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2. Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency

Author

Das, A, Sudhaman, S, Morgenstern, D, Coblentz, A, Chung, J, Stone, SC, Alsafwani, N, Liu, ZA, Abu Al Karsaneh, O, Soleimani, S, Ladany, H, Chen, D, Zatzman, M, Cabric, V, Nobre, L, Bianchi, V, Edwards, M, Nahum, LCS, Ercan, AB, Nabbi, A, Constantini, S, Dvir, R, Yalon-Oren, M, Campino, GA, Caspi, S, Larouche, V, Reddy, A, Osborn, M, Mason, G, Lindhorst, S, Bronsema, A, Magimairajan, V, Opocher, E, De Mola, RL, Sabel, M, Frojd, C, Sumerauer, D, Samuel, D, Cole, K, Chiaravalli, S, Massimino, M, Tomboc, P, Ziegler, DS, George, B, Van Damme, A, Hijiya, N, Gass, D, McGee, RB, Mordechai, O, Bowers, DC, Laetsch, TW, Lossos, A, Blumenthal, DT, Sarosiek, T, Yen, LY, Knipstein, J, Bendel, A, Hoffman, LM, Luna-Fineman, S, Zimmermann, S, Scheers, I, Nichols, KE, Zapotocky, M, Hansford, JR, Maris, JM, Dirks, P, Taylor, MD, Kulkarni, A, Shroff, M, Tsang, DS, Villani, A, Xu, W, Aronson, M, Durno, C, Shlien, A, Malkin, D, Getz, G, Maruvka, YE, Ohashi, PS, Hawkins, C, Pugh, TJ, Bouffet, E, Tabori, U, Das, A, Sudhaman, S, Morgenstern, D, Coblentz, A, Chung, J, Stone, SC, Alsafwani, N, Liu, ZA, Abu Al Karsaneh, O, Soleimani, S, Ladany, H, Chen, D, Zatzman, M, Cabric, V, Nobre, L, Bianchi, V, Edwards, M, Nahum, LCS, Ercan, AB, Nabbi, A, Constantini, S, Dvir, R, Yalon-Oren, M, Campino, GA, Caspi, S, Larouche, V, Reddy, A, Osborn, M, Mason, G, Lindhorst, S, Bronsema, A, Magimairajan, V, Opocher, E, De Mola, RL, Sabel, M, Frojd, C, Sumerauer, D, Samuel, D, Cole, K, Chiaravalli, S, Massimino, M, Tomboc, P, Ziegler, DS, George, B, Van Damme, A, Hijiya, N, Gass, D, McGee, RB, Mordechai, O, Bowers, DC, Laetsch, TW, Lossos, A, Blumenthal, DT, Sarosiek, T, Yen, LY, Knipstein, J, Bendel, A, Hoffman, LM, Luna-Fineman, S, Zimmermann, S, Scheers, I, Nichols, KE, Zapotocky, M, Hansford, JR, Maris, JM, Dirks, P, Taylor, MD, Kulkarni, A, Shroff, M, Tsang, DS, Villani, A, Xu, W, Aronson, M, Durno, C, Shlien, A, Malkin, D, Getz, G, Maruvka, YE, Ohashi, PS, Hawkins, C, Pugh, TJ, Bouffet, E, and Tabori, U

Abstract

Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion-deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10-100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in 'immunologically cold' tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy.

Published
2022

3. NASPGHAN Annual Meeting Abstracts

Author

Durno, C, Ercan, A, Aronson, M, Villani, A, Bouffet, E, Erdman, S, Scheers, Isabelle, Bronsema, A, Tabori, U, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique

Subjects
and Child Health, Pediatrics, Perinatology and Child Health, Gastroenterology, Pediatrics, Perinatology
Abstract

Background: Constitutional mismatch repair deficiency syndrome (CMMRD) is a severe cancer predisposition syndrome causing intestinal polyposis and a high risk of early onset gastrointestinal, brain, and hematological cancers. International guidelines for surveillance exist but no study has systematically evaluated the efficacy of this protocol. Aim: Our aim was to determine if surveillance affects outcome. The primary outcome measure was overall survival. The secondary outcome measure was detection of new cancers. Methods: Patients referred to the International Replication Repair Consortium undergo genetic testing to confirm CMMRD. All individuals were diagnosed with CMMRD through diagnostic criteria by the genetic counsellor at the consortium. A surveillance protocol consisting of frequent biochemical, endoscopic and imaging studies was recommended and initiated internationally on Jan 1, 2012. Protocol included upper endoscopy, colonoscopy, video capsule endoscopy and/or magnetic resonance enterography, and brain MRI. Whole-body MRI was recommended as of Jan 1, 2018. Surveillance questionnaire was sent to the responsible physician with diagnostic fields completed by the registry coordinator as a double check of reliability. Survival analyses was completed using an as-treated approach. Results: Cancer and surveillance data was collected from 64 (50%) of 127 CMMRD individuals registered in the Consortium from 41 countries. There were 114 tumours reported in 60 patients including 55 brain, 28 gastrointestinal (GI), 17 hematological and 14 other malignancies. Surveillance data was available on 110 cancers; 16 were incidental cancers, 68 were symptomatic and 26 were discovered through surveillance. Surveillance identified 13 GI cancers, 11 brain, and 2 hematological malignancies. The gastrointestinal cancers included 5 colorectal, 7 small bowel, and one gastric. Four patients were unaffected. Five-year overall survival was 95% for tumors discovered by surveillance, compared to 43% for symptomatic tumors (p=0.001). Overall survival for gastrointestinal tumors identified by surveillance was 100% (n=13) compared to 79% (n=19) for symptomatic lesions (p=0.1). Similarly, 5-year survival was 83+/-15% and 32+/-7% for surveillance and non-surveillance of brain tumors (p=0.03). Median age at diagnosis of gastrointestinal cancer was 14.6 years (range 9.0-50.6 years). Conclusion: These data support a survival benefit in CMMRD patients undergoing a surveillance protocol.

Published
2019
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4. 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

6. Management of Familial Adenomatous Polyposis in Children and Adolescents: Position Paper From the ESPGHAN Polyposis Working Group

Author

Hyer W, Cohen S, Attard T, Vila-Miravet V, Pienar C, Auth M, Septer S, Hawkins J, Durno C, and Latchford A

Subjects
digestive system diseases
Abstract

Familial adenomatous polyposis (FAP) is a well-described inherited syndrome, characterized by the development of hundreds to thousands of adenomas in the colorectum, with implications in children and adolescents. Almost all adult patients will develop colorectal cancer if they are not identified and treated early enough. Identifying and screening for FAP commences in adolescence. The syndrome is inherited as an autosomal dominant trait and caused by mutations in the adenomatous polyposis (APC) gene. This European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) position paper provides a guide for diagnosis, assessment, and management of FAP in children and adolescents.This is the first position paper regarding FAP published by ESPGHAN. Literature from PubMed, Medline, and Embase was reviewed and in the absence of evidence, recommendations reflect the opinion of paediatric and adult experts involved in the care of polyposis syndromes. Because many of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, these of the recommendations are supported on expert opinion. This position paper will instruct on the appropriate management and timing of procedures in children and adolescents with FAP.

