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Review
. 2021 Apr 28;22(9):4629.
doi: 10.3390/ijms22094629.

The Challenge of Diagnosing Constitutional Mismatch Repair Deficiency Syndrome in Brain Malignancies from Young Individuals

Cristina Carrato  1 , Carolina Sanz  1 , Ana María Muñoz-Mármol  1 , Ignacio Blanco  2 , Marta Pineda  3   4 , Jesús Del Valle  3   4 , Estela Dámaso  3 , Manel Esteller  4   5   6   7 , Eva Musulen  1   5   8
Affiliations
Review

The Challenge of Diagnosing Constitutional Mismatch Repair Deficiency Syndrome in Brain Malignancies from Young Individuals

Cristina Carrato et al. Int J Mol Sci. .

Abstract

Biallelic germline mismatch repair (MMR) gene (MLH1, MSH2, MSH6, and PMS2) mutations are an extremely rare event that causes constitutional mismatch repair deficiency (CMMRD) syndrome. CMMRD is underdiagnosed and often debuts with pediatric malignant brain tumors. A high degree of clinical awareness of the CMMRD phenotype is needed to identify new cases. Immunohistochemical (IHC) assessment of MMR protein expression and analysis of microsatellite instability (MSI) are the first tools with which to initiate the study of this syndrome in solid malignancies. MMR IHC shows a hallmark pattern with absence of staining in both neoplastic and non-neoplastic cells for the biallelic mutated gene. However, MSI often fails in brain malignancies. The aim of this report is to draw attention to the peculiar IHC profile that characterizes CMMRD syndrome and to review the difficulties in reaching an accurate diagnosis by describing the case of two siblings with biallelic MSH6 germline mutations and brain tumors. Given the difficulties involved in early diagnosis of CMMRD we propose the use of the IHC of MMR proteins in all malignant brain tumors diagnosed in individuals younger than 25 years-old to facilitate the diagnosis of CMMRD and to select those neoplasms that will benefit from immunotherapy treatment.

Keywords: MMR gene expression; MSH6 gene; constitutional mismatch repair deficiency syndrome; immunohistochemistry.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Pedigree of the family with biallelic MSH6 mutations. The arrow indicates the proband. Filled symbols indicate affected subject; open symbols unaffected subjects. The age at tumor onset is shown with the tumor type. +/− = MSH6 monoallelic mutation carrier (Lynch syndrome); +/+ = MSH6 biallelic mutation carrier (CMMRD).
Figure 2
Figure 2
MMR protein IHC in brain tumors. (a) Glioblastoma cells and normal brain tissue (*) retained the expression of MLH1, PMS2, and MSH2 proteins. MSH6 staining is lost in both tumor cells and normal tissue (*). (b) In malignant astrocytoma, neoplastic, stromal, and endothelial cells are immunoreactive to anti-MLH1 (*), anti-PMS2, and anti-MSH2 antibodies. In contrast, the lack of MSH6 staining is observed in all cells (*). Scale bar: 100 µm.
Figure 3
Figure 3
Electropherograms showing microsatellite profiles of five mononucleotide repeats markers (NR21, NR24, NR27, BAT25, and BAT26) in each tumor. A broader spectrum is observed in marker NR27 in the malignant astrocytoma.
See this image and copyright information in PMC

References

    1. Ricciardone M.D., Ozçelik T., Cevher B., Ozdağ H., Tuncer M., Gürgey A., Uzunalimoğlu O., Cetinkaya H., Tanyeli A., Erken E., et al. Human MLH1 deficiency predispones to hematological malignancy and neurofibromatosis type 1. Cancer Res. 1999;59:290–293. - PubMed
    1. Wang Q., Lasset C., Desseigne F., Frappaz D., Bergeron C., Navarro C., Ruano E., Puisieux A. Neurofibromatosis and early onset of cancers in hMLH1-deficient children. Cancer Res. 1999;59:294–297. - PubMed
    1. Wimmer K., Kratz C.P., Vasen H.F., Caron O., Colas C., Entz-Werle N., Gerdes A.M., Goldberg Y., Ilencikova I., Muleris M., et al. EU-consortium care for CMMRD (C4CMMRD). Diagnostic criteria for constitutional mismatch repair deficiency syndrome: Suggestions of the European consortium ‘care for CMMRD’ (C4CMMRD) J. Med. Genet. 2014;51:355–365. doi: 10.1136/jmedgenet-2014-102284. - DOI - PubMed
    1. Aronson M., Colas C., Shuen A., Hampel H., Foulkes W.D., Feldman H.B., Goldberg Y., Muleris M., Schneider K.W., McGee R.B., et al. Diagnostic criteria for constitutional mismatch repair deficiency (CMMRD): Recommendations from the international consensus working group. J. Med. Genet. 2021:2020–107627. doi: 10.1136/jmedgenet-2020-107627. - DOI - PubMed
    1. Wang Q., Montmain G., Ruano E., Upadhyaya M., Dudley S., Liskay R.M., Thibodeau S.N., Puisieux A. Neurofibromatosis type 1 gene as a mutational target in a mismatch repair-deficient cell type. Hum. Genet. 2003;112:117–123. doi: 10.1007/s00439-002-0858-4. - DOI - PubMed

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