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

Author

Li, A. (Anqi), Geyer, F. C. (Felipe C.), Blecua, P. (Pedro), Lee, J. Y. (Ju Youn), Selenica, P. (Pier), Brown, D. N. (David N.), Pareja, F. (Fresia), Lee, S. S. (Simon S. K.), Kumar, R. (Rahul), Rivera, B. (Barbara), Bi, R. (Rui), Piscuoglio, S. (Salvatore), Wen, H. Y. (Hannah Y.), Lozada, J. R. (John R.), Gularte-Merida, R. (Rodrigo), Cavallone, L. (Luca), Rezoug, Z. (Zoulikha), Nguyen-Dumont, T. (Tu), Peterlongo, P. (Paolo), Tondini, C. (Carlo), Terkelsen, T. (Thorkild), Ronlund, K. (Karina), Boonen, S. E. (Susanne E.), Mannerma, A. (Arto), Winqvist, R. (Robert), Janatova, M. (Marketa), Rajadurai, P. (Pathmanathan), Xia, B. (Bing), Norton, L. (Larry), Robson, M. E. (Mark E.), Ng, P.-S. (Pei-Sze), Looi, L.-M. (Lai-Meng), Southey, M. C. (Melissa C.), Weigelt, B. (Britta), Soo-Hwang, T. (Teo), Tischkowitz, M. (Marc), Foulkes, W. D. (William D.), Reis-Filho, J. S. (Jorge S.), Aghmesheh, M. (Morteza), Amor, D. (David), Andrews, L. (Leslie), Antill, Y. (Yoland), Balleine, R. (Rosemary), Beesley, J. (Jonathan), Blackburn, A. (Anneke), Bogwitz, M. (Michael), Brown, M. (Melissa), Burgess, M. (Matthew), Burke, J. (Jo), Butow, P. (Phyllis), Caldon, L. (Liz), Campbell, I. (Ian), Christian, A. (Alice), Clarke, C. (Christine), Cohen, P. (Paul), Crook, A. (Ashley), Cui, J. (James), Cummings, M. (Margaret), Dawson, S.-J. (Sarah-Jane), De Fazio, A. (Anna), Delatycki, M. (Martin), Dobrovic, A. (Alex), Dudding, T. (Tracy), Duijf, P. (Pascal), Edkins, E. (Edward), Edwards, S. (Stacey), Farshid, G. (Gelareh), Fellows, A. (Andrew), Field, M. (Michael), Flanagan, J. (James), Fong, P. (Peter), Forbes, J. (John), Forrest, L. (Laura), Fox, S. (Stephen), French, J. (Juliet), Friedlander, M. (Michael), Ortega, D. G. (David Gallego), Gattas, M. (Michael), Giles, G. (Graham), Gill, G. (Grantley), Gleeson, M. (Margaret), Greening, S. (Sian), Haan, E. (Eric), Harris, M. (Marion), Hayward, N. (Nick), Hickie, I. (Ian), Hopper, J. (John), Hunt, C. (Clare), James, P. (Paul), Jenkins, M. (Mark), Kefford, R. (Rick), Kentwell, M. (Maira), Kirk, J. (Judy), Kollias, J. (James), Lakhani, S. (Sunil), Lindeman, G. (Geoff), Lipton, L. (Lara), Lobb, L. (Lizz), Lok, S. (Sheau), Macrea, F. (Finlay), Mane, G. (Graham), Marsh, D. (Deb), Mclachlan, S.-A. (Sue-Anne), Meiser, B. (Bettina), Milne, R. (Roger), Nightingale, S. (Sophie), O'Connell, S. (Shona), Pachter, N. (Nick), Patterson, B. (Briony), Phillips, K. (Kelly), Saleh, M. (Mona), Salisbury, E. (Elizabeth), Saunders, C. (Christobel), Saunus, J. (Jodi), Scott, C. (Clare), Scott, R. (Rodney), Sexton, A. (Adrienne), Shelling, A. (Andrew), Simpson, P. (Peter), Spigelman, A. (Allan), Spurdle, M. (Mandy), Stone, J. (Jennifer), Taylor, J. (Jessica), Thorne, H. (Heather), Trainer, A. (Alison), Trench, G. (Georgia), Tucker, K. (Kathy), Visvader, J. (Jane), Walker, L. (Logan), Wallis, M. (Mathew), Williams, R. (Rachael), Winship, I. (Ingrid), Wu, K. (Kathy), Young, M. A. (Mary Anne), Li, Anqi, Geyer, Felipe C, Blecua, Pedro, Lee, Ju Youn, Duijf, Pascal, Reis-Filho, Jorge S, Li, Anqi [0000-0003-1409-1858], Kumar, Rahul [0000-0002-6927-5390], Rivera, Barbara [0000-0001-9434-6288], Piscuoglio, Salvatore [0000-0003-2686-2939], Lozada, John R. [0000-0001-8953-4110], Gularte-Mérida, Rodrigo [0000-0002-4383-2523], Peterlongo, Paolo [0000-0001-6951-6855], Robson, Mark E. [0000-0002-3109-1692], Looi, Lai-Meng [0000-0001-8325-0117], Foulkes, William D. [0000-0001-7427-4651], Apollo - University of Cambridge Repository, Lozada, John R [0000-0001-8953-4110], Robson, Mark E [0000-0002-3109-1692], and Foulkes, William D [0000-0001-7427-4651]

