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6. Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment: a report from the prospective Lynch syndrome database

Author

Dominguez-Valentin, M, Haupt, S, Seppälä, T, Sampson, J, Sunde, L, Bernstein, I, Jenkins, M, Engel, C, Aretz, S, Nielsen, M, Capella, G, Balaguer, F, Evans, D, Burn, J, Holinski-Feder, E, Bertario, L, Bonanni, B, Lindblom, A, Levi, Z, Macrae, F, Winship, I, Plazzer, J, Sijmons, R, Laghi, L, Della Valle, A, Heinimann, K, Dębniak, T, Fruscio, R, Lopez-Koestner, F, Alvarez-Valenzuela, K, Katz, L, Laish, I, Vainer, E, Vaccaro, C, Carraro, D, Monahan, K, Half, E, Stakelum, A, Winter, D, Kennelly, R, Gluck, N, Sheth, H, Abu-Freha, N, Greenblatt, M, Rossi, B, Bohorquez, M, Cavestro, G, Lino-Silva, L, Horisberger, K, Tibiletti, M, Nascimento, I, Thomas, H, Rossi, N, Apolinário da Silva, L, Zaránd, A, Ruiz-Bañobre, J, Heuveline, V, Mecklin, J, Pylvänäinen, K, Renkonen-Sinisalo, L, Lepistö, A, Peltomäki, P, Therkildsen, C, Madsen, M, Burgdorf, S, Hopper, J, Win, A, Haile, R, Lindor, N, Gallinger, S, Le Marchand, L, Newcomb, P, Figueiredo, J, Buchanan, D, Thibodeau, S, von Knebel Doeberitz, M, Loeffler, M, Rahner, N, Schröck, E, Steinke-Lange, V, Schmiegel, W, Vangala, D, Perne, C, Hüneburg, R, Redler, S, Büttner, R, Weitz, J, Pineda, M, Duenas, N, Vidal, J, Moreira, L, Sánchez, A, Hovig, E, Nakken, S, Green, K, Lalloo, F, Hill, J, Crosbie, E, Mints, M, Goldberg, Y, Dominguez-Valentin M., Haupt S., Seppälä T. T., Sampson J. R., Sunde L., Bernstein I., Jenkins M. A., Engel C., Aretz S., Nielsen M., Capella G., Balaguer F., Evans D. G., Burn J., Holinski-Feder E., Bertario L., Bonanni B., Lindblom A., Levi Z., Macrae F., Winship I., Plazzer J. P., Sijmons R., Laghi L., Della Valle A., Heinimann K., Dębniak T., Fruscio R., Lopez-Koestner F., Alvarez-Valenzuela K., Katz L. H., Laish I., Vainer E., Vaccaro C., Carraro D. M., Monahan K., Half E., Stakelum A., Winter D., Kennelly R., Gluck N., Sheth H., Abu-Freha N., Greenblatt M., Rossi B. M., Bohorquez M., Cavestro G. M., Lino-Silva L. S., Horisberger K., Tibiletti M. G., Nascimento I. d., Thomas H., Rossi N. T., Apolinário da Silva L., Zaránd A., Ruiz-Bañobre J., Heuveline V., Mecklin J. P., Pylvänäinen K., Renkonen-Sinisalo L., Lepistö A., Peltomäki P., Therkildsen C., Madsen M. G., Burgdorf S. K., Hopper J. L., Win A. K., Haile R. W., Lindor N., Gallinger S., Le Marchand L., Newcomb P. A., Figueiredo J., Buchanan D. D., Thibodeau S. N., von Knebel Doeberitz M., Loeffler M., Rahner N., Schröck E., Steinke-Lange V., Schmiegel W., Vangala D., Perne C., Hüneburg R., Redler S., Büttner R., Weitz J., Pineda M., Duenas N., Vidal J. B., Moreira L., Sánchez A., Hovig E., Nakken S., Green K., Lalloo F., Hill J., Crosbie E., Mints M., Goldberg Y., Dominguez-Valentin, M, Haupt, S, Seppälä, T, Sampson, J, Sunde, L, Bernstein, I, Jenkins, M, Engel, C, Aretz, S, Nielsen, M, Capella, G, Balaguer, F, Evans, D, Burn, J, Holinski-Feder, E, Bertario, L, Bonanni, B, Lindblom, A, Levi, Z, Macrae, F, Winship, I, Plazzer, J, Sijmons, R, Laghi, L, Della Valle, A, Heinimann, K, Dębniak, T, Fruscio, R, Lopez-Koestner, F, Alvarez-Valenzuela, K, Katz, L, Laish, I, Vainer, E, Vaccaro, C, Carraro, D, Monahan, K, Half, E, Stakelum, A, Winter, D, Kennelly, R, Gluck, N, Sheth, H, Abu-Freha, N, Greenblatt, M, Rossi, B, Bohorquez, M, Cavestro, G, Lino-Silva, L, Horisberger, K, Tibiletti, M, Nascimento, I, Thomas, H, Rossi, N, Apolinário da Silva, L, Zaránd, A, Ruiz-Bañobre, J, Heuveline, V, Mecklin, J, Pylvänäinen, K, Renkonen-Sinisalo, L, Lepistö, A, Peltomäki, P, Therkildsen, C, Madsen, M, Burgdorf, S, Hopper, J, Win, A, Haile, R, Lindor, N, Gallinger, S, Le Marchand, L, Newcomb, P, Figueiredo, J, Buchanan, D, Thibodeau, S, von Knebel Doeberitz, M, Loeffler, M, Rahner, N, Schröck, E, Steinke-Lange, V, Schmiegel, W, Vangala, D, Perne, C, Hüneburg, R, Redler, S, Büttner, R, Weitz, J, Pineda, M, Duenas, N, Vidal, J, Moreira, L, Sánchez, A, Hovig, E, Nakken, S, Green, K, Lalloo, F, Hill, J, Crosbie, E, Mints, M, Goldberg, Y, Dominguez-Valentin M., Haupt S., Seppälä T. T., Sampson J. R., Sunde L., Bernstein I., Jenkins M. A., Engel C., Aretz S., Nielsen M., Capella G., Balaguer F., Evans D. G., Burn J., Holinski-Feder E., Bertario L., Bonanni B., Lindblom A., Levi Z., Macrae F., Winship I., Plazzer J. P., Sijmons R., Laghi L., Della Valle A., Heinimann K., Dębniak T., Fruscio R., Lopez-Koestner F., Alvarez-Valenzuela K., Katz L. H., Laish I., Vainer E., Vaccaro C., Carraro D. M., Monahan K., Half E., Stakelum A., Winter D., Kennelly R., Gluck N., Sheth H., Abu-Freha N., Greenblatt M., Rossi B. M., Bohorquez M., Cavestro G. M., Lino-Silva L. S., Horisberger K., Tibiletti M. G., Nascimento I. d., Thomas H., Rossi N. T., Apolinário da Silva L., Zaránd A., Ruiz-Bañobre J., Heuveline V., Mecklin J. P., Pylvänäinen K., Renkonen-Sinisalo L., Lepistö A., Peltomäki P., Therkildsen C., Madsen M. G., Burgdorf S. K., Hopper J. L., Win A. K., Haile R. W., Lindor N., Gallinger S., Le Marchand L., Newcomb P. A., Figueiredo J., Buchanan D. D., Thibodeau S. N., von Knebel Doeberitz M., Loeffler M., Rahner N., Schröck E., Steinke-Lange V., Schmiegel W., Vangala D., Perne C., Hüneburg R., Redler S., Büttner R., Weitz J., Pineda M., Duenas N., Vidal J. B., Moreira L., Sánchez A., Hovig E., Nakken S., Green K., Lalloo F., Hill J., Crosbie E., Mints M., and Goldberg Y.

