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6 results on '"Leung SY"'

1. Ganciclovir-induced mutations are present in a diverse spectrum of post-transplant malignancies

Author

Fang, H, Yan, HHN, Bilardi, RA, Flensburg, C, Yang, H, Barbour, JA, Siu, HC, Turski, M, Chew, E, Xu, Z, Lam, ST, Sharma, R, Xu, M, Li, J, Ip, HW, Cheung, CYM, Huen, MSY, Sweet-Cordero, EA, Majewski, IJ, Leung, SY, Wong, JWH, Fang, H, Yan, HHN, Bilardi, RA, Flensburg, C, Yang, H, Barbour, JA, Siu, HC, Turski, M, Chew, E, Xu, Z, Lam, ST, Sharma, R, Xu, M, Li, J, Ip, HW, Cheung, CYM, Huen, MSY, Sweet-Cordero, EA, Majewski, IJ, Leung, SY, and Wong, JWH

Abstract

BACKGROUND: Ganciclovir (GCV) is widely used in solid organ and haematopoietic stem cell transplant patients for prophylaxis and treatment of cytomegalovirus. It has long been considered a mutagen and carcinogen. However, the contribution of GCV to cancer incidence and other factors that influence its mutagenicity remains unknown. METHODS: This retrospective cohort study analysed genomics data for 121,771 patients who had undergone targeted sequencing compiled by the Genomics Evidence Neoplasia Information Exchange (GENIE) or Foundation Medicine (FM). A statistical approach was developed to identify patients with GCV-associated mutational signature (GCVsig) from targeted sequenced data of tumour samples. Cell line exposure models were further used to quantify mutation burden and DNA damage caused by GCV and other antiviral and immunosuppressive drugs. RESULTS: Mutational profiles from 22 of 121,771 patient samples in the GENIE and FM cohorts showed evidence of GCVsig. A diverse range of cancers was represented. All patients with detailed clinical history available had previously undergone solid organ transplantation and received GCV and mycophenolate treatment. RAS hotspot mutations associated with GCVsig were present in 9 of the 22 samples, with all samples harbouring multiple GCV-associated protein-altering mutations in cancer driver genes. In vitro testing in cell lines showed that elevated DNA damage response and GCVsig are uniquely associated with GCV but not acyclovir, a structurally similar antiviral. Combination treatment of GCV with the immunosuppressant, mycophenolate mofetil (MMF), increased the misincorporation of GCV in genomic DNA and mutations attributed to GCVsig in cell lines and organoids. CONCLUSIONS: In summary, GCV can cause a diverse range of cancers. Its mutagenicity may be potentiated by other therapies, such as mycophenolate, commonly co-prescribed with GCV for post-transplant patients. Further investigation of the optimal use of these drugs

Published
2022

2. Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database

Author

Thompson, BA, Spurdle, AB, Plazzer, J-P, Greenblatt, MS, Akagi, K, Al-Mulla, F, Bapat, B, Bernstein, I, Capella, G, den Dunnen, JT, du Sart, D, Fabre, A, Farrell, MP, Farrington, SM, Frayling, IM, Frebourg, T, Goldgar, DE, Heinen, CD, Holinski-Feder, E, Kohonen-Corish, M, Robinson, KL, Leung, SY, Martins, A, Moller, P, Morak, M, Nystrom, M, Peltomaki, P, Pineda, M, Qi, M, Ramesar, R, Rasmussen, LJ, Royer-Pokora, B, Scott, RJ, Sijmons, R, Tavtigian, SV, Tops, CM, Weber, T, Wijnen, J, Woods, MO, Macrae, F, Genuardi, M, Thompson, BA, Spurdle, AB, Plazzer, J-P, Greenblatt, MS, Akagi, K, Al-Mulla, F, Bapat, B, Bernstein, I, Capella, G, den Dunnen, JT, du Sart, D, Fabre, A, Farrell, MP, Farrington, SM, Frayling, IM, Frebourg, T, Goldgar, DE, Heinen, CD, Holinski-Feder, E, Kohonen-Corish, M, Robinson, KL, Leung, SY, Martins, A, Moller, P, Morak, M, Nystrom, M, Peltomaki, P, Pineda, M, Qi, M, Ramesar, R, Rasmussen, LJ, Royer-Pokora, B, Scott, RJ, Sijmons, R, Tavtigian, SV, Tops, CM, Weber, T, Wijnen, J, Woods, MO, Macrae, F, and Genuardi, M