Subjects
0301 basic medicine, IMPACT, DNA repair, PALB2, gene frequency, lcsh:RC254-282, RECOMMENDATIONS, Germline, Article, Loss of heterozygosity, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, breast cancer, Breast cancer, 631/67/68, MUTATIONAL PROCESSES, Cancer genomics, Medicine, Pharmacology (medical), Radiology, Nuclear Medicine and imaging, Allele, AMERICAN SOCIETY, Cancer genetics, Genetics, Science & Technology, Massive parallel sequencing, LANDSCAPE, business.industry, 631/67/1347, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 692/699/67/69, BRCA2, GENE, 3. Good health, 030104 developmental biology, Oncology, gene inactivation, 030220 oncology & carcinogenesis, kConFab Investigators, Homologous recombination, business, Life Sciences & Biomedicine, CLINICAL ONCOLOGY/COLLEGE
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.

Published
2019
Full Text
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16. Homologous recombination DNA repair defects in PALB2-associated breast cancers.

Author

Duijf P., Kentwell M., Kirk J., Kollias J., Lakhani S., Lindeman G., Lipton L., Lobb L., Lok S., Macrea F., Mann G., Marsh D., McLachlan S.-A., Meiser B., Milne R., Nightingale S., O'Connell S., Pachter N., Patterson B., Phillips K., Saleh M., Salisbury E., Saunders C., Saunus J., Scott C., Scott R., Sexton A., Shelling A., Simpson P., Spigelman A., Spurdle M., Stone J., Taylor J., Thorne H., Trainer A., Trench G., Walker L., Wallis M., Williams R., Winship I., Wu K., Young M.A., Rezoug Z., Nguyen-Dumont T., Peterlongo P., Tondini C., Terkelsen T., Ronlund K., Boonen S.E., Mannerma A., Winqvist R., Janatova M., Rajadurai P., Xia B., Norton L., Robson M.E., Ng P.-S., Looi L.-M., Southey M.C., Weigelt B., Soo-Hwang T., Tischkowitz M., Foulkes W.D., Reis-Filho J.S., Harris M., Tucker K., Visvader J., Li A., Geyer F.C., Blecua P., Lee J.Y., Selenica P., Brown D.N., Pareja F., Lee S.S.K., Kumar R., Rivera B., Bi R., Piscuoglio S., Wen H.Y., Lozada J.R., Gularte-Merida R., Cavallone L., Aghmesheh M., Amor D., Andrews L., Antill Y., Balleine R., Beesley J., Blackburn A., Bogwitz M., Brown M., Burgess M., Burke J., Butow P., Caldon L., Campbell I., Christian A., Clarke C., Cohen P., Crook A., Cui J., Cummings M., Dawson S.