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5. Significant benefits of AIP testing and clinical screening in familial isolated and young-onset pituitary tumors

Author

Marques, P, Caimari, F, Hernández-Ramírez, LC, Collier, D, Iacovazzo, D, Ronaldson, A, Magid, K, Lim, CT, Stals, K, Ellard, S, Grossman, AB, Korbonits, M, Abraham, P, Aflorei, E, Agha, A, Ahlquist, J, Akker, SA, Alexandraki, K, Alföldi, S, Anselmo, J, Arlt, W, Atkinson, B, Aulinas-Masó, A, Aylwin, SJ, Baborie, A, Backeljauw, PF, Badiu, C, Baldeweg, S, Ball, S, Bano, G, Barkan, A, Barton, J, Barwell, J, Bates, P, Bernal-González, C, Besser, M, Bevan, JS, Bickerton, A, Blair, J, Bolanowski, M, Bouloux, P, Bradley, L, Bradley, K, Brain, C, Brooke, A, Brown, R, Buchfelder, M, Burren, C, Cakir, M, Canham, N, Capraro, J, Carroll, P, Carter, P, Carty, D, Cavlan, D, Chahal, HS, Cheetham, T, Chentli, F, Choong, C, Christ-Crain, M, Chung, T-T, Clayton, P, Clayton, RN, Cohen, M, Courtney, H, Cove, D, Crowne, E, Cuthbertson, D, Dal, J, Dalantaeva, N, Damjanovic, S, Daousi, C, Darzy, K, Dattani, M, Davies, M, Davies, J, Davis, J, de Castro, M, de Marinis, L, Deal, C, Dénes, J, Dimitri, P, Dorward, N, Dow, G, Drake, W, Druce, M, Drummond, J, Dutta, P, Dzeranova, L, Edén-Engström, B, Eeles, R, Elfving, M, Ellis, K, Elston, M, Emmerson, L, Ezzat, S, Fersht, N, Fica, S, Fischli, S, Fleseriu, M, Forsythe, E, Foulkes, W, Freda, P, Friedman, T, Gadelha, M, Gainsborough, M, Gallacher, S, Gallego, P, Gan, H-W, Georgescu, C, Gevers, E, Gilkes, C, Glynn, N, Goldman, JE, Goldstone, AP, Góth, M, Green, A, Greenhalgh, L, Grieve, J, Griz, L, Guitelman, M, Gürlek, A, Gurnell, M, Hamblin, PS, Hana, V, Harding, P, Hay, E, Hilton, DA, Ho, W, Hong, G, Horváth, K, Howell, S, Howlett, TA, Höybye, C, Hunter, S, Idampitiya, C, Igaz, P, Imran, A, Inder, WJ, Iwata, T, Izatt, L, Jagadeesh, S, Johnston, C, Jose, B, Kaltsas, G, Kaplan, F, Karavitaki, N, Kastelan, D, Katz, M, Kearney, T, Kershaw, M, Khoo, B, Kiraly-Borri, C, Knispelis, R, Kovács, GL, Kumar, A, Kumar, AV, Kun, IZ, Kyriaku, A, Lambrescu, I, Lampe, AK, Laws, ER, Lebek-Szatanska, A, Lechan, RM, Leese, G, Levy, A, Levy, MJ, Lewandowski, K, Lin, E, Lo, J, Lyons, C, Maartens, N, Maghnie, M, Makaya, T, Marcus, H, Niedziela, M, Martin, N, Matsuno, A, McGowan, B, McQuaid, SE, Medic-Stojanoska, M, Mendoza, N, Mercado-Atri, M, Mettananda, S, Mezősi, E, Miljic, D, Miller, KK, Modenesi, S, Molitch, ME, Monson, J, Morris, DG, Morrison, PJ, Mosterman, B, Munir, A, Murray, RD, Musat, M, Musolino, N, Nachtigall, L, Nagi, D, Nair, R, Nelson, R, Newell-Price, J, Nikookam, K, Ogilivie, A, Orme, SM, O´Weickert, M, Pal, A, Pascanu, I, Patócs, A, Patterson, C, Pearce, SH, Giraldi, FP, Penney, L, Perez-Rivas, LG, Pfeifer, M, Pirie, F, Poplawski, N, Popovic, V, Powell, M, Pullan, P, Quinton, R, Radian, S, Randeva, H, Reddy, N, Rees, A, Renals, V, de Oliveira, AR, Richardson, T, Rodd, C, Ross, RJM, Roncaroli, F, Ryan, F, Salvatori, R, Schöfl, C, Shears, D, Shotliff, K, Skelly, R, Snape, K, Soares, BS, Somasundaram, N, Spada, A, Sperber, J, Spoudeas, H, Stelmachowska-Banas, M, Stewart, S, Storr, HL, Strasburger, C, Street, ME, Suter-Widmer, I, Suthers, G, Swords, F, Syro, LV, Swantje, B, Sze, C, Taylor, J, Thakker, RV, Tham, E, Thompson, C, Thorner, MO, Tóth, M, Trainer, PJ, Tsagarakis, S, Twine, G, Tzanela, M, Vadasz, J, Vaidya, B, Vaks, V, Vance, ML, Verkauskiene, R, Von Esch, H, Wass, JA, Waterhouse, M, Webb, S, Weber, A, Wernig, F, Widell, H, Yamada, S, Yap, P, Yarman, S, Yeoh, P, Yoshimoto, K, Yuen, K, and Zammitt, NN

Abstract

Context\ud \ud Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs).\ud \ud \ud \ud Objective\ud \ud To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients.\ud \ud \ud \ud Design\ud \ud 12-year prospective, observational study.\ud \ud \ud \ud Participants & Setting\ud \ud We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases.\ud \ud \ud \ud Interventions & Outcome\ud \ud AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310).\ud \ud \ud \ud Results\ud \ud Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650).\ud \ud \ud \ud Conclusions\ud \ud Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course.

Published
2020

7. Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study

Author

Mitra, Anita V., Bancroft, Elizabeth K., Barbachano, Yolanda, Page, Elizabeth C., Foster, C. S., Jameson, C., Mitchell, G., Lindeman, G. J., Stapleton, A., Suthers, G., Evans, D. G., Cruger, D., Blanco, I., Mercer, C., Kirk, J., Maehle, L., Hodgson, S., Walker, L., Izatt, L., Douglas, F., Tucker, K., Dorkins, H., Clowes, V., Male, A., Donaldson, A., Brewer, C., Doherty, R., Bulman, B., Osther, P. J., Salinas, M., Eccles, D., Axcrona, K., Jobson, I., Newcombe, B., Cybulski, C., Rubinstein, W. S., Buys, S., Townshend, S., Friedman, E., Domchek, S., Ramon y Cajal, T., Spigelman, A., Teo, S. H., Nicolai, N., Aaronson, N., Ardern-Jones, A., Bangma, C., Dearnaley, D., Eyfjord, J., Falconer, A., Grönberg, H., Hamdy, F., Johannsson, O., Khoo, V., Kote-Jarai, Z., Lilja, H., Lubinski, J., Melia, J., Moynihan, C., Peock, S., Rennert, G., Schröder, F., Sibley, P., Suri, M., Wilson, P., Bignon, Y. J., Strom, S., Tischkowitz, M., Liljegren, A., Ilencikova, D., Abele, A., Kyriacou, K., van Asperen, C., Kiemeney, L., Easton, D. F., and Eeles, Rosalind A.

Published
2011
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21. Psychosocial impact of undergoing prostate cancer screening for men with BRCA1 or BRCA2 mutations

