Top

30-04-2024 | Colorectal Cancer | Original Article

Strategies for diagnosis and management of CMMRD in low-resource countries: report of a Tunisian family

Authors: Rania Abdelmaksoud-Dammak, Nihel Ammous-Boukhris, Dorra BenAyed-Guerfali, Yassine Gdoura, Imen Boujelben, Souhir Guidara, Slim Charfi, Wiem Boudabbous, Saloua Ammar, Wiem Rhaiem, Mohamed Zaher Boudawara, Hassen Kamoun, Tahya Sallemi-Boudawara, Riadh Mhiri, Raja Mokdad-Gargouri

Published in: Familial Cancer

Abstract

Constitutional Mismatch Repair Deficiency (CMMRD) is a rare childhood cancer predisposition syndrome, caused by biallelic pathogenic germline variants in the mismatch repair genes. Diagnosis and management of this syndrome is challenging, especially in low-resource settings. This study describes a patient diagnosed with colorectal cancer and grade 3 astrocytoma at the age of 11 and 12 respectively. Immunohistochemistry analysis showed a loss of MSH2 and MSH6 protein expression in CRC tissues of the patient. We identified by Targeted Exome Sequencing a homozygous pathogenic germline variant in exon 9 of the MSH6 gene (c.3991 C > T; p.Ala1268Glyfs*6). Genetic investigation of the family showed that the father was heterozygous for the identified pathogenic variant while the brother was wild type for this variant. Our study highlights the importance of a correct and timely diagnosis of CMMRD which can have implications for treatment. It also underlines the imperative need to enhance awareness, diagnostic standards, and surveillance that are crucial for patients and their families.

Peltomäki P (2003) Role of DNA mismatch repair defects in the pathogenesis of human cancer. J Clin Oncol 21(6):1174–1179. https://doi.org/10.1200/JCO.2003.04.060CrossRefPubMed

Lynch HT, de la Chapelle A (2003) Hereditary colorectal cancer. N Engl J Med 348:919–932. https://doi.org/10.1056/NEJMra012242CrossRefPubMed

Win AK, Jenkins MA, Dowty JG, Antoniou AC, Lee A, Giles GG et al (2017) Prevalence and penetrance of major genes and polygenes for Colorectal Cancer. Cancer Epidemiol Biomarkers Prev 26(3):404–412. https://doi.org/10.1158/1055-9965.EPI-16-0693CrossRefPubMed

Abedalthagafi M (2018) Constitutional mismatch repair-deficiency: current problems and emerging therapeutic strategies. Oncotarget 9(83):35458–35469. https://doi.org/10.18632/oncotarget.26249CrossRefPubMedPubMedCentral

Wimmer K, Etzler J (2008) Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg? Hum Genet 124(2):105–122. https://doi.org/10.1007/s00439-008-0542-4CrossRefPubMed

Wimmer K, Kratz CP, Vasen HF, Caron O, Colas C, Entz-Werle N et al (2014) 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 51(6):355–365. https://doi.org/10.1136/jmedgenet-2014-102284CrossRefPubMed

Durno CA, Sherman PM, Aronson M, Malkin D, Hawkins C, Bakry D, Bouffet E, Gallinger S, Pollett A, Campbell B, Tabori U, International BMMRD, Consortium (2015) Phenotypic and genotypic characterization of biallelic mismatch repair deficiency (BMMR-D) syndrome. Eur J Cancer 51(8):977–983. https://doi.org/10.1016/j.ejca.2015.02.008CrossRefPubMed

Shiran SI, Ben-Sira L, Elhasid R, Roth J, Tabori U, Yalon M et al (2018) Multiple brain developmental venous anomalies as a marker for constitutional Mismatch Repair Deficiency Syndrome. AJNR Am J Neuroradiol 39(10):1943–1946. https://doi.org/10.3174/ajnr.A5766CrossRefPubMedPubMedCentral

Dominguez-Valentin M, Sampson JR, Seppälä TT, Ten Broeke SW, Plazzer JP, Nakken S et al (2020) Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the prospective Lynch Syndrome Database. Genet Med 22(1):15–25. https://doi.org/10.1038/s41436-019-0596-9. Erratum in: Genet Med. 2020;22(9):1569

10.

Tabori U, Hansford JR, Achatz MI, Kratz CP, Plon SE, Frebourg T et al (2017) Clinical Management and Tumor Surveillance Recommendations of InheritedMismatch Repair Deficiency in Childhood. Clin Cancer Res 23(11):e32–e7. https://doi.org/10.1158/1078-0432.CCR-17-0574CrossRefPubMed

11.

Aronson M, Colas C, Shuen A, Hampel H, FoulkesWD, Baris Feldman H et al (2022) Diagnostic Criteria for Constitutional Mismatch Repair Deficiency (CMMRD):recommendations from the International Consensus Working Group. J Med Genet 59(4):318–327. https://doi.org/10.1136/jmedgenet-2020-107627CrossRefPubMed

12.

Suerink M, Wimmer K, Brugieres L, Colas C, Gallon R, Ripperger T et al (2021) Report of the fifth meeting of the European Consortium ‘Care for CMMRD’ (C4CMMRD), Leiden, the Netherlands, July 6th 2019. Fam Cancer 20(1):67–73. https://doi.org/10.1007/s10689-020-00194-1CrossRefPubMed

13.