-J., De Fazio A., Delatycki M., Dobrovic A., Dudding T., Edkins E., Edwards S., Farshid G., Fellows A., Field M., Flanagan J., Fong P., Forbes J., Forrest L., Fox S., French J., Friedlander M., Ortega D.G., Gattas M., Giles G., Gill G., Gleeson M., Greening S., Haan E., Hayward N., Hickie I., Hopper J., Hunt C., James P., Jenkins M., Kefford R., Duijf P., Kentwell M., Kirk J., Kollias J., Lakhani S., Lindeman G., Lipton L., Lobb L., Lok S., Macrea F., Mann G., Marsh D., McLachlan S.-A., Meiser B., Milne R., Nightingale S., O'Connell S., Pachter N., Patterson B., Phillips K., Saleh M., Salisbury E., Saunders C., Saunus J., Scott C., Scott R., Sexton A., Shelling A., Simpson P., Spigelman A., Spurdle M., Stone J., Taylor J., Thorne H., Trainer A., Trench G., Walker L., Wallis M., Williams R., Winship I., Wu K., Young M.A., Rezoug Z., Nguyen-Dumont T., Peterlongo P., Tondini C., Terkelsen T., Ronlund K., Boonen S.E., Mannerma A., Winqvist R., Janatova M., Rajadurai P., Xia B., Norton L., Robson M.E., Ng P.-S., Looi L.-M., Southey M.C., Weigelt B., Soo-Hwang T., Tischkowitz M., Foulkes W.D., Reis-Filho J.S., Harris M., Tucker K., Visvader J., Li A., Geyer F.C., Blecua P., Lee J.Y., Selenica P., Brown D.N., Pareja F., Lee S.S.K., Kumar R., Rivera B., Bi R., Piscuoglio S., Wen H.Y., Lozada J.R., Gularte-Merida R., Cavallone L., Aghmesheh M., Amor D., Andrews L., Antill Y., Balleine R., Beesley J., Blackburn A., Bogwitz M., Brown M., Burgess M., Burke J., Butow P., Caldon L., Campbell I., Christian A., Clarke C., Cohen P., Crook A., Cui J., Cummings M., Dawson S.-J., De Fazio A., Delatycki M., Dobrovic A., Dudding T., Edkins E., Edwards S., Farshid G., Fellows A., Field M., Flanagan J., Fong P., Forbes J., Forrest L., Fox S., French J., Friedlander M., Ortega D.G., Gattas M., Giles G., Gill G., Gleeson M., Greening S., Haan E., Hayward N., Hickie I., Hopper J., Hunt C., James P., Jenkins M., and Kefford R.

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.Copyright © 2019, The Author(s).

Published
2019

17. Publisher Correction: Homologous recombination DNA repair defects in PALB2-associated breast cancers (npj Breast Cancer, (2019), 5, 1, (23), 10.1038/s41523-019-0115-9).