Author

Bancroft, EK, Saya, S, Page, EC, Myhill, K, Thomas, S, Pope, J, Chamberlain, A, Hart, R, Glover, W, Cook, J, Rosario, DJ, Helfand, BT, Selkirk, CH, Davidson, R, Longmuir, M, Eccles, DM, Gadea, N, Brewer, C, Barwell, J, Salinas, M, Greenhalgh, L, Tischkowitz, M, Henderson, A, Evans, DG, Buys, SS, Eeles, RA, Aaronson, NK, Eeles, R, Bancroft, E, Page, E, Kote-Jarai, Z, Ardern-Jones, A, Bangma, C, Castro, E, Dearnaley, D, Falconer, A, Foster, C, Gronberg, H, Hamdy, FC, Johannsson, OT, Khoo, V, Eccles, D, Lilja, H, Evans, G, Eyfjord, J, Lubinski, J, Maehle, L, Mikropoulos, C, Millner, A, Mitra, A, Offman, J, Moynihan, C, Rennert, G, Suri, M, Dias, A, Taylor, N, D'Mello, L, James, P, Mitchell, G, Shanley, S, Richardson, K, McKinley, J, Petelin, L, Murphy, M, Mascarenhas, L, Murphy, D, Lam, J, Taylor, L, Miller, C, Stapleton, A, Chong, M, Suthers, G, Poplawski, N, Tucker, K, Andrews, L, Duffy, J, Millard, R, Ward, R, Williams, R, Stricker, P, Kirk, J, Bowman, M, Patel, M, Harris, M, O'Connell, S, Hunt, C, Smyth, C, Frydenberg, M, Lindeman, G, Shackleton, K, Morton, C, Susman, R, McGaughran, J, Boon, M, Pachter, N, Townshend, S, Schofield, L, Nicholls, C, Spigelman, A, Gleeson, M, Amor, D, Burke, J, Patterson, B, Swindle, P, Scott, R, Foulkes, W, Boshari, T, Aprikian, A, Jensen, T, Bojeson, A, Osther, P, Skytte, A-B, Cruger, D, Tondering, MK, Gerdes, A-M, Schmutzler, R, Rhiem, K, Wihler, P, Kast, K, Griebsch, C, Johannsson, O, Stefansdottir, V, Murthy, V, Sarin, R, Awatagiri, K, Ghonge, S, Kowtal, P, Mulgund, G, Gallagher, D, Bambury, R, Farrell, M, Gallagher, F, Kiernan, I, Friedman, E, Chen-Shtoyerman, R, Basevitch, A, Leibovici, D, Melzer, E, Ben-Yehoshua, SJ, Nicolai, N, Radice, P, Valdagni, R, Magnani, T, Gay, S, Teo, SH, Tan, HM, Yoon, S-Y, Thong, MK, Vasen, H, Ringleberg, J, van Asperen, C, Kiemeney, B, van Zelst-Stams, W, Ausems, MGEM, van der Luijt, RB, van Os, T, Ruijs, MWG, Adank, MA, Oldenburg, RA, Helderman-van den Enden, APTJM, Caanen, BAH, Oosterwijk, JC, Moller, P, Brennhovd, B, Medvik, H, Hanslien, E, Grindedal, EM, Cybulski, C, Wokolorczyk, D, Teixeira, M, Maia, S, Peixoto, A, Henrique, R, Oliveira, J, Goncalves, N, Araujo, L, Seixas, M, Souto, JP, Nogueira, P, Copakova, L, Zgajnar, J, Krajc, M, Vrecar, A, Capella, G, Ramon y Cajal, T, Fisas, D, Mora, J, Esquena, S, Balmana, J, Morote, J, Liljegren, A, Hjalm-Eriksson, M, Ekdahl, K-J, Carlsson, S, George, A, Kemp, Z, Wiggins, J, Moss, C, Van As, N, Thompson, A, Ogden, C, Woodhouse, C, Kumar, P, Bulman, B, Rothwell, J, Tricker, K, Wise, G, Mercer, C, McBride, D, Costello, P, Pearce, A, Torokwa, A, Paterson, J, Clowes, V, Taylor, A, Newcombe, B, Walker, L, Halliday, D, Stayner, B, Fleming-Brown, D, Snape, K, Hanson, H, Hodgson, S, Brice, G, Homfray, T, Hammond, C, Kohut, K, Anjum, U, Dearing, A, Mencias, M, Potter, A, Renton, C, Searle, A, Hill, K, Goodman, S, Garcia, L, Devlin, G, Everest, S, Nadolski, M, Douglas, F, Jobson, I, Paez, E, Donaldson, A, Tomkins, S, Langman, C, Jacobs, C, Pichert, G, Shaw, A, Kulkarni, A, Tripathi, V, Rose, S, Compton, C, Watson, M, Reinholtz, C, Brady, A, Dorkins, H, Melville, A, Kosicka-Slawinska, M, Cummings, C, Kiesel, V, Bartlett, M, Randhawa, K, Ellery, N, Side, L, Male, A, Simon, K, Rees, K, Tidey, L, Gurasashvili, J, Nevitt, L, Ingram, S, Howell, A, Rosario, D, Catto, J, Howson, J, Ong, K-R, Chapman, C, Cole, T, Heaton, T, Hoffman, J, Burgess, L, Huber, C, Islam, F, Watt, C, Duncan, A, Kockelbergh, R, Mzazi, S, Dineen, A, Sattar, A, Kaemba, B, Sidat, Z, Patel, N, Siguake, K, Birt, A, Poultney, U, Umez-Eronini, N, Mom, J, Sutton, V, Cornford, P, Bermingham, N, Yesildag, P, Treherne, K, Griffiths, J, Cogley, L, Gott, H, Rubinstein, WS, Hulick, P, McGuire, M, Shevrin, D, Kaul, K, Weissman, S, Newlin, A, Vogel, K, Weiss, S, Hook, N, Buys, S, Goldgar, D, Conner, T, Venne, V, Stephenson, R, Dechet, C, Domchek, S, Powers, J, Rustgi, N, Strom, S, Arun, B, Davis, JW, Yamamura, Y, Obeid, E, Giri, V, Gross, L, Bealin, L, Cooney, K, Stoffel, E, Okoth, L, Bancroft, EK, Saya, S, Page, EC, Myhill, K, Thomas, S, Pope, J, Chamberlain, A, Hart, R, Glover, W, Cook, J, Rosario, DJ, Helfand, BT, Selkirk, CH, Davidson, R, Longmuir, M, Eccles, DM, Gadea, N, Brewer, C, Barwell, J, Salinas, M, Greenhalgh, L, Tischkowitz, M, Henderson, A, Evans, DG, Buys, SS, Eeles, RA, Aaronson, NK, Eeles, R, Bancroft, E, Page, E, Kote-Jarai, Z, Ardern-Jones, A, Bangma, C, Castro, E, Dearnaley, D, Falconer, A, Foster, C, Gronberg, H, Hamdy, FC, Johannsson, OT, Khoo, V, Eccles, D, Lilja, H, Evans, G, Eyfjord, J, Lubinski, J, Maehle, L, Mikropoulos, C, Millner, A, Mitra, A, Offman, J, Moynihan, C, Rennert, G, Suri, M, Dias, A, Taylor, N, D'Mello, L, James, P, Mitchell, G, Shanley, S, Richardson, K, McKinley, J, Petelin, L, Murphy, M, Mascarenhas, L, Murphy, D, Lam, J, Taylor, L, Miller, C, Stapleton, A, Chong, M, Suthers, G, Poplawski, N, Tucker, K, Andrews, L, Duffy, J, Millard, R, Ward, R, Williams, R, Stricker, P, Kirk, J, Bowman, M, Patel, M, Harris, M, O'Connell, S, Hunt, C, Smyth, C, Frydenberg, M, Lindeman, G, Shackleton, K, Morton, C, Susman, R, McGaughran, J, Boon, M, Pachter, N, Townshend, S, Schofield, L, Nicholls, C, Spigelman, A, Gleeson, M, Amor, D, Burke, J, Patterson, B, Swindle, P, Scott, R, Foulkes, W, Boshari, T, Aprikian, A, Jensen, T, Bojeson, A, Osther, P, Skytte, A-B, Cruger, D, Tondering, MK, Gerdes, A-M, Schmutzler, R, Rhiem, K, Wihler, P, Kast, K, Griebsch, C, Johannsson, O, Stefansdottir, V, Murthy, V, Sarin, R, Awatagiri, K, Ghonge, S, Kowtal, P, Mulgund, G, Gallagher, D, Bambury, R, Farrell, M, Gallagher, F, Kiernan, I, Friedman, E, Chen-Shtoyerman, R, Basevitch, A, Leibovici, D, Melzer, E, Ben-Yehoshua, SJ, Nicolai, N, Radice, P, Valdagni, R, Magnani, T, Gay, S, Teo, SH, Tan, HM, Yoon, S-Y, Thong, MK, Vasen, H, Ringleberg, J, van Asperen, C, Kiemeney, B, van Zelst-Stams, W, Ausems, MGEM, van der Luijt, RB, van Os, T, Ruijs, MWG, Adank, MA, Oldenburg, RA, Helderman-van den Enden, APTJM, Caanen, BAH, Oosterwijk, JC, Moller, P, Brennhovd, B, Medvik, H, Hanslien, E, Grindedal, EM, Cybulski, C, Wokolorczyk, D, Teixeira, M, Maia, S, Peixoto, A, Henrique, R, Oliveira, J, Goncalves, N, Araujo, L, Seixas, M, Souto, JP, Nogueira, P, Copakova, L, Zgajnar, J, Krajc, M, Vrecar, A, Capella, G, Ramon y Cajal, T, Fisas, D, Mora, J, Esquena, S, Balmana, J, Morote, J, Liljegren, A, Hjalm-Eriksson, M, Ekdahl, K-J, Carlsson, S, George, A, Kemp, Z, Wiggins, J, Moss, C, Van As, N, Thompson, A, Ogden, C, Woodhouse, C, Kumar, P, Bulman, B, Rothwell, J, Tricker, K, Wise, G, Mercer, C, McBride, D, Costello, P, Pearce, A, Torokwa, A, Paterson, J, Clowes, V, Taylor, A, Newcombe, B, Walker, L, Halliday, D, Stayner, B, Fleming-Brown, D, Snape, K, Hanson, H, Hodgson, S, Brice, G, Homfray, T, Hammond, C, Kohut, K, Anjum, U, Dearing, A, Mencias, M, Potter, A, Renton, C, Searle, A, Hill, K, Goodman, S, Garcia, L, Devlin, G, Everest, S, Nadolski, M, Douglas, F, Jobson, I, Paez, E, Donaldson, A, Tomkins, S, Langman, C, Jacobs, C, Pichert, G, Shaw, A, Kulkarni, A, Tripathi, V, Rose, S, Compton, C, Watson, M, Reinholtz, C, Brady, A, Dorkins, H, Melville, A, Kosicka-Slawinska, M, Cummings, C, Kiesel, V, Bartlett, M, Randhawa, K, Ellery, N, Side, L, Male, A, Simon, K, Rees, K, Tidey, L, Gurasashvili, J, Nevitt, L, Ingram, S, Howell, A, Rosario, D, Catto, J, Howson, J, Ong, K-R, Chapman, C, Cole, T, Heaton, T, Hoffman, J, Burgess, L, Huber, C, Islam, F, Watt, C, Duncan, A, Kockelbergh, R, Mzazi, S, Dineen, A, Sattar, A, Kaemba, B, Sidat, Z, Patel, N, Siguake, K, Birt, A, Poultney, U, Umez-Eronini, N, Mom, J, Sutton, V, Cornford, P, Bermingham, N, Yesildag, P, Treherne, K, Griffiths, J, Cogley, L, Gott, H, Rubinstein, WS, Hulick, P, McGuire, M, Shevrin, D, Kaul, K, Weissman, S, Newlin, A, Vogel, K, Weiss, S, Hook, N, Buys, S, Goldgar, D, Conner, T, Venne, V, Stephenson, R, Dechet, C, Domchek, S, Powers, J, Rustgi, N, Strom, S, Arun, B, Davis, JW, Yamamura, Y, Obeid, E, Giri, V, Gross, L, Bealin, L, Cooney, K, Stoffel, E, and Okoth, L