Kebudi R, Amayiri N, Abedalthagafi M, Rana AN, Kirmani S, International RRD Consortium on Low-Resource Settings Panel (2020) Musthaq N. Position paper: Challenges and specific strategies for constitutional mismatch repair deficiency syndrome in low-resource settings. Pediatr Blood Cancer. 67(8):e28309. https://doi.org/10.1002/pbc.28309

14.

Romdhane L, Mezzi N, Hamdi Y, El-Kamah G, Barakat A, Abdelhak S (2019) Consanguinity and inbreeding in Health and Disease in north African populations. Annu Rev Genomics Hum Genet 20:155–179. https://doi.org/10.1146/annurev-genom-083118-014954CrossRefPubMed

15.

Roberts ME, Jackson SA, Susswein LR, Zeinomar N, Ma X, Marshall ML et al (2018) MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer. Genet Med 20(10):1167–1174. https://doi.org/10.1038/gim.2017.254CrossRefPubMedPubMedCentral

16.

Lavoine N, Colas C, Muleris M, Bodo S, Duval A, Entz-Werle N et al (2015) Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort. J Med Genet 52(11):770–778. https://doi.org/10.1136/jmedgenet-2015-103299CrossRefPubMed

17.

Plaschke J, Linnebacher M, Kloor M, Gebert J, Cremer FW, Tinschert S et al (2006) Compound heterozygosity for two MSH6 mutations in a patient with early onset of HNPCC-associated cancers, but without hematological malignancy and brain tumor. Eur J Hum Genet 14(5):561–566. https://doi.org/10.1038/sj.ejhg.5201568CrossRefPubMed

18.

Edelbrock MA, Kaliyaperumal S, Williams KJ (2013) Structural, molecular and cellular functions of MSH2 and MSH6 during DNA mismatch repair, damage signaling and other noncanonical activities. Mut Res 743–744. https://doi.org/10.1016/j.mrfmmm.2012.12.008

19.

Gallon R, Mühlegger B, Wenzel SS, Sheth H, Hayes C, Aretz S et al (2019) A sensitive and scalable microsatellite instability assay to diagnose constitutional mismatch repair deficiency by sequencing of peripheral blood leukocytes. Hum Mut 40(5):649–655. https://doi.org/10.1002/humu.23721CrossRefPubMed

20.

Gallon R, Phelps R, Hayes C, Brugieres L, Guerrini-Rousseau L, Colas C et al (2023) Constitutional microsatellite instability, Genotype, and phenotype correlations in constitutional Mismatch Repair Deficiency. Gastroenterology 164(4):579–592e8. https://doi.org/10.1053/j.gastro.2022.12.017CrossRefPubMed

21.

Wu D, Chen Q, Chen J (2022) Case Report: malignant brain tumors in siblings with MSH6 mutations. Front Oncol 12:920305. https://doi.org/10.3389/fonc.2022.920305CrossRefPubMedPubMedCentral

22.

Hizuka K, Hagiwara SI, Maeyama T, Honma H, Kawai M, Akagi K et al (2021) Constitutional mismatch repair deficiency in childhood colorectal cancer harboring a de novo variant in the MSH6 gene: a case report. BMC Gastroenterol 21(1):60. https://doi.org/10.1186/s12876-021-01646-3CrossRefPubMedPubMedCentral

23.

Citak EC, Sagcan F, Gundugan BD, Bozdogan ST, Yilmaz EB, Avci E et al (2021) 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 43(2):e198–e202. https://doi.org/10.1097/MPH.0000000000001687CrossRefPubMed

24.

Hamad RS, Ibrahim ME (2022) CMMRD caused by PMS1 mutation in a Sudanese consanguineous family. Hered Cancer Clin Pract 20(1):16. https://doi.org/10.1186/s13053-022-00222-4CrossRefPubMedPubMedCentral

25.

Akrout F, Achour A, Tops CMJ, Gallon R, Meddeb R, Achoura S et al (2023) Constitutional mismatch repair deficiency syndrome with atypical features caused by a homozygous MLH1 missense variant (c.1918C > A, p.(Pro640Thr)): a case report. Front Oncol 131195814. https://doi.org/10.3389/fonc.2023.1195814

Title: Strategies for diagnosis and management of CMMRD in low-resource countries: report of a Tunisian family
Authors: Rania Abdelmaksoud-Dammak
Nihel Ammous-Boukhris
Dorra BenAyed-Guerfali
Yassine Gdoura
Imen Boujelben
Souhir Guidara
Slim Charfi
Wiem Boudabbous
Saloua Ammar
Wiem Rhaiem
Mohamed Zaher Boudawara
Hassen Kamoun
Tahya Sallemi-Boudawara
Riadh Mhiri
Raja Mokdad-Gargouri
Publication date: 30-04-2024
Publisher: Springer Netherlands
Keywords: Colorectal Cancer
Colorectal Cancer
Astrocytoma
Astrocytoma
Astrocytoma
Published in: Familial Cancer
Print ISSN: 1389-9600
Electronic ISSN: 1573-7292
DOI: https://doi.org/10.1007/s10689-024-00386-z

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Keynote webinar | Spotlight on antibody–drug conjugates in cancer