Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study.

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Ercan, Ayse BaharArthur & Sonia Labatt Brain Tumor Res Ctr, Canada (author)

Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study.

Article/chapterEnglish2024

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ELSEVIER SCIENCE INC,2024

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LIBRIS-ID:oai:gup.ub.gu.se/338586
https://gup.ub.gu.se/publication/338586URI
https://doi.org/10.1016/S1470-2045(24)00026-3DOI
https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-206756URI

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Language:English

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Notes

Funding Agencies|CIHR [PJT-156006]; CIHR Joint Canada-Israel Health Research Program [MOP-137899]; Stand Up to Cancer-Bristol Myers Squibb Catalyst Research grant [SU2C-AACR-CT07-17]; Children's Oncology Group National Cancer Institute Community Oncology Research Program Research Base Administrative Supplement Request [3UG1CA189955-08S2]; CCS/CIHR/BC Spark Grants (Novel Technology Applications in Cancer Prevention and Early Detection - Canadian Cancer Society) [SPARK-21, 707089]; V Foundation for Cancer Research [T2019-016]; BioCanRx [FY17/18/ES8]; Canada's Immunotherapy Network (a Network Centre of Excellence); CCS/CIHR/BC Spark Grants (Novel Technology Applications in Cancer Prevention and Early Detection - Brain Canada) [SPARK-21, 707089]; Meagan's Walk [MW-2014-10]; BRAINchild Canada; LivWise Foundation; Kai Slockers Pediatric Cancer Research Fund St Baldrick's International Scholar Grant [697257]; Stand Up to Cancer Maverick award; Hold'em for Life Oncology Fellowship Award; Garron Family Cancer Centre; Canadian Imperial Bank of Commerce Children's Foundation Chair in Child Health Research; Giant Pledge via the Royal Marsden Cancer Charity; Hall-Hunter Foundation; Ministry of Health of the Czech Republic [NU21-07-00419]
Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD.In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions.We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions.The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD.The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Pediatrik hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Pediatrics hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Cancer och onkologi hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Cancer and Oncology hsv//eng
Humans
Male
Female
Child
Child
Preschool
Neoplastic Syndromes
Hereditary
genetics
therapy
Cross-Sectional Studies
Adolescent
Brain Neoplasms
genetics
therapy
mortality
pathology
epidemiology
DNA Mismatch Repair
Longitudinal Studies
Colorectal Neoplasms
genetics
pathology
mortality
Incidence
MutS Homolog 2 Protein
genetics
MutL Protein Homolog 1
genetics
Adult
Young Adult
Mutation
DNA-Binding Proteins