Published
2019

7. NASPGHAN Annual Meeting Abstracts

Author

UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, Durno, C, Ercan, A, Aronson, M, Villani, A, Bouffet, E, Erdman, S, Scheers, Isabelle, Bronsema, A, Tabori, U, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, Durno, C, Ercan, A, Aronson, M, Villani, A, Bouffet, E, Erdman, S, Scheers, Isabelle, Bronsema, A, and Tabori, U

Abstract

Background: Constitutional mismatch repair deficiency syndrome (CMMRD) is a severe cancer predisposition syndrome causing intestinal polyposis and a high risk of early onset gastrointestinal, brain, and hematological cancers. International guidelines for surveillance exist but no study has systematically evaluated the efficacy of this protocol. Aim: Our aim was to determine if surveillance affects outcome. The primary outcome measure was overall survival. The secondary outcome measure was detection of new cancers. Methods: Patients referred to the International Replication Repair Consortium undergo genetic testing to confirm CMMRD. All individuals were diagnosed with CMMRD through diagnostic criteria by the genetic counsellor at the consortium. A surveillance protocol consisting of frequent biochemical, endoscopic and imaging studies was recommended and initiated internationally on Jan 1, 2012. Protocol included upper endoscopy, colonoscopy, video capsule endoscopy and/or magnetic resonance enterography, and brain MRI. Whole-body MRI was recommended as of Jan 1, 2018. Surveillance questionnaire was sent to the responsible physician with diagnostic fields completed by the registry coordinator as a double check of reliability. Survival analyses was completed using an as-treated approach. Results: Cancer and surveillance data was collected from 64 (50%) of 127 CMMRD individuals registered in the Consortium from 41 countries. There were 114 tumours reported in 60 patients including 55 brain, 28 gastrointestinal (GI), 17 hematological and 14 other malignancies. Surveillance data was available on 110 cancers; 16 were incidental cancers, 68 were symptomatic and 26 were discovered through surveillance. Surveillance identified 13 GI cancers, 11 brain, and 2 hematological malignancies. The gastrointestinal cancers included 5 colorectal, 7 small bowel, and one gastric. Four patients were unaffected. Five-year overall survival was 95% for tumors discovered by surveillance, comp

Published
2019

9. GE-09 * COMBINED HEREDITARY AND SOMATIC MUTATIONS OF REPLICATION ERROR REPAIR GENES RESULT IN RAPID ONSET OF ULTRA-HYPERMUTATED MALIGNANT BRAIN TUMORS IN CHILDREN

Author

Shlien, A., primary, Campbell, B. B., additional, de Borja, R., additional, Alexandrov, L. B., additional, Merino, D. M., additional, Remke, M., additional, Bakry, D., additional, Dirks, P., additional, Huang, A., additional, Grundy, R. G., additional, Durno, C., additional, Aronson, M., additional, Taylor, M. D., additional, Pursell, Z. F., additional, Pearson, C. E., additional, Malkin, D., additional, Bouffet, E., additional, Hawkins, C., additional, Campbell, P. J., additional, and Tabori, U., additional

Published
2015
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10. RADIOLOGY

Author

Kelly, T., primary, Prah, M., additional, Jogal, S., additional, Maheshwari, M., additional, Lew, S., additional, Schmainda, K., additional, Kannan, G., additional, Khatua, S., additional, Zaky, W., additional, Ketonen, L., additional, Drogosiewicz, M., additional, Dembowska-Baginska, B., additional, Jurkiewicz, E., additional, Nowak, K., additional, Perek, D., additional, Hirpara, D., additional, Bhatt, M., additional, Scheinemann, K., additional, Shimizu, Y., additional, Kondo, A., additional, Miyajima, M., additional, Arai, H., additional, Dvir, R., additional, Shiran, S., additional, Sira, L. B.-, additional, Roth, J., additional, Tabori, U., additional, Bouffet, E., additional, Durno, C., additional, Aronson, M., additional, Constantini, S., additional, Elhasid, R., additional, Fangusaro, J., additional, Marsh, J., additional, Bregman, C., additional, Diaz, A., additional, Byrne, R., additional, Ziel, E., additional, Goldman, S., additional, Calmon, R., additional, Grevent, D., additional, Blauwblomme, T., additional, Puget, S., additional, Sainte-Rose, C., additional, Varlet, P., additional, Dufour, C., additional, Grill, J., additional, Saitovich, A., additional, Zilbovicius, M., additional, Brunelle, F., additional, Boddaert, N., additional, Wei, L., additional, Tan, A. M., additional, Tang, P. H., additional, Orphanidou-Vlachou, E., additional, Vlachos, N., additional, Davies, N., additional, Arvanitis, T., additional, Grundy, R., additional, Peet, A., additional, Withey, S., additional, Novak, J., additional, MacPherson, L., additional, Avula, S., additional, Kumar, R., additional, Pizer, B., additional, Pettorini, B., additional, Garlick, D., additional, Mallucci, C., additional, Reddick, W., additional, Guo, J., additional, Glass, J., additional, Pryweller, J., additional, Gajjar, A., additional, Thust, S., additional, Blanco, E., additional, Mankad, K., additional, and Michalski, A., additional

Published
2014
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11. HIGH GRADE GLIOMAS AND DIPG