Abstract

Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time. Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender. Findings: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers. Interpretation: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. Funding: We ackno

Published
2023

7. Local Procrustes for Manifold Embedding: A Measure of Embedding Quality and Embedding Algorithms

Author

Goldberg, Y. and Ritov, Y.

Subjects
Statistics - Machine Learning
Abstract

We present the Procrustes measure, a novel measure based on Procrustes rotation that enables quantitative comparison of the output of manifold-based embedding algorithms (such as LLE (Roweis and Saul, 2000) and Isomap (Tenenbaum et al, 2000)). The measure also serves as a natural tool when choosing dimension-reduction parameters. We also present two novel dimension-reduction techniques that attempt to minimize the suggested measure, and compare the results of these techniques to the results of existing algorithms. Finally, we suggest a simple iterative method that can be used to improve the output of existing algorithms., Comment: Submitted to Journal of Machine Learning

Published
2008

8. Manifold Learning: The Price of Normalization

Author

Goldberg, Y., Zakai, A., Kushnir, D., and Ritov, Y.

Subjects
Statistics - Machine Learning
Abstract

We analyze the performance of a class of manifold-learning algorithms that find their output by minimizing a quadratic form under some normalization constraints. This class consists of Locally Linear Embedding (LLE), Laplacian Eigenmap, Local Tangent Space Alignment (LTSA), Hessian Eigenmaps (HLLE), and Diffusion maps. We present and prove conditions on the manifold that are necessary for the success of the algorithms. Both the finite sample case and the limit case are analyzed. We show that there are simple manifolds in which the necessary conditions are violated, and hence the algorithms cannot recover the underlying manifolds. Finally, we present numerical results that demonstrate our claims., Comment: Submitted to JMLR

Published
2008

9. Results from the first four regimens of the HEALEY ALS Platform Trial (PL5.004)

Author

Paganoni, Sabrina, primary, Berry, James, additional, Quintana, Melanie, additional, Macklin, Eric, additional, Saville, Benjamin, additional, Andrews, Jinsy, additional, Shefner, Jeremy, additional, Fournier, Christina, additional, Babu, Suma, additional, Maragakis, Nicholas, additional, Oskarsson, Bjorn, additional, Detry, Michelle, additional, Chase, Marianne, additional, Sherman, Alex, additional, Yu, Hong, additional, Pothier, Lindsay, additional, Drake, Kristin, additional, Chibnik, Lori, additional, Bind, Marie-Abele, additional, Vestrucci, Matteo, additional, McGlothlin, Anna, additional, Marion, Joseph, additional, Duda, Petra, additional, Harvey, Brittany, additional, Qureshi, Irfan, additional, Donohue, Mary, additional, Granit, Volkan, additional, Grossman, Katheryn, additional, Glanzman, Robert, additional, Hotchkin, Michael, additional, Goldberg, Y Paul, additional, Leitner, Melanie, additional, Hayden, Michael, additional, and Cudkowicz, Merit, additional