Author

Cummings M., Walker L., Wallis M., Williams R., Winship I., Wu K., Young M.A., Rezoug Z., Nguyen-Dumont T., Peterlongo P., Tondini C., Terkelsen T., Ronlund K., Boonen S.E., Mannerma A., Winqvist R., Janatova M., Rajadurai P., Xia B., Norton L., Robson M.E., Ng P.-S., Looi L.-M., Southey M.C., Weigelt B., Soo-Hwang T., Tischkowitz M., Foulkes W.D., Reis-Filho J.S., Li A., Geyer F.C., Blecua P., Lee J.Y., Selenica P., Brown D.N., Pareja F., Lee S.S.K., Kumar R., Rivera B., Bi R., Piscuoglio S., Wen H.Y., Lozada J.R., Gularte-Merida R., Cavallone L., Aghmesheh M., Amor D., Andrews L., Antill Y., Balleine R., Beesley J., Blackburn A., Bogwitz M., Brown M., Burgess M., Burke J., Butow P., Caldon L., Campbell I., Christian A., Clarke C., Cohen P., Crook A., Cui J., Dawson S.-J., De Fazio A., Delatycki M., Dobrovic A., Dudding T., Duijf P., Edkins E., Edwards S., Farshid G., Fellows A., Field M., Flanagan J., Fong P., Forbes J., Forrest L., Fox S., French J., Friedlander M., Ortega D.G., Gattas M., Giles G., Gill G., Gleeson M., Greening S., Haan E., Harris M., Hayward N., Hickie I., Hopper J., Hunt C., James P., Jenkins M., Kefford R., Kentwell M., Kirk J., Kollias J., Lakhani S., Lindeman G., Lipton L., Lobb L., Lok S., Macrea F., Mann G., Marsh D., McLachlan S.-A., Meiser B., Milne R., Nightingale S., O'Connell S., Pachter N., Patterson B., Phillips K., Saleh M., Salisbury E., Saunders C., Saunus J., Scott C., Scott R., Sexton A., Shelling A., Simpson P., Spigelman A., Spurdle M., Stone J., Taylor J., Thorne H., Trainer A., Trench G., Tucker K., Visvader J., Cummings M., Walker L., Wallis M., Williams R., Winship I., Wu K., Young M.A., Rezoug Z., Nguyen-Dumont T., Peterlongo P., Tondini C., Terkelsen T., Ronlund K., Boonen S.E., Mannerma A., Winqvist R., Janatova M., Rajadurai P., Xia B., Norton L., Robson M.E., Ng P.-S., Looi L.-M., Southey M.C., Weigelt B., Soo-Hwang T., Tischkowitz M., Foulkes W.D., Reis-Filho J.S., Li A., Geyer F.C., Blecua P., Lee J.Y., Selenica P., Brown D.N., Pareja F., Lee S.S.K., Kumar R., Rivera B., Bi R., Piscuoglio S., Wen H.Y., Lozada J.R., Gularte-Merida R., Cavallone L., Aghmesheh M., Amor D., Andrews L., Antill Y., Balleine R., Beesley J., Blackburn A., Bogwitz M., Brown M., Burgess M., Burke J., Butow P., Caldon L., Campbell I., Christian A., Clarke C., Cohen P., Crook A., Cui J., Dawson S.-J., De Fazio A., Delatycki M., Dobrovic A., Dudding T., Duijf P., Edkins E., Edwards S., Farshid G., Fellows A., Field M., Flanagan J., Fong P., Forbes J., Forrest L., Fox S., French J., Friedlander M., Ortega D.G., Gattas M., Giles G., Gill G., Gleeson M., Greening S., Haan E., Harris M., Hayward N., Hickie I., Hopper J., Hunt C., James P., Jenkins M., Kefford R., Kentwell M., Kirk J., Kollias J., Lakhani S., Lindeman G., Lipton L., Lobb L., Lok S., Macrea F., Mann G., Marsh D., McLachlan S.-A., Meiser B., Milne R., Nightingale S., O'Connell S., Pachter N., Patterson B., Phillips K., Saleh M., Salisbury E., Saunders C., Saunus J., Scott C., Scott R., Sexton A., Shelling A., Simpson P., Spigelman A., Spurdle M., Stone J., Taylor J., Thorne H., Trainer A., Trench G., Tucker K., and Visvader J.

Abstract

In the original version of this paper, the link to the data record in the Data Availability Statement was incorrectly listed as https:// doi.org/10.6084/m9.figshare.8138912.44. The link has been corrected to https://doi.org/10.6084/m9.figshare.8138912. This has been corrected in the HTML and PDF versions of this article.Copyright © 2019, The Author(s).