Author

Classen, C. F., primary, William, D., additional, Linnebacher, M., additional, Farhod, A., additional, Kedr, W., additional, Elsabe, B., additional, Fadel, S., additional, Van Gool, S., additional, De Vleeschouwer, S., additional, Koks, C., additional, Garg, A., additional, Ehrhardt, M., additional, Riva, M., additional, Agostinis, P., additional, Graf, N., additional, Yao, T.-W., additional, Yoshida, Y., additional, Zhang, J., additional, Ozawa, T., additional, James, D., additional, Nicolaides, T., additional, Kebudi, R., additional, Cakir, F. B., additional, Gorgun, O., additional, Agaoglu, F. Y., additional, Darendeliler, E., additional, Al-Kofide, A., additional, Al-Shail, E., additional, Khafaga, Y., additional, Al-Hindi, H., additional, Dababo, M., additional, Haq, A. U., additional, Anas, M., additional, Barria, M. G., additional, Siddiqui, K., additional, Hassounah, M., additional, Ayas, M., additional, van Zanten, S. V., additional, Jansen, M., additional, van Vuurden, D., additional, Huisman, M., additional, Vugts, D., additional, Hoekstra, O., additional, van Dongen, G., additional, Kaspers, G., additional, Cockle, J., additional, Ilett, E., additional, Scott, K., additional, Bruning-Richardson, A., additional, Picton, S., additional, Short, S., additional, Melcher, A., additional, Benesch, M., additional, Warmuth-Metz, M., additional, von Bueren, A. O., additional, Hoffmann, M., additional, Pietsch, T., additional, Kortmann, R.-D., additional, Eyrich, M., additional, Rutkowski, S., additional, Fruhwald, M. C., additional, Faber, J., additional, Kramm, C., additional, Porkholm, M., additional, Valanne, L., additional, Lonnqvist, T., additional, Holm, S., additional, Lannering, B., additional, Riikonen, P., additional, Wojcik, D., additional, Sehested, A., additional, Clausen, N., additional, Harila-Saari, A., additional, Schomerus, E., additional, Thorarinsdottir, H. K., additional, Lahteenmaki, P., additional, Arola, M., additional, Thomassen, H., additional, Saarinen-Pihkala, U. M., additional, Kivivuori, S.-M., additional, Buczkowicz, P., additional, Hoeman, C., additional, Rakopoulos, P., additional, Pajovic, S., additional, Morrison, A., additional, Bouffet, E., additional, Bartels, U., additional, Becher, O., additional, Hawkins, C., additional, Gould, T. W. A., additional, Rahman, C. V., additional, Smith, S. J., additional, Barrett, D. A., additional, Shakesheff, K. M., additional, Grundy, R. G., additional, Rahman, R., additional, Barua, N., additional, Cronin, D., additional, Gill, S., additional, Lowisl, S., additional, Hochart, A., additional, Maurage, C.-A., additional, Rocourt, N., additional, Vinchon, M., additional, Kerdraon, O., additional, Escande, F., additional, Grill, J., additional, Pick, V. K., additional, Leblond, P., additional, Burzynski, G., additional, Janicki, T., additional, Burzynski, S., additional, Marszalek, A., additional, Ramani, N., additional, Zaky, W., additional, Kannan, G., additional, Morani, A., additional, Sandberg, D., additional, Ketonen, L., additional, Maher, O., additional, Corrales-Medina, F., additional, Meador, H., additional, Khatua, S., additional, Brassesco, M., additional, Delsin, L., additional, Roberto, G., additional, Silva, C., additional, Ana, L., additional, Rego, E., additional, Scrideli, C., additional, Umezawa, K., additional, Tone, L., additional, Kim, S. J., additional, Kim, C.-Y., additional, Kim, I.-A., additional, Han, J. H., additional, Choi, B.-S., additional, Ahn, H. S., additional, Choi, H. S., additional, Haque, F., additional, Layfield, R., additional, Grundy, R., additional, Gandola, L., additional, Pecori, E., additional, Biassoni, V., additional, Schiavello, E., additional, Chiruzzi, C., additional, Spreafico, F., additional, Modena, P., additional, Bach, F., additional, Pignoli, E., additional, Massimino, M., additional, Drogosiewicz, M., additional, Dembowska-Baginska, B., additional, Jurkiewicz, E., additional, Filipek, I., additional, Perek-Polnik, M., additional, Swieszkowska, E., additional, Perek, D., additional, Bender, S., additional, Jones, D. T., additional, Warnatz, H.-J., additional, Hutter, B., additional, Zichner, T., additional, Gronych, J., additional, Korshunov, A., additional, Eils, R., additional, Korbel, J. O., additional, Yaspo, M.-L., additional, Lichter, P., additional, Pfister, S. M., additional, Yadavilli, S., additional, Becher, O. J., additional, Kambhampati, M., additional, Packer, R. J., additional, Nazarian, J., additional, Lechon, F. C., additional, Fowkes, L., additional, Khabra, K., additional, Martin-Retortillo, L. M., additional, Marshall, L. V., additional, Vaidya, S., additional, Koh, D.-M., additional, Leach, M. O., additional, Pearson, A. D., additional, Zacharoulis, S., additional, Schrey, D., additional, Barone, G., additional, Panditharatna, E., additional, Stampar, M., additional, Siu, A., additional, Gordish-Dressman, H., additional, Devaney, J., additional, Hwang, E. I., additional, Chung, A. H., additional, Mittapalli, R. K., additional, Elmquist, W. F., additional, Castel, D., additional, Debily, M.-A., additional, Philippe, C., additional, Truffaux, N., additional, Taylor, K., additional, Calmon, R., additional, Boddaert, N., additional, Le Dret, L., additional, Saulnier, P., additional, Lacroix, L., additional, Mackay, A., additional, Jones, C., additional, Puget, S., additional, Sainte-Rose, C., additional, Blauwblomme, T., additional, Varlet, P., additional, Entz-Werle, N., additional, Maugard, C., additional, Bougeard, G., additional, Nguyen, A., additional, Chenard, M. P., additional, Schneider, A., additional, Gaub, M. P., additional, Tsoli, M., additional, Vanniasinghe, A., additional, Luk, P., additional, Dilda, P., additional, Haber, M., additional, Hogg, P., additional, Ziegler, D., additional, Simon, S., additional, Monje, M., additional, Gurova, K., additional, Gudkov, A., additional, Zapotocky, M., additional, Churackova, M., additional, Malinova, B., additional, Zamecnik, J., additional, Kyncl, M., additional, Tichy, M., additional, Puchmajerova, A., additional, Stary, J., additional, Sumerauer, D., additional, Boult, J., additional, Vinci, M., additional, Perryman, L., additional, Box, G., additional, Jury, A., additional, Popov, S., additional, Ingram, W., additional, Eccles, S., additional, Robinson, S., additional, Emir, S., additional, Demir, H. A., additional, Bayram, C., additional, Cetindag, F., additional, Kabacam, G. B., additional, Fettah, A., additional, Li, J., additional, Jamin, Y., additional, Cummings, C., additional, Bamber, J., additional, Sinkus, R., additional, Nandhabalan, M., additional, Bjerke, L., additional, Burford, A., additional, von Bueren, A., additional, Baudis, M., additional, Clarke, P., additional, Collins, I., additional, Workman, P., additional, Olaciregui, N., additional, Mora, J., additional, Carcaboso, A., additional, Bullock, A., additional, Alonso, M., additional, de Torres, C., additional, Cruz, O., additional, Pencreach, E., additional, Moussalieh, F. M., additional, Guenot, D., additional, Namer, I., additional, Pollack, I., additional, Jakacki, R., additional, Butterfield, L., additional, Hamilton, R., additional, Panigrahy, A., additional, Potter, D., additional, Connelly, A., additional, Dibridge, S., additional, Whiteside, T., additional, Okada, H., additional, Ahsan, S., additional, Raabe, E., additional, Haffner, M., additional, Warren, K., additional, Quezado, M., additional, Ballester, L., additional, Eberhart, C., additional, Rodriguez, F., additional, Ramachandran, C., additional, Nair, S., additional, Quirrin, K.