Published
2023
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10. Potent, Gut-Restricted Inhibitors of Divalent Metal Transporter 1 (DMT1): Preclinical Efficacy Against Iron Overload and Safety Evaluation

Author

Cutts, Alison J, primary, Chowdhury, Sultan, additional, Ratkay, Laszlo, additional, Eyers, Maryanne, additional, Young, Clint, additional, Namdari, Rostam, additional, Cadieux, Jay, additional, Chahal, Navjot, additional, Grimwood, Michael, additional, Zhang, Zaihui, additional, Lin, Sophia, additional, Tietjen, Ian, additional, Xie, Zhiwei, additional, Robinette, Lee, additional, Sojo, Luis, additional, Waldbrook, Matthew, additional, Hayden, Michael R, additional, Mansour, Tarek, additional, Pimstone, Simon, additional, Goldberg, Y Paul, additional, Webb, Michael, additional, and Cohen, Charles J, additional

Published
2023
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11. Adverse outcome following selective termination of presenting twin vs non‐presenting twin

Author

Miremberg, H., primary, Rosen, H., additional, Weisz, B., additional, Tirosh, D., additional, Hershkovitz, R., additional, Stern, S., additional, Porat, S., additional, Beloshevski, B., additional, Melcer, Y., additional, Goldberg, Y., additional, Boms Yonai, N., additional, Awawdeh, M., additional, Leibovitz, Z., additional, Shalev, J., additional, and Gindes, L., additional

Published
2023
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13. Early- and subsequent- response of cognitive functioning in Alzheimer's disease: Individual-participant data from five pivotal randomized clinical trials of donepezil

Author

Levine, SZ, Goldberg, Y, Yoshida, K, Samara, M, Cipriani, A, Iwatsubo, T, Leucht, S, and Furawaka, TA

Subjects
Psychiatry and Mental health, Cognition, Double-Blind Method, Alzheimer Disease, Indans, Humans, Donepezil, Cholinesterase Inhibitors, Nootropic Agents, Biological Psychiatry, Randomized Controlled Trials as Topic
Abstract

The association between early improvement and subsequent change in cognition is unexamined in antidementia clinical trials. We aimed to examine the consequences of early-response to antidementia medication in Alzheimer's disease. Participant-level data were analyzed from five pivotal clinical trials of donepezil for Alzheimer's disease lasting up to 24 weeks (N = 1917). Early-response was based on Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) change scores under minus four from baseline to week six, otherwise classified non-response; then subgrouped by donepezil or placebo. The primary analysis tested the group differences in ADAS-Cog change from baseline for the interval after week six up to 24, based on a three-level mixed-effects model repeated measures (MMRM) model. Four models of increasing complexity were tested, and the most parsimonious model was examined in the primary analysis. The remaining models were tested in sensitivity analysis. In the analytic sample, 32.09% (N = 396/1234) of donepezil and 24.01% (N = 164/683) of placebo participants were classified as early responders, and 67.91% donepezil (N = 838/1234), 75.99% (N = 519/683) placebo participants were not. MMRM identified a statistically significant (P < 0.05) responder group effect. Marginal means (MM) demonstrated more improvement for the early responders (donepezil: MM = −4.13, 95% CI = -5.93, −2.32; placebo MM = 1.81, 95% CI = −4.12, 0.50), compared to non-early responders (donepezil MM = 0.05, 95% CI = -1.40, 1.51; placebo MM = 2.59, 95% CI = 0.99, 4.19). Results replicated in sensitivity analysis. Our results inform clinicians regarding the extent and consequences of early improvement in cognitive functioning and potentially contribute to treatment monitoring and the design of clinical trials for Alzheimer's disease.

Published
2022

14. Lymphomas Associated with Constitutional Mismatch Repair Deficiency: A Joint International Analysis of C4CMMRD, IRRDC and EICNH Intergroups

Author

Rigaud, Charlotte, primary, Forster, VJ, additional, Al-Tarrah, Hiba, additional, Attarbaschi, Andishe, additional, Bianchi, Vanessa, additional, Burke, GAA, additional, Burkhardt, Birgit, additional, Colas, Chrystelle, additional, Devalck, Christine, additional, Edwards, Melissa, additional, Elitzur, Sarah, additional, Garthe, AK, additional, Goldberg, Y, additional, Horpaopan, S, additional, Januszkiewicz-Lewandowska, D, additional, Kabíčková, Edita, additional, Kratz, Christian, additional, Loeffen, J, additional, Pérez-Alonso, V, additional, Pineda, Marta, additional, Minard, Véronique, additional, Rueda, D, additional, Ruiz-Ponte, C, additional, Trinquand, Amelie, additional, Uyttebroeck, Anne, additional, Wimmer, katharina, additional, Aupérin, Anne, additional, Tabori, Uri, additional, and Brugieres, Laurence, additional

Published
2023
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15. Sodium channel [Na.sub.v]1.9 mutations associated with insensitivity to pain dampen neuronal excitability

Author

Huang, Jianying, Vanoye, Carlos G., Cutts, Alison, Goldberg, Y. Paul, Dib-Hajj, Sulayman D., Cohen, Charles J., Waxman, Stephen G., and George, Alfred L., Jr.

