Constitutional mismatch repair deficiency

Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors.

Durno et al. designed a surveillance protocol for early tumor detection in these individuals.

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.

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.

Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD ¹⁾.

2: Suwala AK, Stichel D, Schrimpf D, Kloor M, Wefers AK, Reinhardt A, Maas SLN, Kratz CP, Schweizer L, Hasselblatt M, Snuderl M, Abedalthagafi MSJ, Abdullaev Z, Monoranu CM, Bergmann M, Pekrun A, Freyschlag C, Aronica E, Kramm CM, Hinz F, Sievers P, Korshunov A, Kool M, Pfister SM, Sturm D, Jones DTW, Wick W, Unterberg A, Hartmann C, Dodgshun A, Tabori U, Wesseling P, Sahm F, von Deimling A, Reuss DE. Primary mismatch repair deficient IDH-mutant astrocytoma (PMMRDIA) is a distinct type with a poor prognosis. Acta Neuropathol. 2021 Jan;141(1):85-100. doi: 10.1007/s00401-020-02243-6. Epub 2020 Nov 20. PMID: 33216206; PMCID: PMC7785563.

3: Citak EC, Sagcan F, Gundugan BD, Bozdogan ST, Yilmaz EB, Avci E, Balci Y, Karabulut YY. Metachronous Wilms Tumor, Glioblastoma, and T-cell Leukemia in an Child With Constitutional Mismatch Repair Deficiency syndrome due to Novel Mutation in MSH6 (c.2590G>T). J Pediatr Hematol Oncol. 2021 Mar 1;43(2):e198-e202. doi: 10.1097/MPH.0000000000001687. PMID: 31815888.

4: Shiran SI, Ben-Sira L, Elhasid R, Roth J, Tabori U, Yalon M, Constantini S, Dvir R. Multiple Brain Developmental Venous Anomalies as a Marker for Constitutional Mismatch Repair Deficiency Syndrome. AJNR Am J Neuroradiol. 2018 Oct;39(10):1943-1946. doi: 10.3174/ajnr.A5766. Epub 2018 Aug 30. PMID: 30166433; PMCID: PMC7410739.

5: Larouche V, Atkinson J, Albrecht S, Laframboise R, Jabado N, Tabori U, Bouffet E; international bMMRD consortium. Sustained complete response of Glioblastoma recurrence to combined checkpoint inhibition in a young patient with constitutional mismatch repair deficiency. Pediatr Blood Cancer. 2018 Dec;65(12):e27389. doi: 10.1002/pbc.27389. Epub 2018 Aug 29. PMID: 30160041.

6: Galuppini F, Opocher E, Tabori U, Mammi I, Edwards M, Campbell B, Kelly J, Viel A, Quaia M, Rivieri F, D'Avella D, Arcella A, Giangaspero F, Fassan M, Gardiman MP. Concomitant IDH-wildtype glioblastoma and IDH1-mutant anaplastic astrocytoma in a patient with constitutional mismatch repair deficiency syndrome. Neuropathol Appl Neurobiol. 2018 Feb;44(2):233-239. doi: 10.1111/nan.12450. PMID: 29130549.

7: Cheyuo C, Radwan W, Ahn J, Gyure K, Qaiser R, Tomboc P. Biallelic PMS2 Mutation and Heterozygous DICER1 Mutation Presenting as Constitutional Mismatch Repair Deficiency With Corpus Callosum Agenesis: Case Report and Review of Literature. J Pediatr Hematol Oncol. 2017 Oct;39(7):e381-e387. doi: 10.1097/MPH.0000000000000863. PMID: 28562508.

8: Bodo S, Colas C, Buhard O, Collura A, Tinat J, Lavoine N, Guilloux A, Chalastanis A, Lafitte P, Coulet F, Buisine MP, Ilencikova D, Ruiz-Ponte C, Kinzel M, Grandjouan S, Brems H, Lejeune S, Blanché H, Wang Q, Caron O, Cabaret O, Svrcek M, Vidaud D, Parfait B, Verloes A, Knappe UJ, Soubrier F, Mortemousque I, Leis A, Auclair-Perrossier J, Frébourg T, Fléjou JF, Entz-Werle N, Leclerc J, Malka D, Cohen-Haguenauer O, Goldberg Y, Gerdes AM, Fedhila F, Mathieu-Dramard M, Hamelin R, Wafaa B, Gauthier-Villars M, Bourdeaut F, Sheridan E, Vasen H, Brugières L, Wimmer K, Muleris M, Duval A; European Consortium “Care for CMMRD”. Diagnosis of Constitutional Mismatch Repair-Deficiency Syndrome Based on Microsatellite Instability and Lymphocyte Tolerance to Methylating Agents. Gastroenterology. 2015 Oct;149(4):1017-29.e3. doi: 10.1053/j.gastro.2015.06.013. Epub 2015 Jun 25. PMID: 26116798.

9: Daou B, Zanello M, Varlet P, Brugieres L, Jabbour P, Caron O, Lavoine N, Dhermain F, Willekens C, Beuvon F, Malka D, Lechapt-Zalcmann E, Abi Lahoud G. An Unusual Case of Constitutional Mismatch Repair Deficiency Syndrome With Anaplastic Ganglioglioma, Colonic Adenocarcinoma, Osteosarcoma, Acute Myeloid Leukemia, and Signs of Neurofibromatosis Type 1: Case Report. Neurosurgery. 2015 Jul;77(1):E145-52; discussion E152. doi: 10.1227/NEU.0000000000000754. PMID: 25850602.

10: Bakry D, Aronson M, Durno C, Rimawi H, Farah R, Alharbi QK, Alharbi M, Shamvil A, Ben-Shachar S, Mistry M, Constantini S, Dvir R, Qaddoumi I, Gallinger S, Lerner-Ellis J, Pollett A, Stephens D, Kelies S, Chao E, Malkin D, Bouffet E, Hawkins C, Tabori U. Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: report from the constitutional mismatch repair deficiency consortium. Eur J Cancer. 2014 Mar;50(5):987-96. doi: 10.1016/j.ejca.2013.12.005. Epub 2014 Jan 15. PMID: 24440087.

11: Yeung JT, Pollack IF, Shah S, Jaffe R, Nikiforova M, Jakacki RI. Optic pathway glioma as part of a constitutional mismatch-repair deficiency syndrome in a patient meeting the criteria for neurofibromatosis type 1. Pediatr Blood Cancer. 2013 Jan;60(1):137-9. doi: 10.1002/pbc.24254. Epub 2012 Jul 27. PMID: 22848017.

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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, Loret De Mola R, 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. Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance. J Clin Oncol. 2021 May 4:JCO2002636. doi: 10.1200/JCO.20.02636. Epub ahead of print. PMID: 33945292.