title: High frequency of mismatch repair deficiency among pediatric high grade gliomas in Jordan.
abstract: Biallelic mismatch repair deficiency (bMMRD) is a cancer predisposition syndrome affecting primarily individuals from consanguinous families resulting in multiple childhood cancers including high grade gliomas (HGG). This is the first study to assess the prevalence of bMMRD among patients with HGG in countries where consanguinity is high. We collected molecular and clinical information on all children diagnosed with HGG and supratentorial primitive neuroectodermal tumors (sPNET) between 2003 and 2013 at King Hussein Cancer Center, Jordan. Comparison was made to a similar cohort from Toronto. Clinical data regarding presence of café au lait macules(CAL), family history of cancer, consanguinity, pathology and treatment were collected. Tumors were centrally reviewed and tested for MMRD by immunohistochemistry of the corresponding proteins. Forty-two patients fulfilled the inclusion criteria, including 36 with HGG. MMRD was observed in 39% of HGG of whom 79% also lost MMR staining in the corresponding normal cells suggestive of bMMRD. P53 dysfunction was highly enriched in MMR deficient tumors (p = 0.0003).The frequency of MMRD was significantly lower in Toronto cohort (23%, p = 0.03). Both evidence of CAL and consanguinity correlated with bMMRD (p = 0.005 and 0.05,respectively) but family history of cancer didn't. HGG with all three bMMRD risk factors had evidence of MMRD and all children affected by multiple bMMRD related cancers had identical gene loss by immunohistochemical staining. In Jordan, the frequency of clinical and immunohistochemical alterations suggestive of bMMRD in pediatric HGG is high. Genetic testing will enable appropriate counseling and cancer screening to improve survival of these patients.
authors: Department of Pediatrics Hematology/Oncology, King Hussein Cancer Center, Amman, Jordan.
authors: Nisreen
authors: N
authors: Amayiri
authors: Division of Hematology/Oncology, The Hospital for Sick Children, Institute of Medical Sciences, the University of Toronto, Toronto, Canada.|Department of Pediatrics, The Hospital for Sick Children, Institute of Medical Sciences, the University of Toronto, Toronto, Canada.|Arthur and Sonia Labbatt Brain Tumor Research Center, Toronto, Canada.
authors: Uri
authors: U
authors: Tabori
authors: Division of Hematology/Oncology, The Hospital for Sick Children, Institute of Medical Sciences, the University of Toronto, Toronto, Canada.|Department of Pediatrics, The Hospital for Sick Children, Institute of Medical Sciences, the University of Toronto, Toronto, Canada.
authors: Brittany
authors: B
authors: Campbell
authors: Division of Hematology/Oncology, The Hospital for Sick Children, Institute of Medical Sciences, the University of Toronto, Toronto, Canada.|Department of Pediatrics, The Hospital for Sick Children, Institute of Medical Sciences, the University of Toronto, Toronto, Canada.
authors: Doua
authors: D
authors: Bakry
authors: The Familial Gastrointestinal Cancer Registry at the Zane Cohen Centre for Digestive Disease and Department of Surgery, Mount Sinai Hospital, Toronto, Canada.
authors: Melyssa
authors: M
authors: Aronson
authors: The Familial Gastrointestinal Cancer Registry at the Zane Cohen Centre for Digestive Disease and Department of Surgery, Mount Sinai Hospital, Toronto, Canada.|Division of Gastroenterology, Nutrition and Hepatology, The Hospital for Sick Children, Toronto, Canada.
authors: Carol
authors: C
authors: Durno
authors: Division of Pathology, Arthur and Sonia Labatt Brain Tumour Research Center, The Hospital for Sick Children, Toronto, Canada.
authors: Patricia
authors: P
authors: Rakopoulos
authors: Division of Hematology/Oncology, The Hospital for Sick Children, Institute of Medical Sciences, the University of Toronto, Toronto, Canada.|Department of Pediatrics, The Hospital for Sick Children, Institute of Medical Sciences, the University of Toronto, Toronto, Canada.
authors: David
authors: D
authors: Malkin
authors: St. Jude Children's Research Hospital, Memphis, TN.
authors: Ibrahim
authors: I
authors: Qaddoumi
authors: Department of Surgery, King Hussein Cancer Center, Amman, Jordan.
authors: Awni
authors: A
authors: Musharbash
authors: Department of Radiology, King Hussein Cancer Center, Amman, Jordan.
authors: Maisa
authors: M
authors: Swaidan
authors: Division of Hematology/Oncology, The Hospital for Sick Children, Institute of Medical Sciences, the University of Toronto, Toronto, Canada.|Department of Pediatrics, The Hospital for Sick Children, Institute of Medical Sciences, the University of Toronto, Toronto, Canada.
authors: Eric
authors: E
authors: Bouffet
authors: Division of Pathology, Arthur and Sonia Labatt Brain Tumour Research Center, The Hospital for Sick Children, Toronto, Canada.
authors: Cynthia
authors: C
authors: Hawkins
authors: Department of Pathology, King Hussein Cancer Center, Amman, Jordan.
authors: Maysa
authors: M
authors: Al-Hussaini
mesh_terms: D000293:Adolescent; D001932:Brain Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D015179:Colorectal Neoplasms / Q000453:epidemiology*; D053843:DNA Mismatch Repair / Q000235:genetics*; D005260:Female; D005910:Glioma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007231:Infant, Newborn; D007597:Jordan; D053208:Kaplan-Meier Estimate; D008297:Male; D060787:Neoplasm Grading; D009386:Neoplastic Syndromes, Hereditary / Q000453:epidemiology*; D012189:Retrospective Studies; D012307:Risk Factors
keywords: biallelic mismatch repair deficiency; café au lait macules; consanguinity; high grade glioma; low income countries