Subjects
Gene mutation -- Research, Neurons -- Genetic aspects -- Analysis, Health care industry
Abstract

Voltage-gated sodium channel ([Na.sub.v]) mutations cause genetic pain disorders that range from severe paroxysmal pain to a congenital inability to sense pain. Previous studies on [Na.sub.v]1.7 and [Na.sub.v]1.8 established clear relationships between perturbations in channel function and divergent clinical phenotypes. By contrast, studies of [Na.sub.v]1.9 mutations have not revealed a clear relationship of channel dysfunction with the associated and contrasting clinical phenotypes. Here, we have elucidated the functional consequences of a [Na.sub.v]1.9 mutation (L1302F) that is associated with insensitivity to pain. We investigated the effects of L1302F and a previously reported mutation (L811P) on neuronal excitability. In transfected heterologous cells, the L1302F mutation caused a large hyperpolarizing shift in the voltage-dependence of activation, leading to substantially enhanced overlap between activation and steady-state inactivation relationships. In transfected small rat dorsal root ganglion neurons, expression of L1302F and L811P evoked large depolarizations of the resting membrane potential and impaired action potential generation. Therefore, our findings implicate a cellular loss of function as the basis for impaired pain sensation. We further demonstrated that a U-shaped relationship between the resting potential and the neuronal action potential threshold explains why [Na.sub.v]1.9 mutations that evoke small degrees of membrane depolarization cause hyperexcitability and familial episodic pain disorder or painful neuropathy, while mutations evoking larger membrane depolarizations cause hypoexcitability and insensitivity to pain., Introduction Chronic pain is a prevalent and pernicious medical problem that represents an enormous public health burden. Understanding the molecular mechanisms and identifying critically important proteins involved in nociception may [...]

Published
2017
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16. Potent, Gut-Restricted Inhibitors of Divalent Metal Transporter 1 (DMT1): Preclinical Efficacy Against Iron Overload and Safety Evaluation

Author

Cutts, Alison, primary, Chowdhury, Sultan, additional, Ratkay, Laszlo G, additional, Eyers, Maryanne, additional, Young, Clint, additional, Namdari, Rostam, additional, Cadieux, Jay A, additional, Chahal, Navjot, additional, Grimwood, Michael, additional, Zhang, Zaihui, additional, Lin, Sophia, additional, Tietjen, Ian, additional, Xie, Zhiwei, additional, Robinette, Lee, additional, Sojo, Luis, additional, Waldbrook, Matthew, additional, Hayden, Michael, additional, Mansour, Tarek, additional, Pimstone, Simon, additional, Goldberg, Y. Paul, additional, Webb, Michael, additional, and Cohen, Charles J., additional

Published
2022
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22. Clinical Characteristics and Prognosis of Gastric Cancer Patients with BRCA 1/2 Germline Mutations: Report of Ten Cases and a Literature Review

Author

Halpern N, Grinshpun A, Boursi B, Golan T, Margalit O, Aderka D, Friedman E, Laitman Y, Hubert A, Kadouri L, Hamburger T, Barnes-Kedar I, Levi Z, Ben-Aharon I, Brenner B, Goldberg Y, Peretz T, and Shacham-Shmueli E

Subjects
brca1, brca2, gastric cancer, parp inhibitors, dna damaging agents, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282
Abstract

Naama Halpern,1,2 Albert Grinshpun,3 Ben Boursi,1,2 Talia Golan,1,2 Ofer Margalit,1,2 Dan Aderka,1,2 Eitan Friedman,2,4 Yael Laitman,2,3 Ayala Hubert,3 Luna Kadouri,3 Tamar Hamburger,3 Inbal Barnes-Kedar,2,5 Zohar Levi,2,6 Irit Ben-Aharon,2,7 Baruch Brenner,2,7 Yael Goldberg,2,5 Tamar Peretz,3 Einat Shacham-Shmueli1,2 1Department of Oncology, Sheba Medical Center, Tel-Hashomer, Israel; 2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 3Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; 4The Susanne Levy Gertner Oncogenetics Unit, The Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, Tel-Hashomer, Israel; 5Recanati Genetics Institute, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel; 6Division of Gastroenterology, Rabin Medical Center, Early Detection and High Risk Unit, Petach Tikva, Israel; 7Institute of Oncology, Davidoff Center, Rabin Medical Center, Petach Tikva, IsraelCorrespondence: Naama HalpernDepartment of Oncology, Sheba Medical Center, Tel-Hashomer, Rmat Gan, IsraelTel +972-3-530-2668Fax +972-3-5304958Email naama.halpern@sheba.gov.ilBackground: The prognosis of gastric cancer (GC) is poor with a median overall survival (OS) of less than 12 months in advanced-stage disease. The search for distinct genetic subgroups of GC patients and predictive biomarkers is ongoing. While BRCA1 or BRCA2 germline mutations (gBRCAm) have potential therapeutic implications in ovarian, breast and pancreatic cancers, their significance in GC patients has not been established.Patients and Methods: A retrospective multi-center data analysis of GC patients with gBRCAm was conducted, detailing the clinical characteristics and disease course in this unique subset of patients.Results: Ten GC patients with gBRCAm were identified, six of them with metastatic disease. The median OS of all ten GC patients was 47.5 (13– 192) months. Median OS for patients diagnosed with operable disease was 55.5 (13– 192) months and of the patients with metastatic disease (calculated from metastatic disease diagnosis) 32 (15– 52) months with an exceptional 1-, 2- and 3-year survival rate of 100%, 83.3% and 50%, respectively.Conclusion: These preliminary data suggest that gBRCAm in GC patients are associated with a favorable prognosis. Furthermore, gBRCAm might be a predictive biomarker to DNA-damaging agents response in GC patients, similarly to its established role in other malignancies. Further research is needed to confirm our findings.Keywords: gastric cancer, BRCA1, BRCA2, DNA-damaging agents, PARP inhibitors