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Aronson, MelyssaSinai Hlth Syst, Canada (author)
Fernandez, Nicholas RArthur & Sonia Labatt Brain Tumor Res Ctr, Canada,UCSF, CA USA (author)
Chang, YuanArthur & Sonia Labatt Brain Tumor Res Ctr, Canada (author)
Levine, AdrianHosp Sick Children, Canada (author)
Liu, Zhihui AmyUniv Hlth Network, Canada (author)
Negm, LogineArthur & Sonia Labatt Brain Tumor Res Ctr, Canada (author)
Edwards, MelissaArthur & Sonia Labatt Brain Tumor Res Ctr, Canada (author)
Bianchi, VanessaArthur & Sonia Labatt Brain Tumor Res Ctr, Canada (author)
Stengs, LucieArthur & Sonia Labatt Brain Tumor Res Ctr, Canada (author)
Chung, JiilArthur & Sonia Labatt Brain Tumor Res Ctr, Canada (author)
Al-Battashi, AbeerRoyal Hosp, Oman (author)
Reschke, AgnesStanford Med, CA USA (author)
Lion, AlexIndiana Univ Sch Med, IN USA (author)
Ahmad, AliaChildrens Hosp Lahore, Pakistan,Childrens Hosp Philadelphia, PA USA,SUNY Upstate, NY USA (author)
Lassaletta, AlvaroHosp Infantil Univ Nino Jesus, Spain (author)
Reddy, Alyssa TUniv Calif San Francisco, CA USA (author)
Al-Darraji, Amir FUniv Baghdad, Iraq (author)
Shah, Amish CChildrens Hosp Philadelphia, PA USA (author)
Van Damme, AnClin Univ St Luc, Belgium (author)
Bendel, AnneChildrens Minnesota, MN USA (author)
Rashid, AqeelaShaukat Khanum Mem Canc Hosp & Res Ctr, Pakistan (author)
Margol, Ashley SUniv Southern Calif, CA USA,Kokilaben Dhirubhai Ambani Hosp & Med Res Inst, India (author)
Kelly, Bethany LCHI St Joseph Hlth Canc Care, KY USA (author)
Pencheva, BojanaChildrens Healthcare Atlanta, GA USA (author)
Heald, BrandieCleveland Clin, OH USA (author)
Lemieux-Anglin, BriannaMcGill Univ, Canada (author)
Crooks, BruceIWK Hlth, Canada (author)
Koschmann, CarlUniv Michigan, MI USA (author)
Gilpin, CatherineChildrens Hosp Eastern Ontario, Canada (author)
Porter, Christopher CChildrens Healthcare Atlanta, GA USA (author)
Gass, DavidAtrium Hlth, NC USA (author)
Samuel, DavidValley Childrens Hosp, CA USA,Sydney Childrens Hosp, Australia (author)
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Basel, DonaldMed Coll Wisconsin, WI USA (author)
Khuong-Quang, Dong-AnhRoyal Childrens Hosp, Australia (author)
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Carceller, FernandoRoyal Marsden NHS Fdn Trust, England; Inst Canc Res, England (author)
Baris Feldman, HagitTel Aviv Sourasky Med Ctr, Israel; Tel Aviv Sourasky Med Ctr, Israel; Tel Aviv Univ, Israel (author)
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Fedorakova, IvanaUniv Childrens Hosp, Slovakia (author)
Su, Jack MBaylor Coll Med, TX USA,Oregon Hlth & Sci Univ, OR USA,Fdn IRCCS Ist Nazl Tumori, Italy (author)
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Sterba, JaroslavMasaryk Univ, Czech Republic; Kokilaben Dhirubhai Ambani Hosp & Med Res Inst, India (author)
Knipstein, JeffreyMed Coll Wisconsin, WI USA (author)
Hansford, Jordan RWomens & Childrens Hosp, Australia; South Australia Hlth & Med Res Inst Adelaide, Australia; Univ Adelaide, Australia (author)
Gonzales-Santos, Julieta RitaDe La Salle Med & Hlth Sci Inst, Philippines (author)
Bhatia, KanikaRoyal Childrens Hosp, Australia (author)
Bielamowicz, Kevin JUniv Arkansas Med Sci, AR USA (author)
Minhas, KhurramAga Khan Univ, Pakistan (author)
Nichols, Kim ESt Jude Childrens Res Hosp, TN USA (author)
Cole, Kristina A (author)
Penney, LynetteIWK Hlth Ctr, Canada (author)
Hjort, Magnus AasvedSt Olavs Univ Hosp, Norway (author)
Sabel, Magnus,1966Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för pediatrik,Institute of Clinical Sciences, Department of Pediatrics,Univ Gothenburg, Sweden(Swepub:gu)xsabma (author)
Gil-da-Costa, Maria JoaoUniv Hosp Sao Joao, Portugal (author)
Murray, Matthew JUniv Cambridge, England (author)
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Zapotocky, MichalCharles Univ Prague, Czech Republic (author)
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Pichurin, Pavel NMayo Clin, MN USA (author)
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Pearlman, RachelOhio State Univ, OH USA (author)
Auer, Rebecca COttawa Hosp, Canada (author)
Sukumaran, Reghu KTata Med Ctr, India (author)
Kebudi, RejinIstanbul Univ, Turkiye (author)
Dvir, RinaTel Aviv Sourasky Med Ctr, Israel (author)
Raphael, Robert (author)
Elhasid, RonitTel Aviv Med Ctr & Sch Med, Israel (author)
McGee, Rose BSt Jude Childrens Res Hosp, TN USA (author)
Chami, RoseHosp Sick Children, Canada (author)
Noss, RyanCleveland Clin, OH USA (author)
Tanaka, RyumaMed Coll Wisconsin, WI USA (author)
Raskin, SalmoUniv Fed Parana, Brazil (author)
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Lindhorst, ScottMed Univ South Carolina, SC USA (author)
Perreault, SebastienUniv Montreal, Canada (author)
Caspi, ShaniSheba Med Ctr, Israel (author)
Riaz, ShaziaChildrens Hosp, Pakistan; Univ Child Hlth Sci, Pakistan (author)
Constantini, ShlomiTel Aviv Sourasky Med Ctr, Israel (author)
Albert, SophieJewish Gen Hosp, Canada (author)
Chaleff, StanleyMaine Childrens Canc Program, ME USA (author)
Bielack, StefanOlga Hosp, Germany (author)
Chiaravalli, StefanoFdn IRCCS Ist Nazl Tumori, Italy (author)
Cramer, Stuart LouisPrisma Hlth, SC USA (author)
Roy, SumitaCent Michigan Univ, MI USA; Childrens Hosp Michigan, MI USA (author)
Cahn, SuzanneEmory Univ Hosp, GA USA (author)
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Hamid, Syed AhmerInd Hosp & Hlth Network, Pakistan (author)
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Imam, UzmaNatl Inst Child Hlth, Pakistan (author)
Larouche, ValerieCHU Quebec Univ Laval, Canada (author)
Magimairajan Issai, VananCancerCare Manitoba, Canada (author)
Foulkes, William DMcGill Univ, Canada (author)
Lee, Yi YenTaipei Vet Gen Hosp, Taiwan (author)
Nathan, Paul CHosp Sick Children, Canada (author)
Maruvka, Yosef ETECHNION Israel Inst Technol, Israel (author)
Greer, Mary-Louise C (author)
Durno, CarolHosp Sick Children, Canada (author)
Shlien, AdamHosp Sick Children, Canada (author)
Ertl-Wagner, BirgitHosp Sick Children, Canada; Univ Toronto, Canada (author)
Villani, AnitaHosp Sick Children, Canada (author)
Malkin, DavidHosp Sick Children, Canada (author)
Hawkins, CynthiaHosp Sick Children, Canada (author)
Bouffet, EricHosp Sick Children, Canada (author)
Das, AnirbanArthur & Sonia Labatt Brain Tumor Res Ctr, Canada; Hosp Sick Children, Canada (author)
Tabori, UriArthur & Sonia Labatt Brain Tumor Res Ctr, Canada; Hosp Sick Children, Canada (author)
Arthur & Sonia Labatt Brain Tumor Res Ctr, CanadaSinai Hlth Syst, Canada (creator_code:org_t)