Abstract

The clinical classification of hereditary sequence variants identified in disease-related genes directly affects clinical management of patients and their relatives. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) undertook a collaborative effort to develop, test and apply a standardized classification scheme to constitutional variants in the Lynch syndrome-associated genes MLH1, MSH2, MSH6 and PMS2. Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution. The scheme was refined by multidisciplinary expert committee review of the clinical and functional data available for variants, applied to 2,360 sequence alterations, and disseminated online. Assessment using validated criteria altered classifications for 66% of 12,006 database entries. Clinical recommendations based on transparent evaluation are now possible for 1,370 variants that were not obviously protein truncating from nomenclature. This large-scale endeavor will facilitate the consistent management of families suspected to have Lynch syndrome and demonstrates the value of multidisciplinary collaboration in the curation and classification of variants in public locus-specific databases.

Published
2014

3. Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.

Author

Genuardi, Maurizio, Spurdle, Ab, Plazzer, Jp, Greenblatt, M, Akagi, K, Al Mulla, F, Bapat, B, Bernstein, I, Capellá, G, Den Dunnen, Jt, Du Sart, D, Fabre, A, Farrell, Mp, Farrington, Sm, Frayling, Im, Frebourg, T, Goldgar, De, Heinen, Cd, Holinski Feder, E, Kohonen Corish, M, Robinson, Kl, Leung, Sy, Martins, A, Moller, P, Morak, M, Nystrom, M, Peltomaki, P, Pineda, M, Qi, M, Ramesar, R, Rasmussen, Lj, Royer Pokora, B, Scott, Rj, Sijmons, R, Tavtigian, Sv, Tops, Cm, Weber, T, Wijnen, J, Woods, Mo, Macrae, F, Thompson, Ba, Genuardi, Maurizio (ORCID:0000-0002-7410-8351), Genuardi, Maurizio, Spurdle, Ab, Plazzer, Jp, Greenblatt, M, Akagi, K, Al Mulla, F, Bapat, B, Bernstein, I, Capellá, G, Den Dunnen, Jt, Du Sart, D, Fabre, A, Farrell, Mp, Farrington, Sm, Frayling, Im, Frebourg, T, Goldgar, De, Heinen, Cd, Holinski Feder, E, Kohonen Corish, M, Robinson, Kl, Leung, Sy, Martins, A, Moller, P, Morak, M, Nystrom, M, Peltomaki, P, Pineda, M, Qi, M, Ramesar, R, Rasmussen, Lj, Royer Pokora, B, Scott, Rj, Sijmons, R, Tavtigian, Sv, Tops, Cm, Weber, T, Wijnen, J, Woods, Mo, Macrae, F, Thompson, Ba, and Genuardi, Maurizio (ORCID:0000-0002-7410-8351)

Abstract

The clinical classification of hereditary sequence variants identified in disease-related genes directly affects clinical management of patients and their relatives. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) undertook a collaborative effort to develop, test and apply a standardized classification scheme to constitutional variants in the Lynch syndrome-associated genes MLH1, MSH2, MSH6 and PMS2. Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution. The scheme was refined by multidisciplinary expert committee review of the clinical and functional data available for variants, applied to 2,360 sequence alterations, and disseminated online. Assessment using validated criteria altered classifications for 66% of 12,006 database entries. Clinical recommendations based on transparent evaluation are now possible for 1,370 variants that were not obviously protein truncating from nomenclature. This large-scale endeavor will facilitate the consistent management of families suspected to have Lynch syndrome and demonstrates the value of multidisciplinary collaboration in the curation and classification of variants in public locus-specific databases.