Abstract

OBJECTIVES: To report the baseline results of a longitudinal psychosocial study that forms part of the IMPACT study, a multi-national investigation of targeted prostate cancer (PCa) screening among men with a known pathogenic germline mutation in the BRCA1 or BRCA2 genes. PARTICPANTS AND METHODS: Men enrolled in the IMPACT study were invited to complete a questionnaire at collaborating sites prior to each annual screening visit. The questionnaire included sociodemographic characteristics and the following measures: the Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), 36-item short-form health survey (SF-36), Memorial Anxiety Scale for Prostate Cancer, Cancer Worry Scale-Revised, risk perception and knowledge. The results of the baseline questionnaire are presented. RESULTS: A total of 432 men completed questionnaires: 98 and 160 had mutations in BRCA1 and BRCA2 genes, respectively, and 174 were controls (familial mutation negative). Participants' perception of PCa risk was influenced by genetic status. Knowledge levels were high and unrelated to genetic status. Mean scores for the HADS and SF-36 were within reported general population norms and mean IES scores were within normal range. IES mean intrusion and avoidance scores were significantly higher in BRCA1/BRCA2 carriers than in controls and were higher in men with increased PCa risk perception. At the multivariate level, risk perception contributed more significantly to variance in IES scores than genetic status. CONCLUSION: This is the first study to report the psychosocial profile of men with BRCA1/BRCA2 mutations undergoing PCa screening. No clinically concerning levels of general or cancer-specific distress or poor quality of life were detected in the cohort as a whole. A small subset of participants reported higher levels of distress, suggesting the need for healthcare professionals offering PCa screening to identify these risk factors and offer additional information and support t

Published
2019

27. RAD51B in familial breast cancer.

Author

Antill Y., Garcia-Closas M., Michailidou K., Links M., Grygiel J., Hill J., Brand A., Byth K., Jaworski R., Harnett P., Wain G., Purdie D., Whiteman D., Ward B., Papadimos D., Crandon A., Horwood K., Obermair A., Perrin L., Wyld D., Nicklin J., Davy S.A.-M., Oehler M.K., Hall C., Dodd T., Healy T., Pittman K., Henderson D., Miller J., Pierdes J., Achan A., Blomfield P., Challis D., McIntosh R., Parker A., Brown B., Rome R., Allen D., Grant P., Hyde S., Laurie R., Robbie M., Healy D., Manolitsas T., McNealage J., Rogers P., Susil B., Sumithran E., Simpson I., Haviv I., Rischin D., Johnson D., Lade S., Loughrey M., O'Callaghan N., Murray B., Mileshkin L., Allan P., Billson V., Pyman J., Neesham D., Quinn M., Hamilton A., McNally O., Underhill C., Ng L.F., Blum R., Ganju V., Hammond I., Leung Y., McCartney A., Stewart C., Zeps N., Bell R., Harris M., Healey S., Jobling T., Jones A., Wilson J., Pelttari L.M., Khan S., Vuorela M., Kiiski J.I., Vilske S., Nevanlinna V., Ranta S., Schleutker J., Winqvist R., Kallioniemi A., Dork T., Bogdanova N.V., Figueroa J., Pharoah P.D.P., Schmidt M.K., Dunning A.M., Bolla M.K., Dennis J., Wang Q., Hopper J.L., Southey M.C., Rosenberg E.H., Fasching P.A., Beckmann M.W., Peto J., Dos-Santos-silva I., Sawyer E.J., Tomlinson I., Burwinkel B., Surowy H., Guenel P., Truong T., Bojesen S.E., Nordestgaard B.G., Benitez J., Gonzalez-Neira A., Neuhausen S.L., Anton-Culver H., Brenner H., Arndt V., Meindl A., Schmutzler R.K., Brauch H., Bruning T., Lindblom A., Margolin S., Mannermaa A., Hartikainen J.M., Chenevix-Trench G., Van Dyck L., Janssen H., Chang-Claude J., Rudolph A., Radice P., Peterlongo P., Hallberg E., Olson J.E., Giles G.G., Milne R.L., Haiman C.A., Schumacher F., Simard J., Dumont M., Kristensen V., Borresen-Dale A.-L., Zheng W., Beeghly-Fadiel A., Grip M., Andrulis I.L., Glendon G., Devilee P., Seynaeve C., Hooning M.J., Collee M., Cox A., Cross S.S., Shah M., Luben R.N., Hamann U., Torres D., Jakubowska A., Lubinski J., Couch F.J., Yannoukakos D., Orr N., Swerdlow A., Darabi H., Li J., Czene K., Hall P., Easton D.F., Mattson J., Blomqvist C., Aittomaki K., Nevanlinna H., Aghmesheh M., Amor D., Andrews L., Armitage S., Arnold L., Balleine R., Bankier A., Bastick P., Beesley J., Beilby J., Bennett B., Bennett I., Berry G., Blackburn A., Bogwitz M., Brennan M., Brown M., Buckley M., Burgess M., Burke J., Butow P., Byron K., Callen D., Campbell I., Chauhan D., Christian A., Clarke C., Colley A., Cotton D., Crook A., Cui J., Culling B., Cummings M., Dawson S.-J., DeFazio A., Delatycki M., Dickson R., Dixon J., Dobrovic A., Dudding T., Edkins T., Edwards S., Eisenbruch M., Farshid G., Fawcett S., Fellows A., Fenton G., Field M., Firgaira F., Flanagan J., Fleming J., Fong P., Forbes J., Fox S., French J., Friedlander M., Gaff C., Gardner M., Gattas M., George P., Gill G., Goldblatt J., Greening S., Grist S., Haan E., Hardie K., Hart S., Hayward N., Heiniger L., Humphrey E., Hunt C., James P., Jenkins M., Kefford R., Kidd A., Kiely B., Kirk J., Koehler J., Kollias J., Kovalenko S., Lakhani S., Leaming A., Leary J., Lim J., Lindeman G., Lipton L., Lobb L., Mann G., Marsh D., McLachlan S.A., Meiser B., Meldrum C., Mitchell G., Newman B., Nightingale S., O'Connell S., O'Loughlin I., Osborne R., Pachter N., Patterson B., Peters L., Phillips K., Price M., Purser L., Reeve T., Reeve J., Richards R., Rickard E., Robinson B., Rudzki B., Saleh M., Salisbury E., Sambrook J., Saunders C., Saunus J., Sayer R., Scott E., Scott R., Scott C., Seshadri R., Sexton A., Sharma R., Shelling A., Simpson P., Spurdle A., Suthers G., Sykes P., Taylor D., Taylor J., Thierry B., Thompson E., Thorne H., Townshend S., Trainer A., Tran L., Tucker K., Tyler J., Visvader J., Walker L., Walpole I., Ward R., Waring P., Warner B., Warren G., Williams R., Winship I., Wu K., Young M.A., Stuart-Harris R., Kirsten F., Rutovitz J., Clingan P., Glasgow A., Proietto A., Braye S., Otton G., Shannon J., Bonaventura T., Stewart J., Begbie S., Bell D., Baron-Hay S., Ferrier A., Gard G., Nevell D., Pavlakis N., Valmadre S., Young B., Camaris C., Crouch R., Edwards L., Hacker N., Marsden D., Robertson G., Beale P., Beith J., Carter J., Dalrymple C., Houghton R., Russell P., Anderson L., Antill Y., Garcia-Closas M., Michailidou K., Links M., Grygiel J., Hill J., Brand A., Byth K., Jaworski R., Harnett P., Wain G., Purdie D., Whiteman D., Ward B., Papadimos D., Crandon A., Horwood K., Obermair A., Perrin L., Wyld D., Nicklin J., Davy S.A.-M., Oehler M.K., Hall C., Dodd T., Healy T., Pittman K., Henderson D., Miller J., Pierdes J., Achan A., Blomfield P., Challis D., McIntosh R., Parker A., Brown B., Rome R., Allen D., Grant P., Hyde S., Laurie R., Robbie M., Healy D., Manolitsas T., McNealage J., Rogers P., Susil B., Sumithran E., Simpson I., Haviv I., Rischin D., Johnson D., Lade S., Loughrey M., O'Callaghan N., Murray B., Mileshkin L., Allan P., Billson V., Pyman J., Neesham D., Quinn M., Hamilton A., McNally O., Underhill C., Ng L.F., Blum R., Ganju V., Hammond I., Leung Y., McCartney A., Stewart C., Zeps N., Bell R., Harris M., Healey S., Jobling T., Jones A., Wilson J., Pelttari L.M., Khan S., Vuorela M., Kiiski J.I., Vilske S., Nevanlinna V., Ranta S., Schleutker J., Winqvist R., Kallioniemi A., Dork T., Bogdanova N.V., Figueroa J., Pharoah P.D.P., Schmidt M.K., Dunning A.M., Bolla M.K., Dennis J., Wang Q., Hopper J.L., Southey M.C., Rosenberg E.H., Fasching P.A., Beckmann M.W., Peto J., Dos-Santos-silva I., Sawyer E.J., Tomlinson I., Burwinkel B., Surowy H., Guenel P., Truong T., Bojesen S.E., Nordestgaard B.G., Benitez J., Gonzalez-Neira A., Neuhausen S.L., Anton-Culver H., Brenner H., Arndt V., Meindl A., Schmutzler R.K., Brauch H., Bruning T., Lindblom A., Margolin S., Mannermaa A., Hartikainen J.M., Chenevix-Trench G., Van Dyck L., Janssen H., Chang-Claude J., Rudolph A., Radice P., Peterlongo P., Hallberg E., Olson J.E., Giles G.G., Milne R.L., Haiman C.A., Schumacher F., Simard J., Dumont M., Kristensen V., Borresen-Dale A.-L., Zheng W., Beeghly-Fadiel A., Grip M., Andrulis I.L., Glendon G., Devilee P., Seynaeve C., Hooning M.J., Collee M., Cox A., Cross S.S., Shah M., Luben R.N., Hamann U., Torres D., Jakubowska A., Lubinski J., Couch F.J., Yannoukakos D., Orr N., Swerdlow A., Darabi H., Li J., Czene K., Hall P., Easton D.F., Mattson J., Blomqvist C., Aittomaki K., Nevanlinna H., Aghmesheh M., Amor D., Andrews L., Armitage S., Arnold L., Balleine R., Bankier A., Bastick P., Beesley J., Beilby J., Bennett B., Bennett I., Berry G., Blackburn A., Bogwitz M., Brennan M., Brown M., Buckley M., Burgess M., Burke J., Butow P., Byron K., Callen D., Campbell I., Chauhan D., Christian A., Clarke C., Colley A., Cotton D., Crook A., Cui J., Culling B., Cummings M., Dawson S.-J., DeFazio A., Delatycki M., Dickson R., Dixon J., Dobrovic A., Dudding T., Edkins T., Edwards S., Eisenbruch M., Farshid G., Fawcett S., Fellows A., Fenton G., Field M., Firgaira F., Flanagan J., Fleming J., Fong P., Forbes J., Fox S., French J., Friedlander M., Gaff C., Gardner M., Gattas M., George P., Gill G., Goldblatt J., Greening S., Grist S., Haan E., Hardie K., Hart S., Hayward N., Heiniger L., Humphrey E., Hunt C., James P., Jenkins M., Kefford R., Kidd A., Kiely B., Kirk J., Koehler J., Kollias J., Kovalenko S., Lakhani S., Leaming A., Leary J., Lim J., Lindeman G., Lipton L., Lobb L., Mann G., Marsh D., McLachlan S.A., Meiser B., Meldrum C., Mitchell G., Newman B., Nightingale S., O'Connell S., O'Loughlin I., Osborne R., Pachter N., Patterson B., Peters L., Phillips K., Price M., Purser L., Reeve T., Reeve J., Richards R., Rickard E., Robinson B., Rudzki B., Saleh M., Salisbury E., Sambrook J., Saunders C., Saunus J., Sayer R., Scott E., Scott R., Scott C., Seshadri R., Sexton A., Sharma R., Shelling A., Simpson P., Spurdle A., Suthers G., Sykes P., Taylor D., Taylor J., Thierry B., Thompson E., Thorne H., Townshend S., Trainer A., Tran L., Tucker K., Tyler J., Visvader J., Walker L., Walpole I., Ward R., Waring P., Warner B., Warren G., Williams R., Winship I., Wu K., Young M.A., Stuart-Harris R., Kirsten F., Rutovitz J., Clingan P., Glasgow A., Proietto A., Braye S., Otton G., Shannon J., Bonaventura T., Stewart J., Begbie S., Bell D., Baron-Hay S., Ferrier A., Gard G., Nevell D., Pavlakis N., Valmadre S., Young B., Camaris C., Crouch R., Edwards L., Hacker N., Marsden D., Robertson G., Beale P., Beith J., Carter J., Dalrymple C., Houghton R., Russell P., and Anderson L.