Published
2020

23. Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

Author

Palles, C, West, HD, Chew, E, Galavotti, S, Flensburg, C, Grolleman, JE, Jansen, EAM, Curley, H, Chegwidden, L, Arbe-Barnes, EH, Lander, N, Truscott, R, Pagan, J, Bajel, A, Sherwood, K, Martin, L, Thomas, H, Georgiou, D, Fostira, F, Goldberg, Y, Adams, DJ, van der Biezen, SAM, Christie, M, Clendenning, M, Thomas, LE, Deltas, C, Dimovski, AJ, Dymerska, D, Lubinski, J, Mahmood, K, van der Post, RS, Sanders, M, Weitz, J, Taylor, JC, Turnbull, C, Vreede, L, van Wezel, T, Whalley, C, Arnedo-Pac, C, Caravagna, G, Cross, W, Chubb, D, Frangou, A, Gruber, AJ, Kinnersley, B, Noyvert, B, Church, D, Graham, T, Houlston, R, Lopez-Bigas, N, Sottoriva, A, Wedge, D, Jenkins, MA, Kuiper, RP, Roberts, AW, Cheadle, JP, Ligtenberg, MJL, Hoogerbrugge, N, Koelzer, VH, Rivas, AD, Winship, IM, Ponte, CR, Buchanan, DD, Power, DG, Green, A, Tomlinson, IPM, Sampson, JR, Majewski, IJ, de Voer, RM, Palles, C, West, HD, Chew, E, Galavotti, S, Flensburg, C, Grolleman, JE, Jansen, EAM, Curley, H, Chegwidden, L, Arbe-Barnes, EH, Lander, N, Truscott, R, Pagan, J, Bajel, A, Sherwood, K, Martin, L, Thomas, H, Georgiou, D, Fostira, F, Goldberg, Y, Adams, DJ, van der Biezen, SAM, Christie, M, Clendenning, M, Thomas, LE, Deltas, C, Dimovski, AJ, Dymerska, D, Lubinski, J, Mahmood, K, van der Post, RS, Sanders, M, Weitz, J, Taylor, JC, Turnbull, C, Vreede, L, van Wezel, T, Whalley, C, Arnedo-Pac, C, Caravagna, G, Cross, W, Chubb, D, Frangou, A, Gruber, AJ, Kinnersley, B, Noyvert, B, Church, D, Graham, T, Houlston, R, Lopez-Bigas, N, Sottoriva, A, Wedge, D, Jenkins, MA, Kuiper, RP, Roberts, AW, Cheadle, JP, Ligtenberg, MJL, Hoogerbrugge, N, Koelzer, VH, Rivas, AD, Winship, IM, Ponte, CR, Buchanan, DD, Power, DG, Green, A, Tomlinson, IPM, Sampson, JR, Majewski, IJ, and de Voer, RM

Abstract

We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5'-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management.