-W., additional, Khatib, Z., additional, Escalon, E., additional, Melnick, S., additional, Classen, C. F., additional, Hofmann, M., additional, Schmid, I., additional, Simon, T., additional, Maass, E., additional, Russo, A., additional, Fleischhack, G., additional, Becker, M., additional, Hauch, H., additional, Sander, A., additional, Grasso, C., additional, Berlow, N., additional, Liu, L., additional, Davis, L., additional, Huang, E., additional, Woo, P., additional, Tang, Y., additional, Ponnuswami, A., additional, Chen, S., additional, Huang, Y., additional, Hutt-Cabezas, M., additional, Dret, L., additional, Meltzer, P., additional, Mao, H., additional, Abraham, J., additional, Fouladi, M., additional, Svalina, M. N., additional, Wang, N., additional, Hulleman, E., additional, Li, X.-N., additional, Keller, C., additional, Spellman, P. T., additional, Pal, R., additional, Jansen, M. H. A., additional, Sewing, A. C. P., additional, Lagerweij, T., additional, Vuchts, D. J., additional, van Vuurden, D. G., additional, Caretti, V., additional, Wesseling, P., additional, Kaspers, G. J. L., additional, Cohen, K., additional, Pearl, M., additional, Kogiso, M., additional, Zhang, L., additional, Qi, L., additional, Lindsay, H., additional, Lin, F., additional, Berg, S., additional, Muscal, J., additional, Amayiri, N., additional, Tabori, U., additional, Campbel, B., additional, Bakry, D., additional, Aronson, M., additional, Durno, C., additional, Gallinger, S., additional, Malkin, D., additional, Qaddumi, I., additional, Musharbash, A., additional, Swaidan, M., additional, Al-Hussaini, M., additional, Shandilya, S., additional, McCully, C., additional, Murphy, R., additional, Akshintala, S., additional, Cole, D., additional, Macallister, R. P., additional, Cruz, R., additional, Widemann, B., additional, Salloum, R., additional, Smith, A., additional, Glaunert, M., additional, Ramkissoon, A., additional, Peterson, S., additional, Baker, S., additional, Chow, L., additional, Sandgren, J., additional, Pfeifer, S., additional, Popova, S., additional, Alafuzoff, I., additional, de Stahl, T. D., additional, Pietschmann, S., additional, Kerber, M. J., additional, Zwiener, I., additional, Henke, G., additional, Muller, K., additional, Sieow, N. Y.-F., additional, Hoe, R. H. M., additional, Tan, A. M., additional, Chan, M. Y., additional, Soh, S. Y., additional, Burrell, K., additional, Chornenkyy, Y., additional, Remke, M., additional, Golbourn, B., additional, Barzczyk, M., additional, Taylor, M., additional, Rutka, J., additional, Dirks, P., additional, Zadeh, G., additional, Agnihotri, S., additional, Hashizume, R., additional, Ihara, Y., additional, Andor, N., additional, Chen, X., additional, Lerner, R., additional, Huang, X., additional, Tom, M., additional, Solomon, D., additional, Mueller, S., additional, Petritsch, C., additional, Zhang, Z., additional, Gupta, N., additional, Waldman, T., additional, Dujua, A., additional, Co, J., additional, Hernandez, F., additional, Doromal, D., additional, Hegde, M., additional, Wakefield, A., additional, Brawley, V., additional, Grada, Z., additional, Byrd, T., additional, Chow, K., additional, Krebs, S., additional, Heslop, H., additional, Gottschalk, S., additional, Yvon, E., additional, Ahmed, N., additional, Cornilleau, G., additional, Paulsson, J., additional, Andreiuolo, F., additional, Guerrini-Rousseau, L., additional, Geoerger, B., additional, Vassal, G., additional, Ostman, A., additional, Parsons, D. W., additional, Trevino, L. R., additional, Gao, F., additional, Shen, X., additional, Hampton, O., additional, Kosigo, M., additional, Baxter, P. A., additional, Su, J. M., additional, Chintagumpala, M., additional, Dauser, R., additional, Adesina, A., additional, Plon, S. E., additional, Wheeler, D. A., additional, Lau, C. C., additional, Gielen, G., additional, Muehlen, A. z., additional, Kwiecien, R., additional, Wolff, J., additional, Lulla, R. R., additional, Laskowski, J., additional, Goldman, S., additional, Gopalakrishnan, V., additional, Fangusaro, J., additional, Kieran, M., additional, Fontebasso, A., additional, Papillon-Cavanagh, S., additional, Schwartzentruber, J., additional, Nikbakht, H., additional, Gerges, N., additional, Fiset, P.-O., additional, Bechet, D., additional, Faury, D., additional, De Jay, N., additional, Ramkissoon, L., additional, Corcoran, A., additional, Jones, D., additional, Sturm, D., additional, Johann, P., additional, Tomita, T., additional, Nagib, M., additional, Bendel, A., additional, Goumnerova, L., additional, Bowers, D. C., additional, Leonard, J. R., additional, Rubin, J. B., additional, Alden, T., additional, DiPatri, A., additional, Browd, S., additional, Leary, S., additional, Jallo, G., additional, Prados, M. D., additional, Banerjee, A., additional, Carret, A.-S., additional, Ellezam, B., additional, Crevier, L., additional, Klekner, A., additional, Bognar, L., additional, Hauser, P., additional, Garami, M., additional, Myseros, J., additional, Dong, Z., additional, Siegel, P. M., additional, Gump, W., additional, Ayyanar, K., additional, Ragheb, J., additional, Krieger, M., additional, Kiehna, E., additional, Robison, N., additional, Harter, D., additional, Gardner, S., additional, Handler, M., additional, Foreman, N., additional, Brahma, B., additional, MacDonald, T., additional, Malkin, H., additional, Chi, S., additional, Manley, P., additional, Bandopadhayay, P., additional, Greenspan, L., additional, Ligon, A., additional, Albrecht, S., additional, Ligon, K. L., additional, Majewski, J., additional, Jabado, N., additional, Cordero, F., additional, Halvorson, K., additional, Taylor, I., additional, Hutt, M., additional, Weingart, M., additional, Price, A., additional, Kantar, M., additional, Onen, S., additional, Kamer, S., additional, Turhan, T., additional, Kitis, O., additional, Ertan, Y., additional, Cetingul, N., additional, Anacak, Y., additional, Akalin, T., additional, Ersahin, Y., additional, Mason, G., additional, Ho, C., additional, Crozier, F., additional, Vezina, G., additional, Packer, R., additional, Hwang, E., additional, Gilheeney, S., additional, Millard, N., additional, DeBraganca, K., additional, Khakoo, Y., additional, Kramer, K., additional, Wolden, S., additional, Donzelli, M., additional, Fischer, C., additional, Petriccione, M., additional, Dunkel, I., additional, Afzal, S., additional, Fleming, A., additional, Larouche, V., additional, Zelcer, S., additional, Johnston, D. L., additional, Kostova, M., additional, Mpofu, C., additional, Decarie, J.-C., additional, Strother, D., additional, Lafay-Cousin, L., additional, Eisenstat, D., additional, Fryer, C., additional, Hukin, J., additional, Hsu, M., additional, Lasky, J., additional, Moore, T., additional, Liau, L., additional, Davidson, T., additional, Prins, R., additional, Hassal, T., additional, Baugh, J., additional, Kirkendall, J., additional, Doughman, R., additional, Leach, J., additional, Jones, B., additional, Miles, L., additional, Hargrave, D., additional, Jacques, T., additional, Savage, S., additional, Saunders, D., additional, Wallace, R., additional, Flutter, B., additional, Morgenestern, D., additional, Blanco, E., additional, Howe, K., additional, Lowdell, M., additional, Samuel, E., additional, Michalski, A., additional, Anderson, J., additional, Arakawa, Y., additional, Umeda, K., additional, Watanabe, K.-i., additional, Mizowaki, T., additional, Hiraoka, M., additional, Hiramatsu, H., additional, Adachi, S., additional, Kunieda, T., additional, Takagi, Y., additional, Miyamoto, S., additional, Venneti, S., additional, Santi, M., additional, Felicella, M. M., additional, Sullivan, L. M., additional, Dolgalev, I., additional, Martinez, D., additional, Perry, A., additional, Lewis, P. W., additional, Allis, D. C., additional, Thompson, C. B., additional, and Judkins, A. R., additional

