, Alison, Tucker, Katherine, Maher, Eamonn R, Field, Michael, and Clifton-Bligh, Roderick J

Subjects
Genotype, Models, Genetic, Australia, Genetic Variation, Bayes Theorem, Penetrance, succinate dehydrogenase, pheochromocytoma, United Kingdom, 3. Good health, Isoenzymes, paraganglioma, pathogenic variant, Phenotype, Humans, Genetic Predisposition to Disease, Algorithms, Alleles, Genetic Association Studies
Abstract

BACKGROUND: Until recently, determining penetrance required large observational cohort studies. Data from the Exome Aggregate Consortium (ExAC) allows a Bayesian approach to calculate penetrance, in that population frequencies of pathogenic germline variants should be inversely proportional to their penetrance for disease. We tested this hypothesis using data from two cohorts for succinate dehydrogenase subunits A, B and C (SDHA-C) genetic variants associated with hereditary pheochromocytoma/paraganglioma (PC/PGL). METHODS: Two cohorts were 575 unrelated Australian subjects and 1240 unrelated UK subjects, respectively, with PC/PGL in whom genetic testing had been performed. Penetrance of pathogenic SDHA-C variants was calculated by comparing allelic frequencies in cases versus controls from ExAC (removing those variants contributed by The Cancer Genome Atlas). RESULTS: Pathogenic SDHA-C variants were identified in 106 subjects (18.4%) in cohort 1 and 317 subjects (25.6%) in cohort 2. Of 94 different pathogenic variants from both cohorts (seven in SDHA, 75 in SDHB and 12 in SDHC), 13 are reported in ExAC (two in SDHA, nine in SDHB and two in SDHC) accounting for 21% of subjects with SDHA-C variants. Combining data from both cohorts, estimated lifetime disease penetrance was 22.0% (95% CI 15.2% to 30.9%) for SDHB variants, 8.3% (95% CI 3.5% to 18.5%) for SDHC variants and 1.7% (95% CI 0.8% to 3.8%) for SDHA variants. CONCLUSION: Pathogenic variants in SDHB are more penetrant than those in SDHC and SDHA. Our findings have important implications for counselling and surveillance of subjects carrying these pathogenic variants.

68. Interacting partners of the SUNN symbiotic kinase

Author

Crook, Ashley Dawn Zearfoss

Abstract

The control of nodule number in legumes is primarily accomplished through a complex systemic signaling pathway termed autoregulation of nodulation (AON). The protein kinase SUNN, a leucine-rich repeat receptor-like kinase, exhibits shoot control of AON. I show subcellular localization of SUNN to the plasma membrane and specifically to the plasmodesmata, a prime location for systemic signaling. To aid in better understanding the mechanisms of signaling in AON, I used different approaches to identify potential protein-protein interactions involving SUNN, including candidate genes, exploratory proteomics, and forward genetic screens. Candidate interactors, including CLAVATA2 (CLV2), CORYNE (CRN) and guanine exchange factors of the RopGEF family, were investigated using the bimolecular fluorescence complementation (BiFC) assay with SUNN and mutant analysis for their role in AON. I report positive BiFC interactions between SUNN and CLV2, CRN, RopGEF1, RopGEF2, and RopGEF5. Mutant analysis of these candidate proteins provide additional support for a role in AON. In legumes, mutations in either CLV2 or CRN, and RNAi of RopGEF1, RopGEF2, or RopGEF5 in roots render hypernodulation phenotypes. Taken together, my results suggest a signaling complex involving SUNN is formed in the shoots to transduce a signal from the roots into a signal back to the roots through the activation of GTPases by RopGEFs, ultimately regulating nodulation events. I also identified 22 novel putative interactors of SUNN stemming from an exploratory proteomics experiment involving transgenic M. truncatula carrying SUNN-YFP/HA that were subjected to co-immunoprecipitation to isolate protein complexes that contain the transgene. The precipitated proteins were identified by LC-MS/MS and are presented here as putative interacting partners. In addition, a forward genetics approach identified components of the AON signaling pathway. Utilizing a genetic suppressor screen of sunn-1, we identified four independent lines carrying mutations that suppress the supernodulation phenotype of sunn-1. The mapping of one of these suppressor lines pinpointed the location of the lesion to an approximately 150 kB region on Linkage Group 2 harboring about 26 annotated genes.

Published
2015

69. CMS-01 Genetic testing for familial amyotrophic lateral sclerosis (ALS): insights and challenges.

Author

Crook A, Hogden A, Mumford V, Blair IP, Williams KL, and Rowe DB

Abstract

Background: Pathogenic variants in ALS genes are known to be present in up to 70% of familial and 10% of apparently sporadic ALS cases, and can be associated with risks for ALS only, or risks for other neurodegenerative diseases (eg. frontotemporal dementia). While there are no changes to medical management for patients confirmed as pathogenic variant carriers, genetic testing may be important for future drug trials. Confirmation of a pathogenic variant also provides relatives with the opportunity to consider predictive and/or reproductive genetic testing. Genetic counselling is an important aspect of testing decision-making as it enables individuals to make informed decisions about genetic testing while minimising adverse psychological, ethical and legal outcomes. Few studies have explored how individuals decide whether to pursue testing, nor the needs and experiences of familial ALS families. Objective: To identify factors that influence patient and family member decision-making about genetic testing for ALS genes, assess the impact of familial disease on the patient and their family, and identify information and support needs. Methods: In-depth, semi-structured interviews with individuals from Australian ALS families with known pathogenic gene variants explored experiences of familial ALS, and factors that influenced genetic testing decision-making. Interviews were analysed using an inductive approach. Results: Thirty-four individuals from 24 families were interviewed and included patients ( n  = 4), spouses ( n  = 4), and asymptomatic at-risk relatives ( n  = 26). Life stage, experience of disease, costs, research opportunities, and attitudes to familial ALS and/or reproductive options influenced decision-making. Some patients and relatives experienced difficulty gaining accurate information from their health professionals about the costs and implications of genetic counselling or testing, resulting in a reluctance to proceed. Discussion and conclusion: This study provides new insight into the Australian experience of genetic testing and counselling for familial ALS. It highlights the need to work together with other health professionals to ensure the complexities of genetic testing decision-making, and referral pathways are better understood.

Published
2019
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