Published
2019

18. Homologous recombination DNA repair defects in PALB2-associated breast cancers (vol 5, 23, 2019)

Author

Li, A, Geyer, FC, Blecua, P, Lee, JY, Selenica, P, Brown, DN, Pareja, F, Lee, SSK, Kumar, R, Rivera, B, Bi, R, Piscuoglio, S, Wen, HY, Lozada, JR, Gularte-Merida, R, Cavallone, L, Rezoug, Z, Tu, N-D, Peterlongo, P, Tondini, C, Terkelsen, T, Ronlund, K, Boonen, SE, Mannerma, A, Winqvist, R, Janatova, M, Rajadurai, P, Xia, B, Norton, L, Robson, ME, Ng, P-S, Looi, L-M, Southey, MC, Weigelt, B, Soo-Hwang, T, Tischkowitz, M, Foulkes, WD, Reis-Filho, JS, Aghmesheh, M, Amor, D, Andrews, L, Antill, Y, Balleine, R, Beesley, J, Blackburn, A, Bogwitz, M, Brown, M, Burgess, M, Burke, J, Butow, P, Caldon, L, Campbell, I, Christian, A, Clarke, C, Cohen, P, Crook, A, Cui, J, Cummings, M, Dawson, S-J, De Fazio, A, Delatycki, M, Dobrovic, A, Dudding, T, Duijf, P, Edkins, E, Edwards, S, Farshid, G, Fellows, A, Field, M, Flanagan, J, Fong, P, Forbes, J, Forrest, L, Fox, S, French, J, Friedlander, M, Ortega, DG, Gattas, M, Giles, G, Gill, G, Gleeson, M, Greening, S, Haan, E, Harris, M, Hayward, N, Hickie, I, Hopper, J, Hunt, C, James, P, Jenkins, M, Kefford, R, Kentwell, M, Kirk, J, Kollias, J, Lakhani, S, Lindeman, G, Lipton, L, Lobb, L, Lok, S, Macrea, F, Mann, G, Marsh, D, McLachlan, S-A, Meiser, B, Milne, R, Nightingale, S, O'Connell, S, Pachter, N, Patterson, B, Phillips, K, Saleh, M, Salisbury, E, Saunders, C, Saunus, J, Scott, C, Scott, R, Sexton, A, Shelling, A, Simpson, P, Spigelman, A, Spurdle, M, Stone, J, Taylor, J, Thorne, H, Trainer, A, Trench, G, Tucker, K, Visvader, J, Walker, L, Wallis, M, Williams, R, Winship, I, Wu, K, Young, MA, Li, A, Geyer, FC, Blecua, P, Lee, JY, Selenica, P, Brown, DN, Pareja, F, Lee, SSK, Kumar, R, Rivera, B, Bi, R, Piscuoglio, S, Wen, HY, Lozada, JR, Gularte-Merida, R, Cavallone, L, Rezoug, Z, Tu, N-D, Peterlongo, P, Tondini, C, Terkelsen, T, Ronlund, K, Boonen, SE, Mannerma, A, Winqvist, R, Janatova, M, Rajadurai, P, Xia, B, Norton, L, Robson, ME, Ng, P-S, Looi, L-M, Southey, MC, Weigelt, B, Soo-Hwang, T, Tischkowitz, M, Foulkes, WD, Reis-Filho, JS, Aghmesheh, M, Amor, D, Andrews, L, Antill, Y, Balleine, R, Beesley, J, Blackburn, A, Bogwitz, M, Brown, M, Burgess, M, Burke, J, Butow, P, Caldon, L, Campbell, I, Christian, A, Clarke, C, Cohen, P, Crook, A, Cui, J, Cummings, M, Dawson, S-J, De Fazio, A, Delatycki, M, Dobrovic, A, Dudding, T, Duijf, P, Edkins, E, Edwards, S, Farshid, G, Fellows, A, Field, M, Flanagan, J, Fong, P, Forbes, J, Forrest, L, Fox, S, French, J, Friedlander, M, Ortega, DG, Gattas, M, Giles, G, Gill, G, Gleeson, M, Greening, S, Haan, E, Harris, M, Hayward, N, Hickie, I, Hopper, J, Hunt, C, James, P, Jenkins, M, Kefford, R, Kentwell, M, Kirk, J, Kollias, J, Lakhani, S, Lindeman, G, Lipton, L, Lobb, L, Lok, S, Macrea, F, Mann, G, Marsh, D, McLachlan, S-A, Meiser, B, Milne, R, Nightingale, S, O'Connell, S, Pachter, N, Patterson, B, Phillips, K, Saleh, M, Salisbury, E, Saunders, C, Saunus, J, Scott, C, Scott, R, Sexton, A, Shelling, A, Simpson, P, Spigelman, A, Spurdle, M, Stone, J, Taylor, J, Thorne, H, Trainer, A, Trench, G, Tucker, K, Visvader, J, Walker, L, Wallis, M, Williams, R, Winship, I, Wu, K, and Young, MA

Abstract

[This corrects the article DOI: 10.1038/s41523-019-0115-9.].