Published
2014
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12. EPIDEMIOLOGY

Author

Khatua, S., primary, Brown, R., additional, Pearlman, M., additional, Vats, T., additional, Satge, D., additional, Stiller, C., additional, Rutkowski, S., additional, von Bueren, A. O., additional, Lacour, B., additional, Sommelet, D., additional, Nishi, M., additional, Massimino, M., additional, Garre, M.-L., additional, Moreno, F., additional, Hasle, H., additional, Jakab, Z., additional, Greenberg, M., additional, von der Weid, N., additional, Kuehni, C., additional, Zurriaga, O., additional, Vicente, M.-L., additional, Peris-Bonet, R., additional, Benesch, M., additional, Vekemans, M., additional, Sullivan, S., additional, Rickert, C., additional, Fisher, P. G., additional, Von Behren, J., additional, Nelson, D. O., additional, Reynolds, P., additional, Fukuoka, K., additional, Yanagisawa, T., additional, Suzuki, T., additional, Koga, T., additional, Wakiya, K., additional, Adachi, J.-i., additional, Mishima, K., additional, Fujimaki, T., additional, Matsutani, M., additional, Nishikawa, R., additional, Gidding, C., additional, Schieving, J., additional, Wesseling, P., additional, Ligtenberg, M., additional, Hoogerbrugge, N., additional, Jongmans, M., additional, Crosier, S., additional, Nicholson, S. L., additional, Robson, K., additional, Jacques, T., additional, Wharton, S., additional, Bown, N., additional, Michalski, A., additional, Pizer, B., additional, Clifford, S., additional, Sanden, E., additional, Visse, E., additional, Siesjo, P., additional, Darabi, A., additional, Nousome, D., additional, Lupo, P. J., additional, Scheurer, M. E., additional, Nulman, I., additional, Barrera, M., additional, Maxwell, C., additional, Koren, G., additional, Gorelyshev, S., additional, Matuev, K., additional, Lubnin, A., additional, Laskov, M., additional, Lemeneva, N., additional, Mazerkina, N., additional, Khuhlaeva, E., additional, Muller, K., additional, Bruns, F., additional, Pietsch, T., additional, Kortmann, R.-D., additional, Krishnatry, R., additional, Shirsat, N., additional, Kunder, R., additional, Epari, S., additional, Gupta, T., additional, Kurkure, P., additional, Vora, T., additional, Arora, B., additional, Moiyadi, A., additional, Jalali, R., additional, Swieszkowska, E., additional, Dembowska-Baginska, B., additional, Drogosiewicz, M., additional, Filipek, I., additional, Perek-Polnik, M., additional, Grajkowska, W., additional, Perek, D., additional, Johnston, D., additional, Cyr, J., additional, Strother, D., additional, Lafay-Cousin, L., additional, Fryer, C., additional, Scheinemann, K., additional, Carret, A.-S., additional, Fleming, A., additional, Larouche, V., additional, Bouffet, E., additional, Friedrich, C., additional, Gnekow, A. K., additional, Fleischhack, G., additional, Kramm, C. M., additional, Fruehwald, M. C., additional, Muller, H. L., additional, Calaminus, G., additional, Kordes, U., additional, Faldum, A., additional, Warmuth-Metz, M., additional, Kortmann, R. D., additional, Jung, I., additional, Kaatsch, P., additional, Caretti, V., additional, Bugiani, M., additional, Boor, I., additional, Schellen, P., additional, Vandertop, W. P., additional, Noske, D. P., additional, Kaspers, G., additional, Wurdinger, T., additional, Robinson, G., additional, Chingtagumpala, M., additional, Adesina, A., additional, Dalton, J., additional, Santi, M., additional, Sievert, A., additional, Wright, K., additional, Armstrong, G., additional, Boue, D., additional, Olshefski, R., additional, Scott, S., additional, Huang, A., additional, Cohn, R., additional, Gururangan, S., additional, Bowers, D., additional, Gilbertson, R., additional, Gajjar, A., additional, Ellison, D., additional, Chick, E., additional, Donson, A., additional, Owens, E., additional, Smith, A. A., additional, Madden, J. R., additional, Foreman, N. K., additional, Bakry, D., additional, Aronson, M., additional, Durno, C., additional, Hala, R., additional, Farah, R., additional, Amayiri, N., additional, Alharbi, Q., additional, Shamvil, A., additional, Ben-Shachar, S., additional, Constantini, S., additional, Rina, D., additional, Ellise, J., additional, Keiles, S., additional, Pollet, A., additional, Qaddoumi, I., additional, Gallinger, S., additional, Malkin, D., additional, Hawkins, C., additional, Tabori, U., additional, Trivedi, M., additional, Goodden, J., additional, Chumas, P., additional, Tyagi, A., additional, O'kane, R., additional, O'Kane, R., additional, Crimmins, D., additional, Picton, S., additional, and Elliott, M., additional

Published
2012
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13. Diagnosis and Management of Cancer Risk in the Gastrointestinal Hamartomatous Polyposis Syndromes: Recommendations From the US Multi-Society Task Force on Colorectal Cancer.

Author

Boland CR, Idos GE, Durno C, Giardiello FM, Anderson JC, Burke CA, Dominitz JA, Gross S, Gupta S, Jacobson BC, Patel SG, Shaukat A, Syngal S, and Robertson DJ

Subjects
Gastrointestinal Hemorrhage, Humans, Intestinal Polyps, Colorectal Neoplasms diagnosis, Colorectal Neoplasms genetics, Colorectal Neoplasms therapy, Hamartoma, Hamartoma Syndrome, Multiple complications, Hamartoma Syndrome, Multiple diagnosis, Hamartoma Syndrome, Multiple genetics, Intestinal Polyposis complications, Intestinal Polyposis congenital, Intestinal Polyposis diagnosis, Intestinal Polyposis genetics, Neoplastic Syndromes, Hereditary diagnosis, Neoplastic Syndromes, Hereditary genetics, Neoplastic Syndromes, Hereditary therapy, Peutz-Jeghers Syndrome complications, Peutz-Jeghers Syndrome diagnosis, Peutz-Jeghers Syndrome genetics, Telangiectasia, Hereditary Hemorrhagic
Abstract

The gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with an increased risk of benign and malignant intestinal and extraintestinal tumors. They include Peutz-Jeghers syndrome, juvenile polyposis syndrome, the PTEN hamartoma tumor syndrome (including Cowden's syndrome and Bannayan-Riley-Ruvalcaba syndrome), and hereditary mixed polyposis syndrome. Diagnoses are based on clinical criteria and, in some cases, confirmed by demonstrating the presence of a germline pathogenic variant. The best understood hamartomatous polyposis syndrome is Peutz-Jeghers syndrome, caused by germline pathogenic variants in the STK11 gene. The management is focused on prevention of bleeding and mechanical obstruction of the small bowel by polyps and surveillance of organs at increased risk for cancer. Juvenile polyposis syndrome is caused by a germline pathogenic variant in either the SMAD4 or BMPR1A genes, with differing clinical courses. Patients with SMAD4 pathogenic variants may have massive gastric polyposis, which can result in gastrointestinal bleeding and/or protein-losing gastropathy. Patients with SMAD4 mutations usually have the simultaneous occurrence of hereditary hemorrhagic telangiectasia (juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia overlap syndrome) that can result in epistaxis, gastrointestinal bleeding from mucocutaneous telangiectasias, and arteriovenous malformations. Germline pathogenic variants in the PTEN gene cause overlapping clinical phenotypes (known as the PTEN hamartoma tumor syndromes), including Cowden's syndrome and related disorders that are associated with an increased risk of gastrointestinal and colonic polyposis, colon cancer, and other extraintestinal manifestations and cancers. Due to the relative rarity of the hamartomatous polyposis syndromes, recommendations for management are based on few studies. This U.S Multi-Society Task Force on Colorectal Cancer consensus statement summarizes the clinical features, assesses the current literature, and provides guidance for diagnosis, assessment, and management of patients with the hamartomatous polyposis syndromes, with a focus on endoscopic management., (Copyright © 2022 American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy, and The American College of Gastroenterology. Published by Elsevier Inc. All rights reserved.)

Published
2022
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14. Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency.

Author

Das A, Sudhaman S, Morgenstern D, Coblentz A, Chung J, Stone SC, Alsafwani N, Liu ZA, Karsaneh OAA, Soleimani S, Ladany H, Chen D, Zatzman M, Cabric V, Nobre L, Bianchi V, Edwards M, Sambira Nahum LC, Ercan AB, Nabbi A, Constantini S, Dvir R, Yalon-Oren M, Campino GA, Caspi S, Larouche V, Reddy A, Osborn M, Mason G, Lindhorst S, Bronsema A, Magimairajan V, Opocher E, De Mola RL, Sabel M, Frojd C, Sumerauer D, Samuel D, Cole K, Chiaravalli S, Massimino M, Tomboc P, Ziegler DS, George B, Van Damme A, Hijiya N, Gass D, McGee RB, Mordechai O, Bowers DC, Laetsch TW, Lossos A, Blumenthal DT, Sarosiek T, Yen LY, Knipstein J, Bendel A, Hoffman LM, Luna-Fineman S, Zimmermann S, Scheers I, Nichols KE, Zapotocky M, Hansford JR, Maris JM, Dirks P, Taylor MD, Kulkarni AV, Shroff M, Tsang DS, Villani A, Xu W, Aronson M, Durno C, Shlien A, Malkin D, Getz G, Maruvka YE, Ohashi PS, Hawkins C, Pugh TJ, Bouffet E, and Tabori U

Subjects
Adolescent, Adult, Biomarkers, Tumor, Child, Female, Humans, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors therapeutic use, Male, Neoplasms drug therapy, Prospective Studies, Retrospective Studies, Survival Analysis, Tumor Microenvironment, Young Adult, B7-H1 Antigen antagonists & inhibitors, DNA Repair genetics, DNA Replication genetics, Germ-Line Mutation
Abstract

Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion-deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10-100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in 'immunologically cold' tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy., (© 2022. The Author(s).)

Published
2022
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15. Cancers from Novel Pole -Mutant Mouse Models Provide Insights into Polymerase-Mediated Hypermutagenesis and Immune Checkpoint Blockade.

Author

Galati MA, Hodel KP, Gams MS, Sudhaman S, Bridge T, Zahurancik WJ, Ungerleider NA, Park VS, Ercan AB, Joksimovic L, Siddiqui I, Siddaway R, Edwards M, de Borja R, Elshaer D, Chung J, Forster VJ, Nunes NM, Aronson M, Wang X, Ramdas J, Seeley A, Sarosiek T, Dunn GP, Byrd JN, Mordechai O, Durno C, Martin A, Shlien A, Bouffet E, Suo Z, Jackson JG, Hawkins CE, Guidos CJ, Pursell ZF, and Tabori U

Subjects
Animals, Humans, Immune Checkpoint Inhibitors, Mice, Mutation, Poly-ADP-Ribose Binding Proteins genetics, DNA Polymerase II genetics, Neoplasms genetics
Abstract

POLE mutations are a major cause of hypermutant cancers, yet questions remain regarding mechanisms of tumorigenesis, genotype-phenotype correlation, and therapeutic considerations. In this study, we establish mouse models harboring cancer-associated POLE mutations P286R and S459F, which cause rapid albeit distinct time to cancer initiation in vivo , independent of their exonuclease activity. Mouse and human correlates enabled novel stratification of POLE mutations into three groups based on clinical phenotype and mutagenicity. Cancers driven by these mutations displayed striking resemblance to the human ultrahypermutation and specific signatures. Furthermore, Pole -driven cancers exhibited a continuous and stochastic mutagenesis mechanism, resulting in intertumoral and intratumoral heterogeneity. Checkpoint blockade did not prevent Pole lymphomas, but rather likely promoted lymphomagenesis as observed in humans. These observations provide insights into the carcinogenesis of POLE -driven tumors and valuable information for genetic counseling, surveillance, and immunotherapy for patients. SIGNIFICANCE: Two mouse models of polymerase exonuclease deficiency shed light on mechanisms of mutation accumulation and considerations for immunotherapy. See related commentary by Wisdom and Kirsch p. 5459 ., (©2020 American Association for Cancer Research.)

Published
2020
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16. Ongoing issues with the management of children with Constitutional Mismatch Repair Deficiency syndrome.

Author

Farah RA, Maalouf F, Chahine NA, Farhat H, Campbell B, Zhukova N, Durno C, Aronson M, Hawkins C, Bouffet E, and Tabori U

Subjects
Brain Neoplasms complications, Brain Neoplasms genetics, Brain Neoplasms pathology, Colorectal Neoplasms complications, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, Consanguinity, Female, Humans, Male, Mutation, Neoplasms complications, Neoplasms genetics, Neoplasms pathology, Neoplastic Syndromes, Hereditary complications, Neoplastic Syndromes, Hereditary genetics, Neoplastic Syndromes, Hereditary pathology, Pedigree, Precancerous Conditions complications, Precancerous Conditions genetics, Precancerous Conditions pathology, Brain Neoplasms therapy, Colorectal Neoplasms therapy, Genetic Testing, Neoplasms therapy, Neoplastic Syndromes, Hereditary therapy, Precancerous Conditions therapy
Abstract

Constitutional Mismatch Repair Deficiency (CMMRD) is a rare cancer predisposition syndrome, presenting in childhood, in which affected patients develop various malignancies such as hematological, gastrointestinal and central nervous system tumors. Although guidelines are being increasingly developed for surveillance and early detection of cancers in affected families, there are no clear recommendations regarding choice of therapy and very scarce information about tolerance to chemotherapy and radiation in these patients. We report the pedigree of a consanguineous family with four affected children. Although clinical and molecular tests confirm CMMRD, genetic testing revealed heterogeneous mutations. The index case developed severe toxicity from therapy for glioblastoma and T-cell leukemia and died from an infection while in complete remission. His sister developed a malignant brain tumor while undergoing surveillance for a low grade brain lesion and is still undergoing follow-up. This family illustrates the difficulties and opportunities with challenging diagnosis, surveillance and choice of therapy for children with CMMRD and the need for increased awareness and more information about this rare but important syndrome., (Copyright © 2019. Published by Elsevier Masson SAS.)

