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

Constitutional mismatch repair deficiency (CMMRD) is a devastating cancer predisposition syndrome for which data regarding clinical manifestations, molecular screening tools and management are limited. 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. 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. 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.

Bakry D ，Aronson M ，Durno C ，Rimawi H ，Farah R ，Alharbi QK ，Alharbi M ，Shamvil A ，Ben-Shachar S ，Mistry M ，Constantini S ，Dvir R ，Qaddoumi I ，Gallinger S ，Lerner-Ellis J ，Pollett A ，Stephens D ，Kelies S ，Chao E ，Malkin D ，Bouffet E ，Hawkins C ，Tabori U ... -  《-》

Constitutional Mismatch Repair Deficiency in Israel: High Proportion of Founder Mutations in MMR Genes and Consanguinity.

Heterozygous germline mutations in any of the mismatch repair (MMR) genes, MLH1, MSH2, MSH6, and PMS2, cause Lynch syndrome (LS), an autosomal dominant cancer predisposition syndrome conferring a high risk of colorectal, endometrial, and other cancers in adulthood. Offspring of couples where both spouses have LS have a 1:4 risk of inheriting biallelic MMR gene mutations. These cause constitutional MMR deficiency (CMMRD) syndrome, a severe recessively inherited cancer syndrome with a broad tumor spectrum including mainly hematological malignancies, brain tumors, and colon cancer in childhood and adolescence. Many CMMRD children also present with café au lait spots and axillary freckling mimicking neurofibromatosis type 1. We describe our experience in seven CMMRD families demonstrating the role and importance of founder mutations and consanguinity on its prevalence. Clinical presentations included brain tumors, colon cancer, lymphoma, and small bowel cancer. In children from two nonconsanguineous Ashkenazi Jewish (AJ) families, the common Ashkenazi founder mutations were detected; these were homozygous in one family and compound heterozygous in the other. In four consanguineous families of various ancestries, different homozygous mutations were identified. In a nonconsanguineous Caucasus/AJ family, lack of PMS2 was demonstrated in tumor and normal tissues; however, mutations were not identified. CMMRD is rare, but, especially in areas where founder mutations for LS and consanguinity are common, pediatricians should be aware of it since they are the first to encounter these children. Early diagnosis will enable tailored cancer surveillance in the entire family and a discussion regarding prenatal genetic diagnosis.

Baris HN ，Barnes-Kedar I ，Toledano H ，Halpern M ，Hershkovitz D ，Lossos A ，Lerer I ，Peretz T ，Kariv R ，Cohen S ，Half EE ，Magal N ，Drasinover V ，Wimmer K ，Goldberg Y ，Bercovich D ，Levi Z ... -  《-》

Rhabdomyosarcoma in patients with constitutional mismatch-repair-deficiency syndrome.

Kratz CP ，Holter S ，Etzler J ，Lauten M ，Pollett A ，Niemeyer CM ，Gallinger S ，Wimmer K ... -  《-》

Diagnosis of Constitutional Mismatch Repair-Deficiency Syndrome Based on Microsatellite Instability and Lymphocyte Tolerance to Methylating Agents.

Patients with bi-allelic germline mutations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2) develop a rare but severe variant of Lynch syndrome called constitutional MMR deficiency (CMMRD). This syndrome is characterized by early-onset colorectal cancers, lymphomas or leukemias, and brain tumors. There is no satisfactory method for diagnosis of CMMRD because screens for mutations in MMR genes are noninformative for 30% of patients. MMR-deficient cancer cells are resistant to genotoxic agents and have microsatellite instability (MSI), due to accumulation of errors in repetitive DNA sequences. We investigated whether these features could be used to identify patients with CMMRD. We examined MSI by PCR analysis and tolerance to methylating or thiopurine agents (functional characteristics of MMR-deficient tumor cells) in lymphoblastoid cells (LCs) from 3 patients with CMMRD and 5 individuals with MMR-proficient LCs (controls). Using these assays, we defined experimental parameters that allowed discrimination of a series of 14 patients with CMMRD from 52 controls (training set). We then used the same parameters to assess 23 patients with clinical but not genetic features of CMMRD. In the training set, we identified parameters, based on MSI and LC tolerance to methylation, that detected patients with CMMRD vs controls with 100% sensitivity and 100% specificity. Among 23 patients suspected of having CMMRD, 6 had MSI and LC tolerance to methylation (CMMRD highly probable), 15 had neither MSI nor LC tolerance to methylation (unlikely to have CMMRD), and 2 were considered doubtful for CMMRD based on having only 1 of the 2 features. The presence of MSI and tolerance to methylation in LCs identified patients with CMMRD with 100% sensitivity and specificity. These features could be used in diagnosis of patients.