Published
2014

4. Functional categories of TP53 mutation in colorectal cancer: results of an International Collaborative Study

Author

Iacopetta, B., Russo, A., Bazan, V., Dardanonoi, G., Gebbia, N., Soussi, T., Kerr, D., Elsaleh, H., Soong, R., Kandioler, D., Janschek, E., Kappel, S., Lung, M., Leung, CS, Ko, JM, Yuen, S., Ho, J., Leung, SY, Crapez, E., Duffour, J., Ychou, M., Leahy, DT, O'donoghue, DP, Agnese, V., Cascio, S., Di Fede, G., Chieco-Bianchi, L., Bertorelle, R., Belluco, C., Giaretti, W., Castagnola, P., Ricevuto, E., Ficorella, C., Bosari, S., Arizzi, CD, Miyaki, M., Onda, M., Kampman, E., Diergaarde, B., Royds, J., Lothe, RA, Diep, CB, Meling, GI, Ostrowski, J., Trzeciak, L., Guzinska-Ustymowicz, K., Zalewski, B., Capella, GM, Moreno, V., Peinado, MA, Lonnroth, C., Lundholm, K., Sun, XF, Jansson, A., Bouzourene, H., Hsieh, LL, Tang, R., Smith, DR, Allen-Mersh, TG, Khan, ZA, Shorthouse, AJ, Silverman, ML, Kato, S., Ishioka, C., Iacopetta, B., Russo, A., Bazan, V., Dardanonoi, G., Gebbia, N., Soussi, T., Kerr, D., Elsaleh, H., Soong, R., Kandioler, D., Janschek, E., Kappel, S., Lung, M., Leung, CS, Ko, JM, Yuen, S., Ho, J., Leung, SY, Crapez, E., Duffour, J., Ychou, M., Leahy, DT, O'donoghue, DP, Agnese, V., Cascio, S., Di Fede, G., Chieco-Bianchi, L., Bertorelle, R., Belluco, C., Giaretti, W., Castagnola, P., Ricevuto, E., Ficorella, C., Bosari, S., Arizzi, CD, Miyaki, M., Onda, M., Kampman, E., Diergaarde, B., Royds, J., Lothe, RA, Diep, CB, Meling, GI, Ostrowski, J., Trzeciak, L., Guzinska-Ustymowicz, K., Zalewski, B., Capella, GM, Moreno, V., Peinado, MA, Lonnroth, C., Lundholm, K., Sun, XF, Jansson, A., Bouzourene, H., Hsieh, LL, Tang, R., Smith, DR, Allen-Mersh, TG, Khan, ZA, Shorthouse, AJ, Silverman, ML, Kato, S., and Ishioka, C.