Abstract

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11-1.19, P = 8.88 x 10-16) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 x 10-11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.

Published
2017

28. Diagnostic performance and costs of contingent screening models for trisomy 21 incorporating non-invasive prenatal testing

Author

Maxwell, S., O'Leary, Peter, Dickinson, J., Suthers, G., Maxwell, S., O'Leary, Peter, Dickinson, J., and Suthers, G.

Abstract

© 2017 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists Background: Contingent screening for trisomy 21 using non-invasive prenatal testing has the potential to reduce invasive diagnostic testing and increase the detection of trisomy 21. Aim: To describe the diagnostic and economic performance of prenatal screening models for trisomy 21 that use non-invasive prenatal testing as a contingent screen across a range of combined first trimester screening risk cut-offs from a public health system perspective. Methods: Using a hypothetical cohort of 300 000 pregnancies, we modelled the outcomes of 25 contingent non-invasive prenatal testing screening models and compared these to conventional screening, offering women with a high-risk (1 > 300) combined first trimester screening result an invasive test. The 25 models used a range of risk cut-offs. High-risk women were offered invasive testing. Intermediate-risk women were offered non-invasive prenatal testing. We report the cost of each model, detection rate, costs per diagnosis, invasive tests per diagnosis and the number of fetal losses per diagnosis. Results: The cost per prenatal diagnosis of trisomy 21 using the conventional model was $51 876 compared to the contingent models which varied from $49 309–66 686. The number of diagnoses and cost per diagnosis increased as the intermediate-risk threshold was lowered. Results were sensitive to trisomy 21 incidence, uptake of testing and cost of non-invasive prenatal testing. Conclusion: Contingent non-invasive prenatal testing models using more sensitive combined first trimester screening risk cut-offs than conventional screening improved the detection rate of trisomy 21, reduced procedure-related fetal loss and could potentially be provided at a lower cost per diagnosis than conventional screening.

Published
2017

29. Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study

Author

Mitra, A, Bancroft, E, Barbachano, Y, Page, E, Foster, C, Jameson, C, Mitchell, G, Lindeman, G, Stapleton, A, Suthers, G, Evans, D, Cruger, D, Blanco, I, Mercer, C, Kirk, J, Maehle, L, Hodgson, S, Walker, L, Izatt, L, Douglas, F, Tucker, K, Dorkins, H, Clowes, V, Male, A, and Donaldson, A

Abstract

OBJECTIVE: To evaluate the role of targeted prostate cancer screening in men with BRCA1 or BRCA2 mutations, an international study, IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls), was established. This is the first multicentre screening study targeted at men with a known genetic predisposition to prostate cancer. A preliminary analysis of the data is reported. PATIENTS AND METHODS: Men aged 40-69 years from families with BRCA1 or BRCA2 mutations were offered annual prostate specific antigen (PSA) testing, and those with PSA > 3 ng/mL, were offered a prostate biopsy. Controls were men age-matched (± 5 years) who were negative for the familial mutation. RESULTS: In total, 300 men were recruited (205 mutation carriers; 89 BRCA1, 116 BRCA2 and 95 controls) over 33 months. At the baseline screen (year 1), 7.0% (21/300) underwent a prostate biopsy. Prostate cancer was diagnosed in ten individuals, a prevalence of 3.3%. The positive predictive value of PSA screening in this cohort was 47·6% (10/21). One prostate cancer was diagnosed at year 2. Of the 11 prostate cancers diagnosed, nine were in mutation carriers, two in controls, and eight were clinically significant. CONCLUSIONS: The present study shows that the positive predictive value of PSA screening in BRCA mutation carriers is high and that screening detects clinically significant prostate cancer. These results support the rationale for continued screening in such men.

Published
2016
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31. Targeted Prostate Cancer Screening in BRCA1 and BRCA2 Mutation Carriers: Results from the Initial Screening Round of the IMPACT Study

Author

Bancroft, EK, Page, EC, Castro, E, Lilja, H, Vickers, A, Sjoberg, D, Assel, M, Foster, CS, Mitchell, G, Drew, K, Maehle, L, Axcrona, K, Evans, DG, Bulman, B, Eccles, D, McBride, D, van Asperen, C, Vasen, H, Kiemeney, LA, Ringelberg, J, Cybulski, C, Wokolorczyk, D, Selkirk, C, Hulick, PJ, Bojesen, A, Skytte, AB, Lam, J, Taylor, L, Oldenburg, R, Cremers, R, Verhaegh, G, van Zelst-Stams, WA, Oosterwijk, JC, Blanco, I, Salinas, M, Cook, J, Rosario, DJ, Buys, S, Conner, T, Ausems, MG, Ong, KR, Hoffman, J, Domchek, S, Powers, J, Teixeira, MR, Maia, S, Foulkes, WD, Taherian, N, Ruijs, M, Helderman-van den Enden, AT, Izatt, L, Davidson, R, Adank, MA, Walker, L, Schmutzler, R, Tucker, K, Kirk, J, Hodgson, S, Harris, M, Douglas, F, Lindeman, GJ, Zgajnar, J, Tischkowitz, M, Clowes, VE, Susman, R, Cajal, TRY, Patcher, N, Gadea, N, Spigelman, A, van Os, T, Liljegren, A, Side, L, Brewer, C, Brady, AF, Donaldson, A, Stefansdottir, V, Friedman, E, Chen-Shtoyerman, R, Amor, DJ, Copakova, L, Barwell, J, Giri, VN, Murthy, V, Nicolai, N, Teo, SH, Greenhalgh, L, Strom, S, Henderson, A, McGrath, J, Gallagher, D, Aaronson, N, Ardern-Jones, A, Bangma, C, Dearnaley, D, Costello, P, Eyfjord, J, Rothwell, J, Falconer, A, Gronberg, H, Hamdy, FC, Johannsson, O, Khoo, V, Kote-Jarai, Z, Lubinski, J, Axcrona, U, Melia, J, McKinley, J, Mitra, AV, Moynihan, C, Rennert, G, Suri, M, Wilson, P, Killick, E, Moss, S, Eeles, RA, Taylor, N, Pope, J, Saya, S, Martin, S, Keating, D, Petelin, L, Murphy, M, Doherty, R, Pratt, S, Murphy, D, Cleeve, L, Miller, C, Stapleton, A, Chong, M, Suthers, G, Andrews, L, Duffy, J, Millard, R, Ward, R, Williams, R, Stricker, P, Bowman, M, Patel, M, O'Connell, S, Hunt, C, Smyth, C, Frydenberg, M, Shackleton, K, McGaughran, J, Boon, M, Pachter, N, Townshend, S, Schofield, L, Gleeson, M, Scott, R, Burke, J, Patterson, B, Bacic, S, Swindle, P, Aprikian, A, Bojeson, A, Cruger, D, Osther, P, Gerdes, AM, Rhiem, K, Luedtke-Heckenkamp, K, Ochsendorf, N, Fiddike, K, Sarin, R, Awatagiri, K, Ghonge, S, Kowtal, P, Mulgund, G, Bambury, R, Farrell, M, Gallagher, F, Ben-Yehoshua, SJ, Nissani, R, Appelman, Z, Moriel, E, Radice, P, Valdagni, R, Magnani, T, Meng, TH, Yoon, SY, Thong, MK, Kiemeney, B, Van der Luijt, RB, Moller, P, Brennhovd, B, Medvik, H, Hanslien, E, Peixoto, A, Henrique, R, Oliveira, J, Goncalves, N, Araujo, L, Seixas, M, Joao, PS, Nogueira, P, Krajc, M, Vrecar, A, Capella, G, Fisas, D, Balmana, J, Morote, J, Hjalm-Eriksson, M, Ekdahl, KJ, Carlsson, S, Hanson, H, Shanley, S, Goh, C, Wiggins, J, Kohut, K, Van As, N, Thompson, A, Ogden, C, Borley, N, Woodhouse, C, Kumar, P, Mercer, C, Paterson, J, Taylor, A, Newcombe, B, Halliday, D, Stayner, B, Fleming-Brown, D, Brice, G, Homfray, T, Hammond, C, Potter, A, Renton, C, Searle, A, Hill, K, Goodman, S, Garcia, L, Devlin, G, Everest, S, Nadolski, M, Jobson, I, Paez, E, Tomkins, S, Pichert, G, Jacobs, C, Langman, C, Weston, M, Dorkins, H, Melville, A, Kosicka-Slawinska, M, Cummings, C, Kiesel, V, Bartlett, M, Randhawa, K, Ellery, N, Male, A, Simon, K, Rees, K, Compton, C, Tidey, L, Nevitt, L, Ingram, S, Catto, J, Howson, J, Chapman, C, Cole, T, Heaton, T, Burgess, L, Longmuir, M, Watt, C, Duncan, A, Kockelbergh, R, Sattar, A, Kaemba, B, Sidat, Z, Patel, N, Siguake, K, Birt, A, Poultney, U, Umez-Eronini, N, Mom, J, Roberts, G, Woodward, A, Sutton, V, Cornford, P, Treherne, K, Griffiths, J, Cogley, L, Rubinstein, W, Brendler, C, Helfand, B, McGuire, M, Kaul, K, Shevrin, D, Weissman, S, Newlin, A, Vogel, K, Weiss, S, Goldgar, D, Venne, V, Stephenson, R, Dechet, C, Arun, B, Davis, JW, Yamamura, Y, and Gross, L