Bodo S ，Colas C ，Buhard O ，Collura A ，Tinat J ，Lavoine N ，Guilloux A ，Chalastanis A ，Lafitte P ，Coulet F ，Buisine MP ，Ilencikova D ，Ruiz-Ponte C ，Kinzel M ，Grandjouan S ，Brems H ，Lejeune S ，Blanché H ，Wang Q ，Caron O ，Cabaret O ，Svrcek M ，Vidaud D ，Parfait B ，Verloes A ，Knappe UJ ，Soubrier F ，Mortemousque I ，Leis A ，Auclair-Perrossier J ，Frébourg T ，Fléjou JF ，Entz-Werle N ，Leclerc J ，Malka D ，Cohen-Haguenauer O ，Goldberg Y ，Gerdes AM ，Fedhila F ，Mathieu-Dramard M ，Hamelin R ，Wafaa B ，Gauthier-Villars M ，Bourdeaut F ，Sheridan E ，Vasen H ，Brugières L ，Wimmer K ，Muleris M ，Duval A ，European Consortium “Care for CMMRD” ... -  《-》

Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort.

Constitutional mismatch repair deficiency (CMMRD) syndrome is a childhood cancer predisposition syndrome involving biallelic germline mutations of MMR genes, poorly recognised by clinicians so far. Retrospective review of all 31 patients with CMMRD diagnosed in French genetics laboratories in order to describe the characteristics, treatment and outcome of the malignancies and biological diagnostic data. 67 tumours were diagnosed in 31 patients, 25 (37%) Lynch syndrome-associated malignancies, 22 (33%) brain tumours, 17 (25%) haematological malignancies and 3 (5%) sarcomas. The median age of onset of the first tumour was 6.9 years (1.2-33.5). Overall, 22 patients died, 9 (41%) due to the primary tumour. Median survival after the diagnosis of the primary tumour was 27 months (0.26-213.2). Failure rate seemed to be higher than expected especially for T-cell non-Hodgkin's lymphoma (progression/relapse in 6/12 patients). A familial history of Lynch syndrome was identified in 6/23 families, and consanguinity in 9/23 families. PMS2 mutations (n=18) were more frequent than other mutations (MSH6 (n=6), MLH1 (n=4) and MSH2 (n=3)). In conclusion, this unselected series of patients confirms the extreme severity of this syndrome with a high mortality rate mostly related to multiple childhood cancers, and highlights the need for its early detection in order to adapt treatment and surveillance.

Lavoine N ，Colas C ，Muleris M ，Bodo S ，Duval A ，Entz-Werle N ，Coulet F ，Cabaret O ，Andreiuolo F ，Charpy C ，Sebille G ，Wang Q ，Lejeune S ，Buisine MP ，Leroux D ，Couillault G ，Leverger G ，Fricker JP ，Guimbaud R ，Mathieu-Dramard M ，Jedraszak G ，Cohen-Hagenauer O ，Guerrini-Rousseau L ，Bourdeaut F ，Grill J ，Caron O ，Baert-Dusermont S ，Tinat J ，Bougeard G ，Frébourg T ，Brugières L ... -  《-》