Published
2022

24. Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

Author

Palles, C., West, H.D., Chew, E., Galavotti, S., Flensburg, C., Grolleman, J.E., Jansen, E.A.M., Curley, H., Chegwidden, L., Arbe-Barnes, E.H., Lander, N., Truscott, R., Pagan, J., Bajel, A., Sherwood, K., Martin, L., Thomas, H, Georgiou, D., Fostira, F., Goldberg, Y., Adams, D.J., Biezen, S.A.M. van der, Christie, M., Clendenning, M., Thomas, L.E., Deltas, C., Dimovski, A.J., Dymerska, D., Lubinski, J., Mahmood, K., Post, R.S. van der, Sanders, M., Weitz, J., Taylor, J.C., Turnbull, C., Vreede, L., Wezel, T. van, Whalley, C., Arnedo-Pac, C., Caravagna, G., Cross, W., Chubb, D., Frangou, A., Gruber, A.J., Kinnersley, B., Noyvert, B., Church, D., Graham, T., Houlston, R., Lopez-Bigas, N., Sottoriva, A., Wedge, D., Jenkins, Mark A., Kuiper, R.P., Roberts, A.W., Cheadle, J.P., Ligtenberg, M.J.L., Hoogerbrugge, N., Koelzer, V.H., Rivas, A.D., Winship, I.M., Ponte, C.R., Buchanan, D.D., Power, D.G., Green, A., Tomlinson, I.P., Sampson, J.R., Majewski, I.J., Voer, R.M. de, Palles, C., West, H.D., Chew, E., Galavotti, S., Flensburg, C., Grolleman, J.E., Jansen, E.A.M., Curley, H., Chegwidden, L., Arbe-Barnes, E.H., Lander, N., Truscott, R., Pagan, J., Bajel, A., Sherwood, K., Martin, L., Thomas, H, Georgiou, D., Fostira, F., Goldberg, Y., Adams, D.J., Biezen, S.A.M. van der, Christie, M., Clendenning, M., Thomas, L.E., Deltas, C., Dimovski, A.J., Dymerska, D., Lubinski, J., Mahmood, K., Post, R.S. van der, Sanders, M., Weitz, J., Taylor, J.C., Turnbull, C., Vreede, L., Wezel, T. van, Whalley, C., Arnedo-Pac, C., Caravagna, G., Cross, W., Chubb, D., Frangou, A., Gruber, A.J., Kinnersley, B., Noyvert, B., Church, D., Graham, T., Houlston, R., Lopez-Bigas, N., Sottoriva, A., Wedge, D., Jenkins, Mark A., Kuiper, R.P., Roberts, A.W., Cheadle, J.P., Ligtenberg, M.J.L., Hoogerbrugge, N., Koelzer, V.H., Rivas, A.D., Winship, I.M., Ponte, C.R., Buchanan, D.D., Power, D.G., Green, A., Tomlinson, I.P., Sampson, J.R., Majewski, I.J., and Voer, R.M. de

Abstract

Contains fulltext : 251996.pdf (Publisher’s version ) (Open Access), We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5'-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management.

Published
2022

29. Sampling-Based Approximations to Minimum Bayes Risk Decoding for Neural Machine Translation

Author

Eikema, B., Aziz, W., Goldberg, Y., Kozareva, Z., Zhang, Y., and ILLC (FNWI)

Subjects
FOS: Computer and information sciences, Computer Science - Computation and Language, Computation and Language (cs.CL)
Abstract

In NMT we search for the mode of the model distribution to form predictions. The mode and other high-probability translations found by beam search have been shown to often be inadequate in a number of ways. This prevents improving translation quality through better search, as these idiosyncratic translations end up selected by the decoding algorithm, a problem known as the beam search curse. Recently, an approximation to minimum Bayes risk (MBR) decoding has been proposed as an alternative decision rule that would likely not suffer from the same problems. We analyse this approximation and establish that it has no equivalent to the beam search curse. We then design approximations that decouple the cost of exploration from the cost of robust estimation of expected utility. This allows for much larger hypothesis spaces, which we show to be beneficial. We also show that mode-seeking strategies can aid in constructing compact sets of promising hypotheses and that MBR is effective in identifying good translations in them. We conduct experiments on three language pairs varying in amounts of resources available: English into and from German, Romanian, and Nepali., Comment: EMNLP 2022 camera-ready

Published
2022

30. Towards Pragmatic Production Strategies for Natural Language Generation

Author

Giulianelli, M., Goldberg, Y., Kozareva, Z., Zhang, Y., and ILLC (FNWI)

Abstract

This position paper proposes a conceptual framework for the design of Natural Language Generation (NLG) systems that follow efficient and effective production strategies in order to achieve complex communicative goals. In this general framework, efficiency is characterised as the parsimonious regulation of production and comprehension costs while effectiveness is measured with respect to task-oriented and contextually grounded communicative goals. We provide concrete suggestions for the estimation of goals, costs, and utility via modern statistical methods, demonstrating applications of our framework to the classic pragmatic task of visually grounded referential games and to abstractive text summarisation, two popular generation tasks with real-world applications. In sum, we advocate for the development of NLG systems that learn to make pragmatic production decisions from experience, by reasoning about goals, costs, and utility in a human-like way.

Published
2022

33. COG6-CDG: Expanding the phenotype with emphasis on glycosylation defects involved in the causation of male disorders of sex development

Author

Odeh M, Falik-Zaccai Tc, Cohen Kfir N, Goldberg Y, Kalfon L, Fleischer Sheffer, Shuster Biton E, Fedida A, Eran A, Tiosano D, Dinwiddie A, Hoffman Y, Mandel H, Apel-Sarid L, Ben Harouch S, and Dumin E

Subjects
Genetics, chemistry.chemical_compound, Glycosylation, chemistry, business.industry, Medicine, Disorders of sex development, Causation, business, medicine.disease, Phenotype
Published
2021

41. Germline loss-of-function variants in the base-excision repair gene MBD4 cause a Mendelian recessive syndrome of adenomatous colorectal polyposis and acute myeloid leukaemia