Published
2019

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

Author

Li, A, Geyer, FC, Blecua, P, Lee, JY, Selenica, P, Brown, DN, Pareja, F, Lee, SSK, Kumar, R, Rivera, B, Bi, R, Piscuoglio, S, Wen, HY, Lozada, JR, Gularte-Merida, R, Cavallone, L, Rezoug, Z, Nguyen-Dumont, T, Peterlongo, P, Tondini, C, Terkelsen, T, Ronlund, K, Boonen, SE, Mannerma, A, Winqvist, R, Janatova, M, Rajadurai, P, Xia, B, Norton, L, Robson, ME, Ng, P-S, Looi, L-M, Southey, MC, Weigelt, B, Soo-Hwang, T, Tischkowitz, M, Foulkes, WD, Reis-Filho, JS, Aghmesheh, M, Amor, D, Andrews, L, Antill, Y, Balleine, R, Beesley, J, Blackburn, A, Bogwitz, M, Brown, M, Burgess, M, Burke, J, Butow, P, Caldon, L, Campbell, I, Christian, A, Clarke, C, Cohen, P, Crook, A, Cui, J, Cummings, M, Dawson, S-J, De Fazio, A, Delatycki, M, Dobrovic, A, Dudding, T, Duijf, P, Edkins, E, Edwards, S, Farshid, G, Fellows, A, Field, M, Flanagan, J, Fong, P, Forbes, J, Forrest, L, Fox, S, French, J, Friedlander, M, Ortega, DG, Gattas, M, Giles, G, Gill, G, Gleeson, M, Greening, S, Haan, E, Harris, M, Hayward, N, Hickie, I, Hopper, J, Hunt, C, James, P, Jenkins, M, Kefford, R, Kentwell, M, Kirk, J, Kollias, J, Lakhani, S, Lindeman, G, Lipton, L, Lobb, L, Lok, S, Macrea, F, Mane, G, Marsh, D, Mclachlan, S-A, Meiser, B, Milne, R, Nightingale, S, O'Connell, S, Pachter, N, Patterson, B, Phillips, K, Saleh, M, Salisbury, E, Saunders, C, Saunus, J, Scott, C, Scott, R, Sexton, A, Shelling, A, Simpson, P, Spigelman, A, Spurdle, M, Stone, J, Taylor, J, Thorne, H, Trainer, A, Trench, G, Tucker, K, Visvader, J, Walker, L, Wallis, M, Williams, R, Winship, I, Wu, K, Young, MA, Li, A, Geyer, FC, Blecua, P, Lee, JY, Selenica, P, Brown, DN, Pareja, F, Lee, SSK, Kumar, R, Rivera, B, Bi, R, Piscuoglio, S, Wen, HY, Lozada, JR, Gularte-Merida, R, Cavallone, L, Rezoug, Z, Nguyen-Dumont, T, Peterlongo, P, Tondini, C, Terkelsen, T, Ronlund, K, Boonen, SE, Mannerma, A, Winqvist, R, Janatova, M, Rajadurai, P, Xia, B, Norton, L, Robson, ME, Ng, P-S, Looi, L-M, Southey, MC, Weigelt, B, Soo-Hwang, T, Tischkowitz, M, Foulkes, WD, Reis-Filho, JS, Aghmesheh, M, Amor, D, Andrews, L, Antill, Y, Balleine, R, Beesley, J, Blackburn, A, Bogwitz, M, Brown, M, Burgess, M, Burke, J, Butow, P, Caldon, L, Campbell, I, Christian, A, Clarke, C, Cohen, P, Crook, A, Cui, J, Cummings, M, Dawson, S-J, De Fazio, A, Delatycki, M, Dobrovic, A, Dudding, T, Duijf, P, Edkins, E, Edwards, S, Farshid, G, Fellows, A, Field, M, Flanagan, J, Fong, P, Forbes, J, Forrest, L, Fox, S, French, J, Friedlander, M, Ortega, DG, Gattas, M, Giles, G, Gill, G, Gleeson, M, Greening, S, Haan, E, Harris, M, Hayward, N, Hickie, I, Hopper, J, Hunt, C, James, P, Jenkins, M, Kefford, R, Kentwell, M, Kirk, J, Kollias, J, Lakhani, S, Lindeman, G, Lipton, L, Lobb, L, Lok, S, Macrea, F, Mane, G, Marsh, D, Mclachlan, S-A, Meiser, B, Milne, R, Nightingale, S, O'Connell, S, Pachter, N, Patterson, B, Phillips, K, Saleh, M, Salisbury, E, Saunders, C, Saunus, J, Scott, C, Scott, R, Sexton, A, Shelling, A, Simpson, P, Spigelman, A, Spurdle, M, Stone, J, Taylor, J, Thorne, H, Trainer, A, Trench, G, Tucker, K, Visvader, J, Walker, L, Wallis, M, Williams, R, Winship, I, Wu, K, and Young, MA