Subjects
Prostate cancer, BRCA1, BRCA2, Prostate-specific antigen, Targeted screening
Abstract

Background: Men with germline breast cancer 1, early onset (BRCA1) or breast cancer 2, early onset (BRCA2) gene mutations have a higher risk of developing prostate cancer (PCa) than noncarriers. IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls) is an international consortium of 62 centres in 20 countries evaluating the use of targeted PCa screening in men with BRCA1/2 mutations. Objective: To report the first year's screening results for all men at enrolment in the study. Design, setting and participants: We recruited men aged 40-69 yr with germline BRCA1/2 mutations and a control group of men who have tested negative for a pathogenic BRCA1 or BRCA2 mutation known to be present in their families. All men underwent prostate-specific antigen (PSA) testing at enrolment, and those men with PSA > 3 ng/ml were offered prostate biopsy. Outcome measurements and statistical analysis: PSA levels, PCa incidence, and tumour characteristics were evaluated. The Fisher exact test was used to compare the number of PCa cases among groups and the differences among disease types. Results and limitations: We recruited 2481 men (791 BRCA1 carriers, 531 BRCA1 controls; 731 BRCA2 carriers, 428 BRCA2 controls). A total of 199 men (8%) presented with PSA > 3.0 ng/ml, 162 biopsies were performed, and 59 PCas were diagnosed (18 BRCA1 carriers, 10 BRCA1 controls; 24 BRCA2 carriers, 7 BRCA2 controls); 66% of the tumours were classified as intermediate-or high-risk disease. The positive predictive value (PPV) for biopsy using a PSA threshold of 3.0 ng/ml in BRCA2 mutation carriers was 48%-double the PPV reported in population screening studies. A significant difference in detecting intermediate-or high-risk disease was observed in BRCA2 carriers. Ninety-five percent of the men were white, thus the results cannot be generalised to all ethnic groups. Conclusions: The IMPACT screening network will be useful for targeted PCa screening studies in men with germline genetic risk variants as they are discovered. These preliminary results support the use of targeted PSA screening based on BRCA genotype and show that this screening yields a high proportion of aggressive disease. Patient summary: In this report, we demonstrate that germline genetic markers can be used to identify men at higher risk of prostate cancer. Targeting screening at these men resulted in the identification of tumours that were more likely to require treatment. (C) 2014 European Association of Urology. Published by Elsevier B. V. All rights reserved.

Published
2014

32. Familial hypercholesterolaemia: A model of care for Australasia

Author

Watts, GF, Sullivan, DR, Poplawski, N, van Bockxmeer, F, Hamilton-Craig, I, Clifton, PM, O'Brien, R, Bishop, W, George, P, Barter, PJ, Bates, T, Burnett, JR, Coakley, J, Davidson, P, Emery, J, Martin, A, Farid, W, Freeman, L, Geelhoed, E, Juniper, A, Kidd, A, Kostner, K, Krass, I, Livingston, M, Maxwell, S, O'Leary, P, Owaimrin, A, Redgrave, TG, Reid, N, Southwell, L, Suthers, G, Tonkin, A, Towler, S, and Trent, R

Subjects
Adult, Adolescent, Australasia, Anticholesteremic Agents, Coronary Disease, Cholesterol, LDL, Atherosclerosis, Patient Care Management, Hyperlipoproteinemia Type II, Cardiovascular System & Hematology, Risk Factors, Blood Component Removal, Humans, Female, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Child, Apolipoproteins B
Abstract

Familial hypercholesterolaemia (FH) is a dominantly inherited disorder present from birth that causes marked elevation in plasma cholesterol and premature coronary heart disease. There are at least 45,000 people with FH in Australia and New Zealand, but the vast majority remains undetected and those diagnosed with the condition are inadequately treated.To bridge this major gap in coronary prevention the FH Australasia Network (Australian Atherosclerosis Society) has developed a consensus model of care (MoC) for FH. The MoC is based on clinical experience, expert opinion, published evidence and consultations with a wide spectrum of stakeholders, and has been developed for use primarily by specialist centres intending starting a clinical service for FH. This MoC aims to provide a standardised, high-quality and cost-effective system of care that is likely to have the highest impact on patient outcomes.The MoC for FH is presented as a series of recommendations and algorithms focusing on the standards required for the detection, diagnosis, assessment and management of FH in adults and children. The process involved in cascade screening and risk notification, the backbone for detecting new cases of FH, is detailed. Guidance on treatment is based on risk stratifying patients, management of non-cholesterol risk factors, safe and effective use of statins, and a rational approach to follow-up of patients. Clinical and laboratory recommendations are given for genetic testing. An integrative system for providing best clinical care is described.This MoC for FH is not prescriptive and needs to be complemented by good clinical judgment and adjusted for local needs and resources. After initial implementation, the MoC will require critical evaluation, development and appropriate modification. © 2011 Elsevier Ireland Ltd.

Published
2011

33. Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study

Author

Mitra, A.V., Bancroft, E.K., Barbachano, Y., Page, E.C., Foster, C.S., Jameson, C., Mitchell, G., Lindeman, G.J., Stapleton, A., Suthers, G., Evans, D.G., Cruger, D., Blanco, I., Mercer, C., Kirk, J., Maehle, L., Hodgson, S., Walker, L., Izatt, L., Douglas, F., Tucker, K., Dorkins, H., Clowes, V., Male, A., Donaldson, A., Brewer, C., Doherty, R., Bulman, B., Osther, P.J., Salinas, M., Eccles, D., Axcrona, K., Jobson, I., Newcombe, B., Cybulski, C., Rubinstein, W.S., Buys, S., Townshend, S., Friedman, E., Domchek, S., Cajal, T.R.Y., Spigelman, A., Teo, S.H., Nicolai, N., Aaronson, N., Ardern-Jones, A., Bangma, C., Dearnaley, D., Eyfjord, J., Falconer, A., Gronberg, H., Hamdy, F., Johannsson, O., Khoo, V., Kote-Jarai, Z., Lilja, H., Lubinski, J., Melia, J., Moynihan, C., Peock, S., Rennert, G., Schroder, F., Sibley, P., Suri, M., Wilson, P., Bignon, Y.J., Strom, S., Tischkowitz, M., Liljegren, A., Ilencikova, D., Abele, A., Kyriacou, K., Asperen, C. van, Kiemeney, L., Easton, D.F., Eeles, R.A., and IMPACT Study Collaborators

Subjects
prostate cancer BRCA1 BRCA2 PSA genetic predisposition high-risk families jewish men antigen carriers erspc population history trial ng/ml 1st, skin and connective tissue diseases
Abstract