Author

Khalid Mahmood, Chew E, Dagmara Dymerska, Roberts Aw, Mark Clendenning, Christoffer Flensburg, Nicoline Hoogerbrugge, Ben Kinnersley, Goldberg Y, Boris Noyvert, Jenny C. Taylor, Mathijs A. Sanders, van Wezel T, Lilian Vreede, Giulio Caravagna, Daniel D. Buchanan, Curley H, van der Biezen Sa, Richard S. Houlston, Celina Whalley, Michael Christie, Laura Chegwidden, Georgiou D, Judith E. Grolleman, Huw Thomas, Galavotti S, Sherwood K, Sottoriva A, Erik A. M. Jansen, Aleksandar Dimovski, Mark A. Jenkins, M.J.L. Ligtenberg, Roland P. Kuiper, Ian J. Majewski, Bajel A, Jakub Lubiński, Ian Tomlinson, Anna Frangou, Claire Palles, Pac Ca, Florentia Fostira, Deltas C, Clare Turnbull, Ingrid Winship, David N. Church, Lynn Martin, William Cross, Jürgen Weitz, David C. Wedge, Koelzer Vh, Rivas Ad, Barnes Ea, Nuria Lopez-Bigas, David J. Adams, van der Post Rs, Daniel Chubb, de Voer Rm, Trevor A. Graham, Andreas J. Gruber, and Ponte Cr

Subjects
Myeloid, Colorectal cancer, DNA Repair Pathway, Colorectal polyposis, Base excision repair, Biology, medicine.disease, medicine.disease_cause, Germline, MBD4, medicine.anatomical_structure, Cancer research, medicine, KRAS
Abstract

Inherited defects in base-excision repair (BER) predispose to adenomatous polyposis and colorectal cancer (CRC), yet our understanding of this important DNA repair pathway remains incomplete. By combining detailed clinical, histological and molecular profiling, we reveal biallelic germline loss-of-function (LOF) variants in the BER gene MBD4 to predispose to adenomatous polyposis and –uniquely amongst CRC predisposition syndromes– to myeloid neoplasms. Neoplasms from MBD4-deficient patients almost exclusively accumulate somatic CpG>TpG mutations, resembling mutational signature SBS1. MBD4-deficient adenomas harbour mutations in known CRC driver genes, although AMER1 mutations were more common and KRAS mutations less frequent. We did not find an increased risk for colorectal tumours in individuals with a monoallelic MBD4 LOF variant. We suggest that this condition should be termed MBD4-associated neoplasia syndrome (MANS) and that MBD4 is included in testing for the genetic diagnosis of polyposis and/or early-onset AML.

Published
2021

42. Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance

Author

Durno, C, Ercan, AB, Bianchi, V, Edwards, M, Aronson, M, Galati, M, Atenafu, EG, Abebe-Campino, G, Al-Battashi, A, Alharbi, M, Azad, VF, Baris, HN, Basel, D, Bedgood, R, Bendel, A, Ben-Shachar, S, Blumenthal, DT, Blundell, M, Bornhorst, M, Bronsema, A, Cairney, E, Rhode, S, Caspi, S, Chamdin, A, Chiaravalli, S, Constantini, S, Crooks, B, Das, A, Dvir, R, Farah, R, Foulkes, WD, Frenkel, Z, Gallinger, B, Gardner, S, Gass, D, Ghalibafian, M, Gilpin, C, Goldberg, Y, Goudie, C, Hamid, SA, Hampel, H, Hansford, JR, Harlos, C, Hijiya, N, Hsu, S, Kamihara, J, Kebudi, R, Knipstein, J, Koschmann, C, Kratz, C, Larouche, V, Lassaletta, A, Lindhorst, S, Ling, SC, Link, MP, De Mola, RL, Luiten, R, Lurye, M, Maciaszek, JL, MagimairajanIssai, V, Maher, OM, Massimino, M, McGee, RB, Mushtaq, N, Mason, G, Newmark, M, Nicholas, G, Nichols, KE, Nicolaides, T, Opocher, E, Osborn, M, Oshrine, B, Pearlman, R, Pettee, D, Rapp, J, Rashid, M, Reddy, A, Reichman, L, Remke, M, Robbins, G, Roy, S, Sabel, M, Samuel, D, Scheers, I, Schneider, KW, Sen, S, Stearns, D, Sumerauer, D, Swallow, C, Taylor, L, Thomas, G, Toledano, H, Tomboc, P, Van Damme, A, Winer, I, Yalon, M, Yen, LY, Zapotocky, M, Zelcer, S, Ziegler, DS, Zimmermann, S, Hawkins, C, Malkin, D, Bouffet, E, Villani, A, Tabori, U, Durno, C, Ercan, AB, Bianchi, V, Edwards, M, Aronson, M, Galati, M, Atenafu, EG, Abebe-Campino, G, Al-Battashi, A, Alharbi, M, Azad, VF, Baris, HN, Basel, D, Bedgood, R, Bendel, A, Ben-Shachar, S, Blumenthal, DT, Blundell, M, Bornhorst, M, Bronsema, A, Cairney, E, Rhode, S, Caspi, S, Chamdin, A, Chiaravalli, S, Constantini, S, Crooks, B, Das, A, Dvir, R, Farah, R, Foulkes, WD, Frenkel, Z, Gallinger, B, Gardner, S, Gass, D, Ghalibafian, M, Gilpin, C, Goldberg, Y, Goudie, C, Hamid, SA, Hampel, H, Hansford, JR, Harlos, C, Hijiya, N, Hsu, S, Kamihara, J, Kebudi, R, Knipstein, J, Koschmann, C, Kratz, C, Larouche, V, Lassaletta, A, Lindhorst, S, Ling, SC, Link, MP, De Mola, RL, Luiten, R, Lurye, M, Maciaszek, JL, MagimairajanIssai, V, Maher, OM, Massimino, M, McGee, RB, Mushtaq, N, Mason, G, Newmark, M, Nicholas, G, Nichols, KE, Nicolaides, T, Opocher, E, Osborn, M, Oshrine, B, Pearlman, R, Pettee, D, Rapp, J, Rashid, M, Reddy, A, Reichman, L, Remke, M, Robbins, G, Roy, S, Sabel, M, Samuel, D, Scheers, I, Schneider, KW, Sen, S, Stearns, D, Sumerauer, D, Swallow, C, Taylor, L, Thomas, G, Toledano, H, Tomboc, P, Van Damme, A, Winer, I, Yalon, M, Yen, LY, Zapotocky, M, Zelcer, S, Ziegler, DS, Zimmermann, S, Hawkins, C, Malkin, D, Bouffet, E, Villani, A, and Tabori, U