Published
2019
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17. Role of video capsule endoscopy in patients with constitutional mismatch repair deficiency (CMMRD) syndrome: report from the International CMMRD Consortium.

Author

Shimamura Y, Walsh CM, Cohen S, Aronson M, Tabori U, Kortan PP, and Durno CA

Abstract

Background and Study Aims: Constitutional mismatch repair deficiency (CMMRD) syndrome, also known as biallelic mismatch repair deficiency (BMMRD) syndrome is a rare autosomal-recessive genetic disorder that has a high mortality due to malignancy in childhood and early adulthood. The small bowel phenotype in CMMRD is not well described and surveillance protocols for small bowel cancer have not been well established. This study was conducted to evaluate the usefulness and clinical impact of video capsule endoscopy (VCE) for small bowel surveillance., Patients and Methods: We retrospectively reviewed the prospectively maintained International CMMRD Consortium database. Treating physicians were contacted and VCE report data were extracted using a standardized template., Results: Among 58 patients included in the database, 38 VCE reports were collected from 17 patients. Polypoid lesions were first detected on VCE at a median age of 14 years (range: 4 - 17). Of these, 39 % in 7 patients (15/38) showed large polypoid lesions (> 10 mm) or multiple polyps that prompted further investigations. Consequently, three patients were diagnosed with small bowel neoplasia including one patient with adenocarcinoma. Small bowel neoplasia and/or cancer were confirmed histologically in 35 % of the patients (6/17) who had capsule surveillance and the lesions in half of these patients were initially visualized on VCE. Multiple polyps were identified on eight VCEs that were completed on three patients. Ten VCEs (28 %) were incomplete due to slow bowel transit; none required capsule removal., Conclusions: Small bowel surveillance in patients with CMMRD should be initiated early in life. VCE has the potential to detect polyps; however, small bowel neoplasias are often proximal and can be missed, emphasizing the importance of concurrent surveillance with other modalities., Meeting Presentations:  Digestive Disease Week 2017 and World Congress of Pediatric Gastroenterology, Hepatology and Nutrition 2016.

Published
2018
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18. Comprehensive Analysis of Hypermutation in Human Cancer.

Author

Campbell BB, Light N, Fabrizio D, Zatzman M, Fuligni F, de Borja R, Davidson S, Edwards M, Elvin JA, Hodel KP, Zahurancik WJ, Suo Z, Lipman T, Wimmer K, Kratz CP, Bowers DC, Laetsch TW, Dunn GP, Johanns TM, Grimmer MR, Smirnov IV, Larouche V, Samuel D, Bronsema A, Osborn M, Stearns D, Raman P, Cole KA, Storm PB, Yalon M, Opocher E, Mason G, Thomas GA, Sabel M, George B, Ziegler DS, Lindhorst S, Issai VM, Constantini S, Toledano H, Elhasid R, Farah R, Dvir R, Dirks P, Huang A, Galati MA, Chung J, Ramaswamy V, Irwin MS, Aronson M, Durno C, Taylor MD, Rechavi G, Maris JM, Bouffet E, Hawkins C, Costello JF, Meyn MS, Pursell ZF, Malkin D, Tabori U, and Shlien A

Subjects
Adult, Child, Cluster Analysis, DNA Polymerase II genetics, DNA Polymerase III genetics, DNA Replication, Humans, Mutation, Neoplasms classification, Neoplasms pathology, Neoplasms therapy, Poly-ADP-Ribose Binding Proteins genetics, Neoplasms genetics
Abstract

We present an extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors' tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Published
2017
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19. Recommendations on Surveillance and Management of Biallelic Mismatch Repair Deficiency (BMMRD) Syndrome: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer.

Author

Durno C, Boland CR, Cohen S, Dominitz JA, Giardiello FM, Johnson DA, Kaltenbach T, Levin TR, Lieberman D, Robertson DJ, and Rex DK

Subjects
Alleles, Brain Neoplasms genetics, Colorectal Neoplasms genetics, Endometrial Neoplasms genetics, Female, Genetic Counseling, Humans, Liver Neoplasms genetics, Neoplastic Syndromes, Hereditary genetics, Urologic Neoplasms genetics, Brain Neoplasms diagnosis, Brain Neoplasms therapy, Colorectal Neoplasms diagnosis, Colorectal Neoplasms therapy, Endometrial Neoplasms diagnosis, Liver Neoplasms diagnosis, Neoplastic Syndromes, Hereditary diagnosis, Neoplastic Syndromes, Hereditary therapy, Population Surveillance, Urologic Neoplasms diagnosis
Abstract

The US Multi-Society Task Force on Colorectal Cancer, with invited experts, developed a consensus statement and recommendations to assist health care providers with appropriate management of patients with biallelic mismatch repair deficiency (BMMRD) syndrome, also called constitutional mismatch repair deficiency syndrome. This position paper outlines what is known about BMMRD, the unique genetic and clinical aspects of the disease, and reviews the current management approaches to this disorder. This article represents a starting point from which diagnostic and management decisions can undergo rigorous testing for efficacy. There is a lack of strong evidence and a requirement for further research. Nevertheless, providers need direction on how to recognize and care for BMMRD patients today. In addition to identifying areas of research, this article provides guidance for surveillance and management. The major challenge is that BMMRD is rare, limiting the ability to accumulate unbiased data and develop controlled prospective trials. The formation of effective international consortia that collaborate and share data is proposed to accelerate our understanding of this disease., (Copyright © 2017 AGA Institute, The American College of Gastroenterology, the American Society for Gastrointestinal Endoscopy, and European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology. Published by Elsevier Inc. All rights reserved.)

Published
2017
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20. Unifying diagnosis for adenomatous polyps, café-au-lait macules, and a brain mass?

Author

Durno C, Pollett A, and Gallinger S

Subjects
Adaptor Proteins, Signal Transducing genetics, Adolescent, Female, Humans, MutL Protein Homolog 1, Mutation, Missense genetics, Nuclear Proteins genetics, Adenomatous Polyps genetics, Astrocytoma genetics, Brain Neoplasms genetics, Cafe-au-Lait Spots genetics, Colonic Neoplasms genetics, Colorectal Neoplasms, Hereditary Nonpolyposis diagnosis, Colorectal Neoplasms, Hereditary Nonpolyposis genetics
Published
2013
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21. Does early colectomy increase desmoid risk in familial adenomatous polyposis?