What's known on the subject? and What does the study add? Scientists have found a number of genetic factors that increase prostate cancer risk, including heritable mutations in the genes BRCA1 and BRCA2. These mutations are not common but can have major impact, as a BRCA2 mutation increases risk by up to seven-fold while a BRCA1 mutation is thought to double risk in men under 65. The IMPACT study aims to determine whether targeted screening in men with a known BRCA1 or BRCA2 mutation would lead to earlier diagnosis of prostate cancers. This data from the IMPACT study adds to the increasing evidence that BRCA mutation carriers develop more aggressive disease. Although these are early results, it appears that PSA screening is more accurate at predicting potentially aggressive prostate cancer among men at higher risk of the disease due to a genetic predisposition than general population screening. This study provides support for continued screening in men with genetic mutations. OBJECTIVE To evaluate the role of targeted prostate cancer screening in men with BRCA1 or BRCA2 mutations, an international study, IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls), was established. This is the first multicentre screening study targeted at men with a known genetic predisposition to prostate cancer. A preliminary analysis of the data is reported. PATIENTS AND METHODS Men aged 40-69 years from families with BRCA1 or BRCA2 mutations were offered annual prostate specific antigen (PSA) testing, and those with PSA > 3 ng/mL, were offered a prostate biopsy. Controls were men age-matched (+/- 5 years) who were negative for the familial mutation. RESULTS In total, 300 men were recruited (205 mutation carriers; 89 BRCA1, 116 BRCA2 and 95 controls) over 33 months. At the baseline screen (year 1), 7.0% (21/300) underwent a prostate biopsy. Prostate cancer was diagnosed in ten individuals, a prevalence of 3.3%. The positive predictive value of PSA screening in this cohort was 47 center dot 6% (10/21). One prostate cancer was diagnosed at year 2. Of the 11 prostate cancers diagnosed, nine were in mutation carriers, two in controls, and eight were clinically significant. CONCLUSIONS The present study shows that the positive predictive value of PSA screening in BRCA mutation carriers is high and that screening detects clinically significant prostate cancer. These results support the rationale for continued screening in such men.

Published
2011

34. Quality standards for DNA sequence variation databases to improve clinical management under development in Australia

Author

Bennetts, B, Caramins, M, Hsu, A, Lau, C, Mead, S, Meldrum, C, Smith, TD, Suthers, G, Taylor, GR, Cotton, RGH, Tyrrell, V, Bennetts, B, Caramins, M, Hsu, A, Lau, C, Mead, S, Meldrum, C, Smith, TD, Suthers, G, Taylor, GR, Cotton, RGH, and Tyrrell, V

Abstract

Despite the routine nature of comparing sequence variations identified during clinical testing to database records, few databases meet quality requirements for clinical diagnostics. To address this issue, The Royal College of Pathologists of Australasia (RCPA) in collaboration with the Human Genetics Society of Australasia (HGSA), and the Human Variome Project (HVP) is developing standards for DNA sequence variation databases intended for use in the Australian clinical environment. The outputs of this project will be promoted to other health systems and accreditation bodies by the Human Variome Project to support the development of similar frameworks in other jurisdictions.

Published
2014

36. Familial hypercholesterolaemia: A model of care for Australasia

Author

Watts, G., Sullivan, D., Poplawski, N., Van Bockxmeer, F., Hamilton-Craig, I., Clifton, P., O'Brien, R., Bishop, W., George, P., Barter, P., Bates, T., Burnett, J., Coakley, J., Davidson, Patricia, Emery, J., Martin, A., Farid, W., Freeman, L., Geelhoed, E., Juniper, A., Kidd, A., Kostner, K., Krass, I., Livingston, M., Maxwell, Susannah, O'Leary, Peter, Owaimrin, A., Redgrave, T., Reid, N., Southwell, L., Suthers, G., Tonkin, A., Towler, Simon, Trent, R., Watts, G., Sullivan, D., Poplawski, N., Van Bockxmeer, F., Hamilton-Craig, I., Clifton, P., O'Brien, R., Bishop, W., George, P., Barter, P., Bates, T., Burnett, J., Coakley, J., Davidson, Patricia, Emery, J., Martin, A., Farid, W., Freeman, L., Geelhoed, E., Juniper, A., Kidd, A., Kostner, K., Krass, I., Livingston, M., Maxwell, Susannah, O'Leary, Peter, Owaimrin, A., Redgrave, T., Reid, N., Southwell, L., Suthers, G., Tonkin, A., Towler, Simon, and Trent, R.

Abstract

Familial hypercholesterolaemia (FH) is a dominantly inherited disorder present from birth that causes marked elevation in plasma cholesteroland premature coronary heart disease. There are at least 45,000 people with FH in Australia and New Zealand, but the vast majority remainsundetected and those diagnosed with the condition are inadequately treated.To bridge this major gap in coronary prevention the FH Australasia Network (Australian Atherosclerosis Society) has developed a consensusmodel of care (MoC) for FH. The MoC is based on clinical experience, expert opinion, published evidence and consultations with a widespectrum of stakeholders, and has been developed for use primarily by specialist centres intending starting a clinical service for FH. This MoCaims to provide a standardised, high-quality and cost-effective system of care that is likely to have the highest impact on patient outcomes.The MoC for FH is presented as a series of recommendations and algorithms focusing on the standards required for the detection, diagnosis,assessment and management of FH in adults and children. The process involved in cascade screening and risk notification, the backbonefor detecting new cases of FH, is detailed. Guidance on treatment is based on risk stratifying patients, management of non-cholesterol riskfactors, safe and effective use of statins, and a rational approach to follow-up of patients. Clinical and laboratory recommendations are givenfor genetic testing. An integrative system for providing best clinical care is described.This MoC for FH is not prescriptive and needs to be complemented by good clinical judgment and adjusted for local needs and resources.After initial implementation, the MoC will require critical evaluation, development and appropriate modification.

Published
2011

37. Risks of lynch syndrome cancers for msh6 mutation carriers

Author

Baglietto, L. (Laura), Lindor, N.M. (Noralane), Dowty, J.G. (James), White, D.M. (Darren), Wagner, A. (Anja), Gómez García, E.B. (Encarna), Vriends, A.H.J.T. (Anette), Cartwright, N.R. (Nicola), Barnetson, R.A. (Rebecca), Farrington, S.M. (Susan), Tenesa, A. (Albert), Hampel, H. (Heather), Buchanan, D. (Daniel), Arnold, S. (Sven), Young, J. (Joanne), Walsh, M.D. (Michael), Jass, J. (Jeremy), Macrae, F.A. (Finlay), Antill, Y. (Yoland), Winship, I.M. (Ingrid), Giles, G.G. (Graham), Goldblatt, J. (Jack), Parry, S. (Susan), Suthers, G. (Graeme), Leggett, B. (Barbara), Butz, M. (Malinda), Aronson, M. (Melyssa), Poynter, J.N. (Jenny), Baron, J.A. (John), Le Marchand, L. (Loic), Haile, R. (Robert), Gallinger, S. (Steve), Hopper, J.L. (John), Potter, J. (John), La Chapelle, A. (Albert) de, Vasen, H. (Hans), Dunlop, M.G. (Malcolm), Thibodeau, S.N. (Stephen), Jenkins, M.A. (Mark), Baglietto, L. (Laura), Lindor, N.M. (Noralane), Dowty, J.G. (James), White, D.M. (Darren), Wagner, A. (Anja), Gómez García, E.B. (Encarna), Vriends, A.H.J.T. (Anette), Cartwright, N.R. (Nicola), Barnetson, R.A. (Rebecca), Farrington, S.M. (Susan), Tenesa, A. (Albert), Hampel, H. (Heather), Buchanan, D. (Daniel), Arnold, S. (Sven), Young, J. (Joanne), Walsh, M.D. (Michael), Jass, J. (Jeremy), Macrae, F.A. (Finlay), Antill, Y. (Yoland), Winship, I.M. (Ingrid), Giles, G.G. (Graham), Goldblatt, J. (Jack), Parry, S. (Susan), Suthers, G. (Graeme), Leggett, B. (Barbara), Butz, M. (Malinda), Aronson, M. (Melyssa), Poynter, J.N. (Jenny), Baron, J.A. (John), Le Marchand, L. (Loic), Haile, R. (Robert), Gallinger, S. (Steve), Hopper, J.L. (John), Potter, J. (John), La Chapelle, A. (Albert) de, Vasen, H. (Hans), Dunlop, M.G. (Malcolm), Thibodeau, S.N. (Stephen), and Jenkins, M.A. (Mark)

Abstract

Background: Germline mutations in MSH6 account for 10%-20% of Lynch syndrome colorectal cancers caused by hereditary DNA mismatch repair gene

Published
2010
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38. Treatment-focused DNA testing for newly diagnosed breast cancer patients: some implications for clinical practice

Author

Lobb, Elizabeth, Barlow-Stewart, K., Suthers, G., Hallowell, N., Lobb, Elizabeth, Barlow-Stewart, K., Suthers, G., and Hallowell, N.

Abstract

There is accumulating evidence that women with breast cancer due to a familial BRCA1 or BRCA2 mutation benefit from specific surgical and chemotherapeutic treatment strategies. However, the rapid identification of such patients during the acute phase of treatment raises a number of issues. This study investigated Australian opinion leaders' views on the issues arising from such ‘treatment-focused’ genetic testing. Semi-structured interviews with 34 opinion leaders working in cancer genetics were undertaken. Interviewees acknowledged the introduction of treatment-focused DNA testing has the potential to positively transform the management of breast cancer patients, but were concerned that certain ethical and logistical issues have yet to be addressed. These include decision-making and consent, the familial nature of genetic information, and the management of genetics services within familial cancer clinics in the public hospital system in Australia. Service providers will need to have policies and strategies for managing the increased demand. It will also be necessary to include genetic counseling services within familial cancer clinics in the care pathway for newly diagnosed patients prior to any DNA testing to determine adjuvant treatment; such services may be more cost-effective than expecting surgeons and medical oncologists to fulfill this role.

Published
2010

39. Issues faced by unaffected men with a family history of prostate cancer: a multidisciplinary overview

Author

Wakefield, C., Meiser, B., Gaff, C., Barratt, A., Pate, M., Suthers, G., Lobb, Elizabeth, Ramsay, J., Mann, G., Wakefield, C., Meiser, B., Gaff, C., Barratt, A., Pate, M., Suthers, G., Lobb, Elizabeth, Ramsay, J., and Mann, G.

