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


CONCLUSIONS
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.
Division of Hematology/Oncology, The Hospital for Sick Children, Institute of Medical Sciences, The University of Toronto, Toronto, Ontario, Canada; Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada.
Doua
D
Bakry
The Familial Gastrointestinal Cancer Registry at the Zane Cohen Centre for Digestive Disease and Department of Surgery, Mount Sinai Hospital, Toronto, Ontario, Canada.
Melyssa
M
Aronson
The Familial Gastrointestinal Cancer Registry at the Zane Cohen Centre for Digestive Disease and Department of Surgery, Mount Sinai Hospital, Toronto, Ontario, Canada; Division of Gastroenterology, Nutrition and Hepatology, The Hospital for Sick Children, Toronto, Canada.
Carol
C
Durno
Faculty of Medicine, Jordan University of Science & Technology, Irbid, Jordan.
Hala
H
Rimawi
Saint George Hospital University Medical Center, Beirut, Lebanon.
Roula
R
Farah
King Fahad Specialist Hospital, Department of Pediatric Hematology/Oncology and Stem Cell Transplant, Dammam, Saudi Arabia.
Qasim Kholaif
QK
Alharbi
King Fahad City Center, Riyahd, Saudi Arabia.
Musa
M
Alharbi
Children Cancer Hospital, Karachi, Pakistan.
Ashraf
A
Shamvil
The Gilbert Israeli Neurofibromatosis Center (GINFC), Tel-Aviv Medical Center, Tel-Aviv, Israel.
Shay
S
Ben-Shachar
Genetic and Genomic Program, Institute of Medical Sciences, The University of Toronto, Israel.
Matthew
M
Mistry
Department of Pediatric Neurosurgery, Dana Children's Hospital, Tel-Aviv Medical Center, Tel-Aviv, Israel.
Shlomi
S
Constantini
Pediatric Hemato-Oncology Department, Tel Aviv Medical Center, Tel-Aviv, Israel.
Rina
R
Dvir
St. Jude Children's Research Hospital, Memphis, TN, USA.
Ibrahim
I
Qaddoumi
The Familial Gastrointestinal Cancer Registry at the Zane Cohen Centre for Digestive Disease and Department of Surgery, Mount Sinai Hospital, Toronto, Ontario, Canada.
Steven
S
Gallinger
Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Canada; Dept of Lab Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Ontario Institute of Cancer Research, Genome Technologies Platform, Canada.
Jordan
J
Lerner-Ellis
Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Canada; Dept of Lab Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Aaron
A
Pollett
Dalla Lana School of Public Health University of Toronto, Canada; Clinical Research, The Hospital for Sick Children, Canada.
Derek
D
Stephens
Ambry Genetics, Aliso Viejo, CA, USA.
Steve
S
Kelies
Ambry Genetics, Aliso Viejo, CA, USA.
Elizabeth
E
Chao
Division of Hematology/Oncology, The Hospital for Sick Children, Institute of Medical Sciences, The University of Toronto, Toronto, Ontario, Canada; Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada.
David
D
Malkin
Division of Hematology/Oncology, The Hospital for Sick Children, Institute of Medical Sciences, The University of Toronto, Toronto, Ontario, Canada; Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada; Arthur and Sonia Labbatt Brain Tumor Research Center, Toronto, Ontario, Canada.
Eric
E
Bouffet
Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada; Department of Pathology, Hospital for Sick Children, Toronto, Ontario, Canada.
Cynthia
C
Hawkins
Division of Hematology/Oncology, The Hospital for Sick Children, Institute of Medical Sciences, The University of Toronto, Toronto, Ontario, Canada; Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada; Arthur and Sonia Labbatt Brain Tumor Research Center, Toronto, Ontario, Canada. Electronic address: uri.tabori@sickkids.ca.
Uri
U
Tabori
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D019080:Cafe-au-Lait Spots / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D053843:DNA Mismatch Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005192:Family Health; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D053842:Microsatellite Instability; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009369:Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010375:Pedigree; D013577:Syndrome
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes
Constitutional mismatch repair deficiency syndrome; MLH1; MSH2; MSH6; Microsatellite instability; PMS2