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.

Published
2019

23. Problems in the histological assessment of hydatidiform moles: A study on consensus diagnosis and ploidy status by fluorescent in situ hybridisation.

Author

Cheah P.-L., Looi L.-M., Susil B.J., Sumithran E., Cheah P.-L., Looi L.-M., Susil B.J., and Sumithran E.

Abstract

Hydropic villi in products of conception continue to pose a diagnostic problem for the anatomical pathologist. It is important to distinguish between complete hydatidiform mole (CM), partial hydatidiform mole (PM) and hydropic degeneration (HD), as hydatidiform moles (especially CM) have a tendency to develop persistent trophoblastic disease. Several studies have demonstrated interobserver variability in the diagnosis of the three conditions, but there have been no studies testing the accuracy of the consensus diagnosis of pathologists experienced in the field. In this study four anatomical pathologists with experience in diagnosing hydatidiform moles selected five cases of HD, seven cases of PM and ten cases of CM on the basis of consensus diagnosis using established criteria. Ploidy studies were done on these 22 cases using fluorescent in situ hybridisation. The 15 cases of HD and CM were diploid, confirming the histological diagnosis. However only five of the seven cases of PM were triploid, the other two being diploid. Review of these two diploid cases showed a mixture of small and large villi with moderate to marked trophoblastic proliferation. On the basis of the significant trophoblastic proliferation and the DNA information, the two cases were reclassified as early complete moles. This study demonstrates that even pathologists experienced in the field have difficulty separating PM from CM. The findings suggest that, in the absence of DNA information, a lesion with hydropic villi showing moderate to marked trophoblastic proliferation should be classified as a complete mole, even if there is a mixture of small and large villi. Ploidy studies are an important adjunct to histological diagnosis, especially when there is an overlap of features.

Published
2012

24. Synovial juxtafacet cyst of the spine presenting as radiculopathy

Author

Mohd Nasir, Mohd Nizlan, K., Selvakumar, Looi, L. M., R., Kunasegaran, Mohd Nasir, Mohd Nizlan, K., Selvakumar, Looi, L. M., and R., Kunasegaran

Abstract

Juxtafacet cyst of the spine is a rare occurrence. Reports have described them as synovial cysts; ganglion cyst; extradural cysts as well as degenerative cysts of the spine. Patients may present with radicular pain, motor deficits, sensory disturbances, cauda equine syndrome and even myelopathy. Lumbar juxtafacet cysts may be confused clinically with prolapsed intervertebral disc or other conditions involving nerve root compression such as arachnid cysts, ependymal cysts, dermoid cysts or teramatous cycts. In the case of the juxtafacet cysts, surgical excision is usually curative. We report a case of spinal synovial juxtafacet cysts found intraoperatively in a case that was preoperatively diagnosed as prolapsed intervertebral disc. Synovial juxtafacet cysts of the spine should be considered as one of the differential diagnoses in patients, especially in older patients, presenting with nerve root compression.