Abstract

Purpose: Despite the established importance of the role of family history in prostate cancer, relatively little research encompasses the psychosocial issues relevant to unaffected men with a family history of prostate cancer. To determine the completeness and quality of available literature on the issues faced by men with a high risk of prostate cancer, we conducted a multidisciplinary review of the literature to provide some guidance on the information that clinicians might provide to men who are concerned about family history.Materials and Methods: A structured literature search was conducted by a multidisciplinary team of clinicians and researchers who reviewed the medical and psychosocial literature, and identified 21 relevant studies.Results: Research suggests that many high risk patients are concerned about the risk of prostate cancer, and some may significantly overestimate that risk. Several studies have shown high screening rates among high risk patients and high levels of interest in genetic testing for prostate cancer risk should it become available, yet many men also report a desire for more information about their personal risk and risk management options.Conclusions: Given the lack of clear data on the efficacy of prostate cancer screening among high risk patients, clinicians could consider providing men who are concerned about family history with information on their personal risk, help them to clarify the potential benefits, limitations and harms of prostate cancer screening in their situation, and then support their choice regarding the management of prostate cancer risk.

Published
2008

40. Genome-wide association study identifies novel breast cancer susceptibility loci.

Author

Cox A., Farshid G., Fawcett S., Field M., Firgaira F., Fleming J., Forbes J., Friedlander M., Gaff C., Gardner M., Gattas M., George P., Gill G., Goldblatt J., Greening S., Haan E., Hart S., Humphrey E., Jenkins M., Kefford R., Kirk J., Kollias J., Kovalenko S., Lakhani S., Leary J., Lim J., Lindeman G., Lipton L., Lobb L., Maclurcan M., Marsh D., McKay M., Anne McLachlan S., Mitchell G., Newman B., O'Loughlin I., Osborne R., Peters L., Price M., Reeve J., Reeve T., Richards R., Rinehart G., Robinson B., Rudzki B., Salisbury E., Saunders C., Scott E., Seshadri R., Shelling A., Suthers G., Taylor D., Tennant C., Townshend S., Tyler J., Venter D., Visvader J., Walpole I., Ward R., Warner B., Warren G., Watson E., Williams R., Winship I., Bowtell D., Green A., DeFazio A., Gertig D., Webb P., Milne R., Young M.A., Harris M., Wilson J., Easton D.F., Pooley K.A., Dunning A.M., Pharoah P.D.P., Thompson D., Ballinger D.G., Struewing J.P., Morrison J., Field H., Luben R., Wareham N., Ahmed S., Healey C.S., Bowman R., Meyer K.B., Haiman C.A., Kolonel L.K., Henderson B.E., Le Marchand L., Brennan P., Sangrajrang S., Gaborieau V., Odefrey F., Shen C.-Y., Wu P.-E., Wang H.-C., Eccles D., Evans D.G., Peto J., Fletcher O., Johnson N., Seal S., Stratton M.R., Rahman N., Chenevix-Trench G., Bojesen S.E., Nordestgaard B.G., Axelsson C.K., Garcia-Closas M., Brinton L., Chanock S., Lissowska J., Peplonska B., Nevanlinna H., Fagerholm R., Eerola H., Kang D., Yoo K.-Y., Noh D.-Y., Ahn S.-H., Hunter D.J., Hankinson S.E., Cox D.G., Hall P., Wedren S., Liu J., Low Y.-L., Bogdanova N., Schurmann P., Dork T., Tollenaar R.A.E.M., Jacobi C.E., Devilee P., Klijn J.G.M., Sigurdson A.J., Doody M.M., Alexander B.H., Zhang J., Brock I.W., MacPherson G., Reed M.W.R., Couch F.J., Goode E.L., Olson J.E., Meijers-Heijboer H., Van Den Ouweland A., Uitterlinden A., Rivadeneira F., Milne R.L., Ribas G., Gonzalez-Neira A., Benitez J., Hopper J., McCredie M., Southey M., Giles G., Schroen C., Justenhoven C., Brauch H., Hamann U., Ko Y.-D., Spurdle A.B., Beesley J., Chen X., Mannermaa A., Kosma V.-M., Kataja V., Hartikainen J., Day N.E., Cox D.R., Ponder B.A.J., Luccarini C., Conroy D., Shah M., Munday H., Jordan C., Perkins B., West J., Redman K., Driver K., Aghmesheh M., Amor D., Andrews L., Antill Y., Armes J., Armitage S., Arnold L., Balleine R., Begley G., Beilby J., Bennett I., Bennett B., Berry G., Blackburn A., Brennan M., Brown M., Buckley M., Burke J., Butow P., Byron K., Callen D., Campbell I., Clarke C., Colley A., Cotton D., Cui J., Culling B., Cummings M., Dawson S.-J., Dixon J., Dobrovic A., Dudding T., Edkins T., Eisenbruch M., Cox A., Farshid G., Fawcett S., Field M., Firgaira F., Fleming J., Forbes J., Friedlander M., Gaff C., Gardner M., Gattas M., George P., Gill G., Goldblatt J., Greening S., Haan E., Hart S., Humphrey E., Jenkins M., Kefford R., Kirk J., Kollias J., Kovalenko S., Lakhani S., Leary J., Lim J., Lindeman G., Lipton L., Lobb L., Maclurcan M., Marsh D., McKay M., Anne McLachlan S., Mitchell G., Newman B., O'Loughlin I., Osborne R., Peters L., Price M., Reeve J., Reeve T., Richards R., Rinehart G., Robinson B., Rudzki B., Salisbury E., Saunders C., Scott E., Seshadri R., Shelling A., Suthers G., Taylor D., Tennant C., Townshend S., Tyler J., Venter D., Visvader J., Walpole I., Ward R., Warner B., Warren G., Watson E., Williams R., Winship I., Bowtell D., Green A., DeFazio A., Gertig D., Webb P., Milne R., Young M.A., Harris M., Wilson J., Easton D.F., Pooley K.A., Dunning A.M., Pharoah P.D.P., Thompson D., Ballinger D.G., Struewing J.P., Morrison J., Field H., Luben R., Wareham N., Ahmed S., Healey C.S., Bowman R., Meyer K.B., Haiman C.A., Kolonel L.K., Henderson B.E., Le Marchand L., Brennan P., Sangrajrang S., Gaborieau V., Odefrey F., Shen C.-Y., Wu P.-E., Wang H.-C., Eccles D., Evans D.G., Peto J., Fletcher O., Johnson N., Seal S., Stratton M.R., Rahman N., Chenevix-Trench G., Bojesen S.E., Nordestgaard B.G., Axelsson C.K., Garcia-Closas M., Brinton L., Chanock S., Lissowska J., Peplonska B., Nevanlinna H., Fagerholm R., Eerola H., Kang D., Yoo K.-Y., Noh D.-Y., Ahn S.-H., Hunter D.J., Hankinson S.E., Cox D.G., Hall P., Wedren S., Liu J., Low Y.-L., Bogdanova N., Schurmann P., Dork T., Tollenaar R.A.E.M., Jacobi C.E., Devilee P., Klijn J.G.M., Sigurdson A.J., Doody M.M., Alexander B.H., Zhang J., Brock I.W., MacPherson G., Reed M.W.R., Couch F.J., Goode E.L., Olson J.E., Meijers-Heijboer H., Van Den Ouweland A., Uitterlinden A., Rivadeneira F., Milne R.L., Ribas G., Gonzalez-Neira A., Benitez J., Hopper J., McCredie M., Southey M., Giles G., Schroen C., Justenhoven C., Brauch H., Hamann U., Ko Y.-D., Spurdle A.B., Beesley J., Chen X., Mannermaa A., Kosma V.-M., Kataja V., Hartikainen J., Day N.E., Cox D.R., Ponder B.A.J., Luccarini C., Conroy D., Shah M., Munday H., Jordan C., Perkins B., West J., Redman K., Driver K., Aghmesheh M., Amor D., Andrews L., Antill Y., Armes J., Armitage S., Arnold L., Balleine R., Begley G., Beilby J., Bennett I., Bennett B., Berry G., Blackburn A., Brennan M., Brown M., Buckley M., Burke J., Butow P., Byron K., Callen D., Campbell I., Clarke C., Colley A., Cotton D., Cui J., Culling B., Cummings M., Dawson S.-J., Dixon J., Dobrovic A., Dudding T., Edkins T., and Eisenbruch M.

Abstract

Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r2> 0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P < 10-7). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P < 0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach. ©2007 Nature Publishing Group.