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In:The Lancet Oncology: ELSEVIER SCIENCE INC25:5, s. 668-6821470-20451474-5488

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By the author/editor: Ercan, Ayse Baha ...; Aronson, Melyssa; Fernandez, Nicho ...; Chang, Yuan; Levine, Adrian; Liu, Zhihui Amy; show more...; Negm, Logine; Edwards, Melissa; Bianchi, Vanessa; Stengs, Lucie; Chung, Jiil; Al-Battashi, Abe ...; Reschke, Agnes; Lion, Alex; Ahmad, Alia; Lassaletta, Alva ...; Reddy, Alyssa T; Al-Darraji, Amir ...; Shah, Amish C; Van Damme, An; Bendel, Anne; Rashid, Aqeela; Margol, Ashley S; Kelly, Bethany L; Pencheva, Bojana; Heald, Brandie; Lemieux-Anglin, ...; Crooks, Bruce; Koschmann, Carl; Gilpin, Catherin ...; Porter, Christop ...; Gass, David; Samuel, David; Ziegler, David S; Blumenthal, Debo ...; Kuo, Dennis John; Hamideh, Dima; Basel, Donald; Khuong-Quang, Do ...; Stearns, Duncan; Opocher, Enrico; Carceller, Ferna ...; Baris Feldman, H ...; Toledano, Helen; Winer, Ira; Scheers, Isabell ...; Fedorakova, Ivan ...; Su, Jack M; Vengoechea, Jaim ...; Sterba, Jaroslav; Knipstein, Jeffr ...; Hansford, Jordan ...; Gonzales-Santos, ...; Bhatia, Kanika; Bielamowicz, Kev ...; Minhas, Khurram; Nichols, Kim E; Cole, Kristina A; Penney, Lynette; Hjort, Magnus Aa ...; Sabel, Magnus, 1 ...; Gil-da-Costa, Ma ...; Murray, Matthew ...; Miller, Matthew; Blundell, Maude ...; Massimino, Maura; Al-Hussaini, May ...; Al-Jadiry, Mazin ...; Comito, Melanie ...; Osborn, Michael; Link, Michael P; Zapotocky, Micha ...; Ghalibafian, Mit ...; Shaheen, Najma; Mushtaq, Naureen; Waespe, Nicolas; Hijiya, Nobuko; Fuentes-Bolanos, ...; Ahmad, Olfat; Chamdine, Omar; Roy, Paromita; Pichurin, Pavel ...; Nyman, Per; Pearlman, Rachel; Auer, Rebecca C; Sukumaran, Reghu ...; Kebudi, Rejin; Dvir, Rina; Raphael, Robert; Elhasid, Ronit; McGee, Rose B; Chami, Rose; Noss, Ryan; Tanaka, Ryuma; Raskin, Salmo; Sen, Santanu; Lindhorst, Scott; Perreault, Sebas ...; Caspi, Shani; Riaz, Shazia; Constantini, Shl ...; Albert, Sophie; Chaleff, Stanley; Bielack, Stefan; Chiaravalli, Ste ...; Cramer, Stuart L ...; Roy, Sumita; Cahn, Suzanne; Penna, Suzanne; Hamid, Syed Ahme ...; Ghafoor, Tariq; Imam, Uzma; Larouche, Valeri ...; Magimairajan Iss ...; Foulkes, William ...; Lee, Yi Yen; Nathan, Paul C; Maruvka, Yosef E; Greer, Mary-Loui ...; Durno, Carol; Shlien, Adam; Ertl-Wagner, Bir ...; Villani, Anita; Malkin, David; Hawkins, Cynthia; Bouffet, Eric; Das, Anirban; Tabori, Uri; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Pediatrics

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Cancer and Oncol ...

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