Abstract 35: Novel genetic and clinical determinants of Constitutional Mismatch Repair Deficiency syndrome: Report from the CMMRD consortium
Authors: Bakry Doua , Campbell Brittany , Durno Carol , Aronson Melyssa , Alharbi Qasim , Alharbi Musa , Constantini Shlomi , Pollett Aaron , Ben-Shachar Shay , Lerner-Ellis Jordan , Gallinger Steven , Elhasid Ronit , Farah Roula , Qaddoumi Ibrahim , Mistry Matthew , Lily Ramyar , Keiles Steve , Dvir Rina , Stephens Derek , Malkin David , Bouffet Eric , Hawkins Cynthia , Tabori Uri 
Published: May 2015

Abstract
Purpose: Constitutional mismatch repair deficiency (CMMRD) is a devastating cancer predisposition syndrome affecting children born with two mutated alleles in one of four mismatch repair genes. Data regarding clinical manifestations, molecular screening tools and management are limited.
Patients and methods: We established an international CMMRD consortium and collected comprehensive clinical and genetic data. Molecular diagnosis of tumor and germline biospecimens were performed. A surveillance protocol was developed and implemented.
Results: Overall, 27/30 (90%) of children with CMMR-D developed 48 different tumors. While childhood CMMR-D related tumors were observed in all families, Lynch related tumors in adults were observed in only 2/17 families (p&lt;0.0001). All children with CMMR-D had cafe-au-lait spots and 14/17 families were consanguineous.
We detected 17 different germline MMR mutations. These included mutations in PMS2(8), MSH6(7) and MLH1(2). Importantly 7/17 mutations were previously unreported. Brain tumors were the most common cancers reported (44%) followed by gastrointestinal (33%) and hematological malignancies (17%). Importantly, 14 (29%) of these were low grade and respectable cancers. Tumor immunohistochemistry was 100% sensitive and specific in diagnosing MMR deficiency of the corresponding gene while microsatellite instability was neither sensitive nor specific as a diagnostic tool (p&lt;0.0001). Furthermore, screening of normal tissue by immunohistochemistry correlated with genetic confirmation of CMMR-D. The surveillance protocol detected 43 lesions which included asymptomatic malignant gliomas and gastrointestinal carcinomas. All tumors were amenable to complete resection and all patients undergoing surveillance are alive.
Conclusion: CMMR-D is a highly penetrant syndrome where family history of cancer may not be contributory. Screening tumors and normal tissues using immunohistochemistry for abnormal expression of MMR gene products helps in diagnosis and early implementation of surveillance for these children.
Citation Format: Doua Bakry, Brittany Campbell, Carol Durno, Melyssa Aronson, Qasim Alharbi, Musa Alharbi, Shlomi Constantini, Aaron Pollett, Shay Ben-Shachar, Jordan Lerner-Ellis, Steven Gallinger, Ronit Elhasid, Roula Farah, Ibrahim Qaddoumi, Matthew Mistry, Ramyar Lily, Steve Keiles, Rina Dvir, Derek Stephens, David Malkin, Eric Bouffet, Cynthia Hawkins, Uri Tabori. Novel genetic and clinical determinants of Constitutional Mismatch Repair Deficiency syndrome: Report from the CMMRD consortium. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 35. doi:10.1158/1538-7445.CANSUSC14-35