Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: Report from the constitutional mismatch repair deficiency consortium

• Published in: European journal of cancer (1990) Vol. 50; no. 5; pp. 987 - 996
• Main Authors: Bakry, Doua, Aronson, Melyssa, Durno, Carol, Rimawi, Hala, Farah, Roula, Alharbi, Qasim Kholaif, Alharbi, Musa, Shamvil, Ashraf, Ben-Shachar, Shay, Mistry, Matthew, Constantini, Shlomi, Dvir, Rina, Qaddoumi, Ibrahim, Gallinger, Steven, Lerner-Ellis, Jordan, Pollett, Aaron, Stephens, Derek, Kelies, Steve, Chao, Elizabeth, Malkin, David, Bouffet, Eric, Hawkins, Cynthia, Tabori, Uri
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 01.03.2014; Elsevier
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Adenosine Triphosphatases - genetics; Adenosine Triphosphatases - metabolism; Adolescent; Biological and medical sciences; Cafe-au-Lait Spots - diagnosis; Cafe-au-Lait Spots - genetics; Cafe-au-Lait Spots - metabolism; Child; Child, Preschool; Constitutional mismatch repair deficiency syndrome; DNA Mismatch Repair - genetics; DNA Repair Enzymes - genetics; DNA Repair Enzymes - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Family Health; Female; Hematology, Oncology and Palliative Medicine; Humans; Immunohistochemistry; Infant; Male; Medical sciences; Microsatellite Instability; Mismatch Repair Endonuclease PMS2; MLH1; MSH2; MSH6; Mutation; MutL Protein Homolog 1; MutS Homolog 2 Protein - genetics; MutS Homolog 2 Protein - metabolism; Neoplasms - diagnosis; Neoplasms - genetics; Neoplasms - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Pedigree; Pharmacology. Drug treatments; PMS2; Syndrome; Tumors; MSH6; Constitutional mismatch repair deficiency syndrome; PMS2; Microsatellite instability; MSH2; MLH1; Deficiency; Genetic determinism; Repair gene; Cancerology; Base mismatching; Microsatellite DNA; Instability
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2013.12.005

Abstract Background Constitutional mismatch repair deficiency (CMMRD) is a devastating cancer predisposition syndrome for which data regarding clinical manifestations, molecular screening tools and management are limited. Methods We established an international CMMRD consortium and collected comprehensive clinical and genetic data. Molecular diagnosis of tumour and germline biospecimens was performed. A surveillance protocol was developed and implemented. Results Overall, 22/23 (96%) of children with CMMRD developed 40 different tumours. While childhood CMMRD related tumours were observed in all families, Lynch related tumours in adults were observed in only 2/14 families ( p = 0.0007). All children with CMMRD had café-au-lait spots and 11/14 came from consanguineous families. Brain tumours were the most common cancers reported (48%) followed by gastrointestinal (32%) and haematological malignancies (15%). Importantly, 12 (30%) of these were low grade and resectable cancers. Tumour immunohistochemistry was 100% sensitive and specific in diagnosing mismatch repair (MMR) deficiency of the corresponding gene while microsatellite instability was neither sensitive nor specific as a diagnostic tool ( p < 0.0001). Furthermore, screening of normal tissue by immunohistochemistry correlated with genetic confirmation of CMMRD. The surveillance protocol detected 39 lesions which included asymptomatic malignant gliomas and gastrointestinal carcinomas. All tumours were amenable to complete resection and all patients undergoing surveillance are alive. Discussion CMMRD is a highly penetrant syndrome where family history of cancer may not be contributory. Screening tumours and normal tissues using immunohistochemistry for abnormal expression of MMR gene products may help in diagnosis and early implementation of surveillance for these children.