Abstract

PURPOSE: Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. PATIENTS AND METHODS: Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. RESULTS: A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically (P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively (P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance (P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. CONCLUSION: Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.

Published
2021

44. A novel founder MSH2 deletion in Ethiopian Jews is mainly associated with early-onset colorectal cancer

Author

Kedar, I., primary, Walsh, L., additional, Levi, G. Reznick, additional, Lieberman, S., additional, Shtaya, A. Abu, additional, Nathan, S. Naftaly, additional, Lagovsky, I., additional, Tomashov-Matar, R., additional, Goldenberg, M., additional, Basel-Salmon, L., additional, Katz, L., additional, Aleme, O., additional, Peretz, T. Yablonski, additional, Hubert, A., additional, Rothstein, D., additional, Castellvi-Bel, S., additional, Walsh, T., additional, King, M. C., additional, Pritchard, C. C., additional, Levi, Z., additional, Half, E., additional, Laish, I., additional, and Goldberg, Y., additional

Published
2021
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45. The 5th International Lafora Epilepsy Workshop: Basic science elucidating therapeutic options and preparing for therapies in the clinic

Author

National Institute of Neurological Disorders and Stroke (US), National Institutes of Health (US), Ministerio de Educación (España), Fundación Ramón Areces, Ministerio de Economía y Competitividad (España), Sanz, Pascual [0000-0002-2399-4103], Gentry, Matthew S., Afawi, Zaid, Armstrong, Dustin D., Delgado-Escueta, Antonio, Goldberg, Y. Paul, Grossman, Tamar R., Guinovart, Joan J., Harris, Frank, Hurley, Thomas D., Michelucci, Roberto, Minassian, Berge A., Sanz, Pascual, Worby, Carolyn A., Serratosa, Jose M., National Institute of Neurological Disorders and Stroke (US), National Institutes of Health (US), Ministerio de Educación (España), Fundación Ramón Areces, Ministerio de Economía y Competitividad (España), Sanz, Pascual [0000-0002-2399-4103], Gentry, Matthew S., Afawi, Zaid, Armstrong, Dustin D., Delgado-Escueta, Antonio, Goldberg, Y. Paul, Grossman, Tamar R., Guinovart, Joan J., Harris, Frank, Hurley, Thomas D., Michelucci, Roberto, Minassian, Berge A., Sanz, Pascual, Worby, Carolyn A., and Serratosa, Jose M.

Abstract

Lafora disease (LD) is both a fatal childhood epilepsy and a glycogen storage disease caused by recessive mutations in either the Epilepsy progressive myoclonus 2A (EPM2A) or EPM2B genes. Hallmarks of LD are aberrant, cytoplasmic carbohydrate aggregates called Lafora bodies (LBs) that are a disease driver. The 5th International Lafora Epilepsy Workshop was recently held in Alcala de Henares, Spain. The workshop brought together nearly 100 clinicians, academic and industry scientists, trainees, National Institutes of Health (NIH) representation, and friends and family members of patients with LD. The workshop covered aspects of LD ranging from defining basic scientific mechanisms to elucidating a LD therapy or cure and a recently launched LD natural history study.

Published
2020

47. Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the study of Canadian genetic isolates

Author

Lafreniere, Ronald G., MacDonald, Marcia L.E., Dube, Marie-Pierre, MacFarlane, Julie, O'Driscoll, Mary, Brais, Bernard, Meilleur, Sebastien, Brinkman, Ryan R., Dadivas, Owen, Pape, Terry, Platon, Christele, Radomski, Chris, Risler, Jenni, Thompson, Jay, Guerra-Escobio, Ana-Maria, Davar, Gudarz, Breakefield, Xandra O., Pimstone, Simon N., Green, Roger, Pryse-Phillips, William, Goldberg, Y. Paul, Younghusband, H. Banfield, Hayden, Michael R., Sherrington, Robin, Rouleau, Guy A., and Samuels, Mark E.

Subjects
Human genetics -- Research, Biological sciences
Published
2004

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