Published
2006

5. Functional categories of TP53 mutation in colorectal cancer: results of an International Collaborative Study

Author

Iacopetta, B., Russo, A., Bazan, V., Dardanonoi, G., Gebbia, N., Soussi, T., Kerr, D., Elsaleh, H., Soong, R., Kandioler, D., Janschek, E., Kappel, S., Lung, M., Leung, CS, Ko, JM, Yuen, S., Ho, J., Leung, SY, Crapez, E., Duffour, J., Ychou, M., Leahy, DT, O'donoghue, DP, Agnese, V., Cascio, S., Di Fede, G., Chieco-Bianchi, L., Bertorelle, R., Belluco, C., Giaretti, W., Castagnola, P., Ricevuto, E., Ficorella, C., Bosari, S., Arizzi, CD, Miyaki, M., Onda, M., Kampman, E., Diergaarde, B., Royds, J., Lothe, RA, Diep, CB, Meling, GI, Ostrowski, J., Trzeciak, L., Guzinska-Ustymowicz, K., Zalewski, B., Capella, GM, Moreno, V., Peinado, MA, Lonnroth, C., Lundholm, K., Sun, XF, Jansson, A., Bouzourene, H., Hsieh, LL, Tang, R., Smith, DR, Allen-Mersh, TG, Khan, ZA, Shorthouse, AJ, Silverman, ML, Kato, S., Ishioka, C., Iacopetta, B., Russo, A., Bazan, V., Dardanonoi, G., Gebbia, N., Soussi, T., Kerr, D., Elsaleh, H., Soong, R., Kandioler, D., Janschek, E., Kappel, S., Lung, M., Leung, CS, Ko, JM, Yuen, S., Ho, J., Leung, SY, Crapez, E., Duffour, J., Ychou, M., Leahy, DT, O'donoghue, DP, Agnese, V., Cascio, S., Di Fede, G., Chieco-Bianchi, L., Bertorelle, R., Belluco, C., Giaretti, W., Castagnola, P., Ricevuto, E., Ficorella, C., Bosari, S., Arizzi, CD, Miyaki, M., Onda, M., Kampman, E., Diergaarde, B., Royds, J., Lothe, RA, Diep, CB, Meling, GI, Ostrowski, J., Trzeciak, L., Guzinska-Ustymowicz, K., Zalewski, B., Capella, GM, Moreno, V., Peinado, MA, Lonnroth, C., Lundholm, K., Sun, XF, Jansson, A., Bouzourene, H., Hsieh, LL, Tang, R., Smith, DR, Allen-Mersh, TG, Khan, ZA, Shorthouse, AJ, Silverman, ML, Kato, S., and Ishioka, C.

Published
2006

6. Functional categories of TP53 mutation in colorectal cancer: results of an International Collaborative Study

Author

Iacopetta, B., Russo, A., Bazan, V., Dardanonoi, G., Gebbia, N., Soussi, T., Kerr, D., Elsaleh, H., Soong, R., Kandioler, D., Janschek, E., Kappel, S., Lung, M., Leung, CS, Ko, JM, Yuen, S., Ho, J., Leung, SY, Crapez, E., Duffour, J., Ychou, M., Leahy, DT, O'donoghue, DP, Agnese, V., Cascio, S., Di Fede, G., Chieco-Bianchi, L., Bertorelle, R., Belluco, C., Giaretti, W., Castagnola, P., Ricevuto, E., Ficorella, C., Bosari, S., Arizzi, CD, Miyaki, M., Onda, M., Kampman, E., Diergaarde, B., Royds, J., Lothe, RA, Diep, CB, Meling, GI, Ostrowski, J., Trzeciak, L., Guzinska-Ustymowicz, K., Zalewski, B., Capella, GM, Moreno, V., Peinado, MA, Lonnroth, C., Lundholm, K., Sun, XF, Jansson, A., Bouzourene, H., Hsieh, LL, Tang, R., Smith, DR, Allen-Mersh, TG, Khan, ZA, Shorthouse, AJ, Silverman, ML, Kato, S., Ishioka, C., Iacopetta, B., Russo, A., Bazan, V., Dardanonoi, G., Gebbia, N., Soussi, T., Kerr, D., Elsaleh, H., Soong, R., Kandioler, D., Janschek, E., Kappel, S., Lung, M., Leung, CS, Ko, JM, Yuen, S., Ho, J., Leung, SY, Crapez, E., Duffour, J., Ychou, M., Leahy, DT, O'donoghue, DP, Agnese, V., Cascio, S., Di Fede, G., Chieco-Bianchi, L., Bertorelle, R., Belluco, C., Giaretti, W., Castagnola, P., Ricevuto, E., Ficorella, C., Bosari, S., Arizzi, CD, Miyaki, M., Onda, M., Kampman, E., Diergaarde, B., Royds, J., Lothe, RA, Diep, CB, Meling, GI, Ostrowski, J., Trzeciak, L., Guzinska-Ustymowicz, K., Zalewski, B., Capella, GM, Moreno, V., Peinado, MA, Lonnroth, C., Lundholm, K., Sun, XF, Jansson, A., Bouzourene, H., Hsieh, LL, Tang, R., Smith, DR, Allen-Mersh, TG, Khan, ZA, Shorthouse, AJ, Silverman, ML, Kato, S., and Ishioka, C.

Published
2006

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