Author

Durno C, Monga N, Bapat B, Berk T, Cohen Z, and Gallinger S

Subjects
Abdominal Neoplasms epidemiology, Abdominal Neoplasms genetics, Adenomatous Polyposis Coli diagnosis, Adenomatous Polyposis Coli genetics, Adolescent, Adult, Age Factors, Aged, Confidence Intervals, Endoscopy, Gastrointestinal, Female, Fibromatosis, Aggressive diagnosis, Fibromatosis, Aggressive epidemiology, Follow-Up Studies, Genes, APC physiology, Humans, Male, Middle Aged, Mutation, Ontario epidemiology, Prevalence, Prognosis, Retrospective Studies, Risk Factors, Sex Factors, Survival Rate, Time Factors, Abdominal Neoplasms etiology, Adenomatous Polyposis Coli surgery, Colectomy adverse effects, Fibromatosis, Aggressive etiology
Abstract

Background & Aims: Desmoid tumors are non-metastasizing fibromatoses that occur in 10%-20% of subjects with familial adenomatous polyposis (FAP). Intra-abdominal desmoid tumors are a major cause of mortality in FAP. FAP-associated desmoid tumors are linked to trauma, particularly abdominal surgery, family history of desmoids, hormonal factors, and the location of the APC mutation. We hypothesized that prophylactic colectomy at an early age might increase the risk of developing desmoids. The aim of this study was to determine whether colectomy earlier in life is a risk factor for the development of desmoid tumors., Methods: An analysis was made of the association between development of desmoid and age at colectomy, family history of desmoids, gender, and APC mutation in FAP patients in the Registry (1980-2005) at Mount Sinai Hospital, Toronto, Ontario, Canada., Results: FAP patients (n = 930) from 365 kindreds were identified. Desmoid prevalence was 14% (n = 121). Female patients were more likely to develop desmoids than male patients (17% vs 11%, P = .03). Female patients who had an early colectomy were more than 2 times more likely to develop a desmoid, compared with women who had a colectomy at >18 years (P = .01). Early colectomy did not increase risk of developing a desmoid in male patients (P = .42). Female patients who had an early colectomy (

Published
2007
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22. Colonic polyps in children and adolescents.

Author

Durno CA

Subjects
Adenomatous Polyposis Coli genetics, Adenomatous Polyposis Coli pathology, Adolescent, Child, DNA Glycosylases genetics, Genes, APC, Genetic Counseling, Genetic Predisposition to Disease, Genetic Testing, Humans, Mutation, Colonic Polyps genetics, Colonic Polyps pathology
Abstract

Colonic polyps most commonly present with rectal bleeding in children. The isolated juvenile polyp is the most frequent kind of polyp identified in children. 'Juvenile' refers to the histological type of polyp and not the age of onset of the polyp. Adolescents and adults with multiple juvenile polyps are at a significant risk of intestinal cancer. The challenge for adult and pediatric gastroenterologists is determining the precise risk of colorectal cancer in patients with juvenile polyposis syndrome. Attenuated familial adenamatous polyposis (AFAP) can occur either by a mutation at the extreme ends of the adenomatous polyposis coli gene or by biallelic mutations in the mutY homologue (MYH) gene. The identification of MYH-associated polyposis as an autosomal recessive condition has important implications for screening and management strategies. Adult and pediatric gastroenterologists need to be aware of the underlying inheritance patterns of polyposis syndromes so that patients and their families can be adequately evaluated and managed. Colonic polyps, including isolated juvenile polyps, juvenile polyposis syndrome, FAP, AFAP and MYH-associated polyposis, are discussed in the present review.

Published
2007
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23. Genotype and phenotype correlations in patients with cystic fibrosis and pancreatitis.

Author

Durno C, Corey M, Zielenski J, Tullis E, Tsui LC, and Durie P

Subjects
Adult, Alleles, Cohort Studies, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Databases, Factual, Female, Genotype, Humans, Male, Middle Aged, Mutation physiology, Pancreatitis diagnosis, Pancreatitis physiopathology, Phenotype, Prevalence, Prospective Studies, Cystic Fibrosis complications, Cystic Fibrosis genetics, Pancreatitis etiology, Pancreatitis genetics
Abstract

Background & Aims: Pancreatitis is known to occur in some patients with cystic fibrosis (CF), but the prevalence, natural history, and genotypic basis are unclear. We examined a well-defined cohort of patients with CF to answer these questions., Methods: Patients with CF were identified from a computerized database (1966-1996). Chart audit identified all patients with CF and pancreatitis., Results: Among 1075 patients with CF, 937 (87%) were pancreatic insufficient at diagnosis, 28 (3%) were pancreatic sufficient but developed pancreatic insufficiency after diagnosis, and 110 (10%) have remained pancreatic sufficient. No patients with pancreatic insufficiency developed pancreatitis. Nineteen patients (17.3%) with pancreatic sufficiency experienced one or more attacks of pancreatitis. The mean age at diagnosis of pancreatitis was 22.7 +/- 10.3 years (range, 10-35 years), and pancreatitis was recognized before the diagnosis of CF in 6 patients (32%). The diagnosis of CF in pancreatic-sufficient patients, with and without pancreatitis, was established at a significantly older age than in those with pancreatic insufficiency (P < 0.0001). Genotyped patients with pancreatic insufficiency carried 2 severe mutant alleles. All genotyped patients with pancreatic sufficiency and pancreatitis carried at least one mild mutation. No specific genotype was predictive of pancreatitis., Conclusions: Patients with CF with pancreatic sufficiency carry at least one mild mutant allele and are at a significant risk of developing pancreatitis. Symptoms of pancreatitis may precede the diagnosis of CF. Pancreatitis is associated with an otherwise mild CF phenotype.

Published
2002
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24. Keeping an eye on Crohn's disease: orbital myositis as the presenting symptom.

Author

Durno CA, Ehrlich R, Taylor R, Buncic JR, Hughes P, and Griffiths AM

Subjects
Autoimmune Diseases complications, Autoimmune Diseases diagnosis, Child, Crohn Disease diagnosis, Female, Humans, Myositis diagnosis, Orbital Diseases diagnosis, Crohn Disease complications, Myositis complications, Orbital Diseases complications
Abstract

Episodic periorbital swelling due to presumed orbital inflammation and myositis caused intermittent apparent proptosis and was the presenting symptom of ileocecal Crohn's disease (CD) in a teenage female with a family history of autoimmune disorders and CD. Orbital myositis, a very rare extraintestinal manifestation of inflammatory bowel disease (IBD), likely represents a process of impaired immunoregulation related to the underlying intestinal inflammation. This rare manifestation of IBD simulates the more commonly encountered thyroid orbitopathy (ophthalmopathy), but IBD should be considered if all thyroid tests are negative. It is important to recognize that orbital myositis may be an extraintestinal manifestation of Crohn's disease so that the diagnosis can be made and appropriate therapy commenced.

Published
1997
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