Published
2007

41. Analysis of cancer risk and BRCA1 and BRCA2 mutation prevalence in the kConFab familial breast cancer resource

Author

Mann, GJ, Thorne, H, Balleine, RL, Butow, PN, Clarke, CL, Edkins, E, Evans, GM, Fereday, S, Haan, E, Gattas, M, Giles, GG, Goldblatt, J, Hopper, JL, Kirk, J, Leary, JA, Lindeman, G, Niedermayr, E, Phillips, KA, Picken, S, Pupo, GM, Saunders, C, Scott, CL, Spurdle, AB, Suthers, G, Tucker, K, Chenevix-Trench, G, Mann, GJ, Thorne, H, Balleine, RL, Butow, PN, Clarke, CL, Edkins, E, Evans, GM, Fereday, S, Haan, E, Gattas, M, Giles, GG, Goldblatt, J, Hopper, JL, Kirk, J, Leary, JA, Lindeman, G, Niedermayr, E, Phillips, KA, Picken, S, Pupo, GM, Saunders, C, Scott, CL, Spurdle, AB, Suthers, G, Tucker, K, and Chenevix-Trench, G

Abstract

INTRODUCTION: The Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) is a multidisciplinary, collaborative framework for the investigation of familial breast cancer. Based in Australia, the primary aim of kConFab is to facilitate high-quality research by amassing a large and comprehensive resource of epidemiological and clinical data with biospecimens from individuals at high risk of breast and/or ovarian cancer, and from their close relatives. METHODS: Epidemiological, family history and lifestyle data, as well as biospecimens, are collected from multiple-case breast cancer families ascertained through family cancer clinics in Australia and New Zealand. We used the Tyrer-Cuzick algorithms to assess the prospective risk of breast cancer in women in the kConFab cohort who were unaffected with breast cancer at the time of enrolment in the study. RESULTS: Of kConFab's first 822 families, 518 families had multiple cases of female breast cancer alone, 239 had cases of female breast and ovarian cancer, 37 had cases of female and male breast cancer, and 14 had both ovarian cancer as well as male and female breast cancer. Data are currently held for 11,422 people and germline DNAs for 7,389. Among the 812 families with at least one germline sample collected, the mean number of germline DNA samples collected per family is nine. Of the 747 families that have undergone some form of mutation screening, 229 (31%) carry a pathogenic or splice-site mutation in BRCA1 or BRCA2. Germline DNAs and data are stored from 773 proven carriers of BRCA1 or BRCA1 mutations. kConFab's fresh tissue bank includes 253 specimens of breast or ovarian tissue--both normal and malignant--including 126 from carriers of BRCA1 or BRCA2 mutations. CONCLUSION: These kConFab resources are available to researchers anywhere in the world, who may apply to kConFab for biospecimens and data for use in ethically approved, peer-reviewed projects. A high calculated risk from

Published
2006

42. Communication and information-giving in high-risk breast cancer consultations: influence on patient outcomes

Author

Lobb, EA, Butow, PN, Barratt, A, Meiser, B, Gaff, C, Young, MA, Haan, E, Suthers, G, Gattas, M, Tucker, K, Lobb, EA, Butow, PN, Barratt, A, Meiser, B, Gaff, C, Young, MA, Haan, E, Suthers, G, Gattas, M, and Tucker, K

Abstract

This longitudinal study aimed to document (i) the information-giving and patient-communication styles of clinical geneticists and genetic counsellors (consultants) in familial breast cancer clinics and (ii) assess the effect of these styles on women's knowledge, whether their expectations were met, satisfaction, risk perception and psychological status. A total of 158 women from high-risk breast cancer families completed self-report questionnaires at 2 weeks preconsultation and 4 weeks postconsultation. The consultations were audiotaped, transcribed and coded. Multivariate logistic regressions showed that discussing prophylactic mastectomy (P=0.00) and oophorectomy (P=0.01) led to women having significantly more expectations met; discussing genetic testing significantly decreased anxiety (P=0.03) and facilitating understanding significantly decreased depression (P=0.05). Receiving a summary letter of the consultation significantly lowered anxiety (P=0.01) and significantly increased the accuracy of perceived risk (P=0.02). Women whose consultant used more supportive communications experienced significantly more anxiety about breast cancer at the 4 weeks follow-up (P=0.00). These women were not significantly more anxious before genetic counselling. In conclusion, this study found that consultants vary in the amount of information they give and the way they communicate; and this variation can result in better or worse psychosocial outcomes. Greater use of supportive and counselling communications appeared to increase anxiety about breast cancer. Identifying methods to assist consultants to address emotional issues effectively may be helpful.

Published
2004

43. Frequency of the ATM IVS10-6T→G variant in Australian multiple-case breast cancer families

Author

Lindeman, GJ, Hiew, M, Visvader, JE, Leary, J, Field, M, Gaff, CL, Gardner, RJM, Trainor, K, Cheetham, G, Suthers, G, Kirk, J, Lindeman, GJ, Hiew, M, Visvader, JE, Leary, J, Field, M, Gaff, CL, Gardner, RJM, Trainor, K, Cheetham, G, Suthers, G, and Kirk, J

Abstract

BACKGROUND: Germline mutations in the genes BRCA1 and BRCA2 account for only a proportion of hereditary breast cancer, suggesting that additional genes contribute to hereditary breast cancer. Recently a heterozygous variant in the ataxia-telangiectasia mutated (ATM) gene, IVS10-6T-->G, was reported by an Australian multiple-case breast cancer family cohort study (the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer) to confer a substantial breast cancer risk. Although this variant can result in a truncated ATM product, its clinical significance as a high-penetrance breast cancer allele or its role as a low-penetrance risk-modifier is controversial. METHODS: We determined the frequency of ATM IVS10-6T-->G variants in a cohort of individuals affected by breast and/or ovarian cancer who underwent BRCA1 and BRCA2 genetic testing at four major Australian familial cancer clinics. RESULTS: Seven of 495 patients (1.4%) were heterozygous for the IVS10-6T-->G variant; the carrier rate in unselected Australian women with no family history of breast cancer is reported to be 6 of 725 (0.83%) (P = 0.4). Two of the seven probands also harboured a pathogenic BRCA1 mutation and one patient had a BRCA1 unclassified variant of uncertain significance. CONCLUSION: These findings indicate that the ATM IVS10-6T-->G variant does not seem to occur at a significantly higher frequency in affected individuals from high-risk families than in the general population. A role for this variant as a low-penetrance allele or as a modifying gene in association with other genes (such as BRCA1) remains possible. Routine testing for ATM IVS10-6T-->G is not warranted in mutation screening of affected individuals from high-risk families.

Published
2004

44. Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS): a new autosomal dominant syndrome

Author

Worthley, D L, primary, Phillips, K D, additional, Wayte, N, additional, Schrader, K A, additional, Healey, S, additional, Kaurah, P, additional, Shulkes, A, additional, Grimpen, F, additional, Clouston, A, additional, Moore, D, additional, Cullen, D, additional, Ormonde, D, additional, Mounkley, D, additional, Wen, X, additional, Lindor, N, additional, Carneiro, F, additional, Huntsman, D G, additional, Chenevix-Trench, G, additional, and Suthers, G K, additional

Published
2011
Full Text
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45. X-linked alpha-thalassemia/mental retardation (ATR-X) syndrome: localization to Xq12-q21.31 by X inactivation and linkage analysis

Author

Gibbons, R J, Suthers, G K, Wilkie, A O, Buckle, V J, and Higgs, D R

Subjects
Genetic Markers, Male, Risk, X Chromosome, Genetic Linkage, Genetic Carrier Screening, Syndrome, Globins, Pedigree, alpha-Thalassemia, Dosage Compensation, Genetic, Intellectual Disability, Humans, Female, Lod Score, Research Article
Abstract

We have examined seven pedigrees that include individuals with a recently described X-linked form of severe mental retardation associated with alpha-thalassemia (ATR-X syndrome). Using hematologic and molecular approaches, we have shown that intellectually normal female carriers of this syndrome may be identified by the presence of rare cells containing HbH inclusions in their peripheral blood and by an extremely skewed pattern of X inactivation seen in cells from a variety of tissues. Linkage analysis has localized the ATR-X locus to an interval of approximately 11 cM between the loci DXS106 and DXYS1X (Xq12-q21.31), with a peak LOD score of 5.4 (recombination fraction of 0) at DXS72. These findings provide the basis for genetic counseling, assessment of carrier risk, and prenatal diagnosis of the ATR-X syndrome. Furthermore, they represent an important step in developing strategies to understand how the mutant ATR-X allele causes mental handicap, dysmorphism, and down-regulation of the alpha-globin genes.

Published
1992

46. Phenotypic heterogeneity and the single gene

Author

Suthers, G K and Davies, K E

Subjects
Family Health, Male, Muscular Atrophy, Spinal, Blotting, Southern, Phenotype, Genetic Linkage, Homozygote, Chromosomes, Human, Pair 5, Humans, Female, Alleles, Research Article, Pedigree
Abstract

Proximal spinal muscular atrophy (SMA) is a group of progressive muscular diseases recently mapped to chromosome 5q. SMA is usually classified into types I-III, and there are cases of two types of SMA in the same sibship. Becker and others later proposed that these sibships might be due to the existence of several alleles at the same locus predisposing to the different forms of the disease. In a sample of four sibships in which both SMA type II and SMA type III occur, this hypothesis was clearly rejected for the SMA locus on 5q, by using information on the segregation of linked markers (P less than .001). Thus the difference between SMA type II and SMA type III is not due to different alleles at the SMA locus on 5q. This finding is suggestive of an involvement of other factors, genetic or environmental, in the determination of disease severity in SMA.

Published
1992

49. Genetic counseling in rare syndromes: a resampling method for determining an approximate confidence interval for gene location with linkage data from a single pedigree

Author

Suthers, G K and Wilson, S R

Subjects
Male, Heterozygote, Likelihood Functions, Genetic Linkage, Chromosome Mapping, Genetic Counseling, Syndrome, Pedigree, Risk Factors, Confidence Intervals, Humans, Female, Lod Score, Research Article
Abstract

Multipoint linkage analysis is a powerful method for mapping a rare disease gene on the human gene map despite limited genotype and pedigree data. However, there is no standard procedure for determining a confidence interval for gene location by using multipoint linkage analysis. A genetic counselor needs to know the confidence interval for gene location in order to determine the uncertainty of risk estimates provided to a consultant on the basis of DNA studies. We describe a resampling, or "bootstrap," method for deriving an approximate confidence interval for gene location on the basis of data from a single pedigree. This method was used to define an approximate confidence interval for the location of a gene causing nonsyndromal X-linked mental retardation in a single pedigree. The approach seemed robust in that similar confidence intervals were derived by using different resampling protocols. Quantitative bounds for the confidence interval were dependent on the genetic map chosen. Once an approximate confidence interval for gene location was determined for this pedigree, it was possible to use multipoint risk analysis to estimate risk intervals for women of unknown carrier status. Despite the limited genotype data, the combination of the resampling method and multipoint risk analysis had a dramatic impact on the genetic advice available to consultants.

Published
1990

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