Published
2005

30. Double-Exposure Dual Energy Subtraction Microradiography: A Phantom Study.

Author

Kim, Sun I., Suh, Tae Suk, Magjarevic, R., Nagel, J. H., Jamal, Noriah, Ng, K-H, Looi, L-M, and McLean, D.

Abstract

It is well-known that cancerous cells on mastectomy specimens represent glandular tissue, where it originated. This study was undertaken to develop a double-exposure dual energy subtraction microradiography technique and validate it by using a phantom study. The technique is used to quantify glandular component on the mastectomy specimen. This double-exposure dual energy subtraction microradiography technique had been developed using soft energy X-ray in conjunction with computed radiography. The technique involves exposing the phantom at low (15 kV) and high (20 kV; 0.1 mm tin added filtration), image registration, subtraction and image analysis. The phantom is designed to contain 100% glandular embedded in 100% adipose tissue equivalent materials. The subtracted phantom image was analyzed. The radiologist then analyzed five mastectomy specimens using manual delineation and computer techniques respectively. The technique is able to detect glandular tissue when in excess of 49.1% of the material. The resulting fibroglandular tissue area is 90.3% in agreement with the corresponding manually delineated technique used by the radiologist. We had developed a technique to quantify glandular component of the mastectomy specimen and validate its using a phantom study. The technique reported here in combination with histological examination of sliced mastectomy specimen s will enable us to ascertain that radiologically screened lesions have been effectively and totally cut out and extensively evaluated histologically. [ABSTRACT FROM AUTHOR]

Published
2007
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42. Reye-Like Syndrome Due to Margosa Oil Poisoning: Report of a Case with Postmortem Findings.

Author

Sinniah, D., Baskaran, G., Looi, A. H., Looi, L. M., and Leong, K. L.

Subjects
REYE'S syndrome, NEEM, AFLATOXINS, FATTY liver, LABORATORY mice
Abstract

A syndrome similar to Reye's syndrome has been reported in infants and mice after ingestion of margosa oil. Although aflatoxin contamination of the oil has been recognized, autopsy findings in an infant with margosa oil poisoning reveal changes consistent with Reye's syndrome but unlike those described in acute aflatoxicosis. The toxic action of margosa oil may be due to the synergistic effects of aflatoxins and other toxic component(s) present in the oil. [ABSTRACT FROM AUTHOR]

Published
1982

45. Serum levels of hematoporphyrin derivatives in the photodynamic therapy of malignant tumors

Author

Chan, H. K., Low, K. S., Haji Baba, A. S., Arimbalam, S., Yip, C. H., Chang, K. W., Baskaran, G., Lo, Y. L., Jayalakshmi, P., Looi, L. M., and Tan, N. H.

Abstract

In photodynamic therapy (PDT), red light is administered 24 - 72 hours post intravenous (i.v.) injection of hematoporphyrin derivatives (HpD). In an earlier animal model study, more effective therapeutic response was obtained when red light irradiation was carried out 15 mins after the injection of HpD. The effectiveness of this immediate PDT protocol has been correlated to the high serum level of HpD immediately after administration and the destruction of the microcirculation system as the dominant tumor destruction mechanism. This study examines the pharmacokinetics and the serum levels of HpD in rats and also in human patients. Such data can assist in defining the optimum time delay for light irradiation in the PDT of cancer.

Published
1994
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49. Lupus nephritis and lupus band test.

Author

Adam, B. A., Wang, F., Looi, L. M., and Prathap, K.

Abstract

Twenty-seven patients with histologically confirmed lupus nephritis were studied to identify the incidence of lupus band and its significance to histological patterns of nephritis and complement levels. It was found that the kidney involvement is 2.5 times more frequent in lupus band positive patients. The association of a positive lupus and low C3 level signifies the presence of diffuse proliferative glomerulonephritis rather than membranous glomerulonephritis. The results, together with earlier reports, are discussed. [ABSTRACT FROM PUBLISHER]

Published
1981

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