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. 2019 Dec 2;1(1):vdz033.
doi: 10.1093/noajnl/vdz033. eCollection 2019 May-Dec.

Constitutional mismatch repair deficiency-associated brain tumors: report from the European C4CMMRD consortium

Léa Guerrini-Rousseau  1   2 , Pascale Varlet  3 , Chrystelle Colas  4 , Felipe Andreiuolo  3 , Franck Bourdeaut  5 , Karin Dahan  6 , Christine Devalck  7 , Cécile Faure-Conter  8 , Maurizio Genuardi  9   10 , Yael Goldberg  11 , Michaela Kuhlen  12 , Salma Moalla  13 , Enrico Opocher  14 , Vanessa Perez-Alonso  15 , Astrid Sehested  16 , Irene Slavc  17 , Sheila Unger  18 , Katharina Wimmer  19 , Jacques Grill  1   2 , Laurence Brugières  1
Affiliations

Constitutional mismatch repair deficiency-associated brain tumors: report from the European C4CMMRD consortium

Léa Guerrini-Rousseau et al. Neurooncol Adv. .

Abstract

Background: Malignant brain tumors (BT) are among the cancers most frequently associated with constitutional mismatch repair deficiency (CMMRD), a rare childhood cancer predisposition syndrome resulting from biallelic germline mutations in mismatch repair genes. This study analyzed data from the European "Care for CMMRD" (C4CMMRD) database to describe their clinical characteristics, treatments, and outcome with the aim of improving its diagnosis/treatment.

Methods: Retrospective analysis of data on patients with CMMRD and malignant BT from the C4CMMRD database up to July 2017.

Results: Among the 87 registered patients, 49 developed 56 malignant BTs: 50 high-grade gliomas (HGG) (with giant multinucleated cells in 16/21 histologically reviewed tumors) and 6 embryonal tumors. The median age at first BT was 9.2 years [1.1-40.6], with nine patients older than 18. Twenty-seven patients developed multiple malignancies (including16 before the BT). Most patients received standard treatment, and eight patients immunotherapy for relapsed HGG. The 3- and 5-year overall survival (OS) rates were 30% (95% CI: 19-45) and 22% (95% CI: 12-37) after the first BT, with worse prognosis for HGG (3-year OS = 20.5%). Six patients were alive (median follow-up 2.5 years) and 43 dead (38 deaths, 88%, were BT-related). Other CMMRD-specific features were café-au-lait macules (40/41), multiple BTs (5/15), developmental brain anomalies (11/15), and consanguinity (20/38 families).

Conclusions: Several characteristics could help suspecting CMMRD in pediatric malignant BTs: giant cells on histology, previous malignancies, parental consanguinity, café-au-lait macules, multiple BTs, and developmental brain anomalies. The prognosis of CMMRD-associated BT treated with standard therapies is poor requiring new therapeutic up-front approaches.

Keywords: MMR biallelic germline mutation; brain tumor; café-au-lait spot; childhood cancer; constitutional mismatch repair deficiency; high-grade glioma; predisposition.

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Figures

Figure 1.
Figure 1.
Images of a giant cell glioblastoma (A) and a glioblastoma with few giant multinucleated cells (B). Tumor sections were stained with HES (scale 100μm).
Figure 2.
Figure 2.
Brain developmental vascular anomalies and multiple tumor lesions in patients with CMMRD. Brain MRI images from three patients 1) MIP images (a and b) and axial T1 slices with gadolinium (c) showing the arteriovenous abnormality in the right cerebellar lobe, connected with the initial part of the right sinus; 2) MIP images (d) showing the left temporal arteriovenous malformation, with an aspect of “jellyfish head,” associated with an arterial aneurysms; and 3) Axial T1 slice with gadolinium (e) showing the presence of multiple tumor lesions.
Figure 3.
Figure 3.
Outcome of patients with constitutional mismatch repair deficiency (CMMRD) and brain tumor from the C4CMMRD database (n = 49 patients). The median interval between subsequent malignancies was 2.7 years (cancer 1 and cancer 2), 2.9 years (cancer 2 and cancer 3), 1 year (cancer 3 and cancer 4), and 0.9 years (cancer 4 and cancer 5).
Figure 4.
Figure 4.
Overall survival (OS) after the first brain tumor (BT) (A), and after the first tumor (any tumor: n = 49 patients; BT as first tumor: n =33; not BT as first tumor: n = 16 patients) (B).
See this image and copyright information in PMC

References

    1. Kunkel TA, Erie DA. DNA mismatch repair. Annu Rev Biochem. 2005;74:681–710. - PubMed
    1. Lynch HT, Lynch PM, Lanspa SJ, et al. Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet. 2009;76(1):1–18. - PMC - PubMed
    1. Wang Q, Lasset C, Desseigne F, et al. Neurofibromatosis and early onset of cancers in hMLH1-deficient children. Cancer Res. 1999;59(2): 294–297. - PubMed
    1. Ricciardone MD, Ozçelik T, Cevher B, et al. Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1. Cancer Res. 1999;59(2):290–293. - PubMed
    1. Wimmer K, Kratz CP, Vasen HFA, et al. Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium “care for CMMRD” (C4CMMRD). J Med Genet. 2014;51(6):355–365. - PubMed

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