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Amayiri N.,R.O.S.A. | Tabori U.,University of Toronto | Tabori U.,Arthur and Sonia Labbatt Brain Tumor Research Center | Campbell B.,University of Toronto | And 11 more authors.
International Journal of Cancer

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 whom79% 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. What's new? Homozygous germline mutations in mismatch repair (MMR) genes can result in biallelic MMR deficiency (bMMRD), a devastating childhood cancer syndrome frequently associated with consanguinity. This study suggests that in Jordan, where consanguinity is common, the prevalence of MMR dysfunction among pediatric patients with high grade glioma (HGG) may be alarmingly high. In the Jordan cohort, bMMRD occurrence was correlated with consanguinity and presence of café au lait macules. Because bMMRD-related HGGs do not respond to conventional treatment regimens and additional tumor development is common, accurate diagnosis is essential. The findings presented here emphasize the importance of genetic testing. © 2015 UICC. Source

Shlien A.,Program in Genetics and Genome Biology | Shlien A.,University of Toronto | Campbell B.B.,Program in Genetics and Genome Biology | Campbell B.B.,Arthur and Sonia Labatt Brain Tumour Research Center | And 86 more authors.
Nature Genetics

DNA replication-associated mutations are repaired by two components: polymerase proofreading and mismatch repair. The mutation consequences of disruption to both repair components in humans are not well studied. We sequenced cancer genomes from children with inherited biallelic mismatch repair deficiency (bMMRD). High-grade bMMRD brain tumors exhibited massive numbers of substitution mutations (>250/Mb), which was greater than all childhood and most cancers (>7,000 analyzed). All ultra-hypermutated bMMRD cancers acquired early somatic driver mutations in DNA polymerase ε or δ. The ensuing mutation signatures and numbers are unique and diagnostic of childhood germ-line bMMRD (P < 10 -13). Sequential tumor biopsy analysis revealed that bMMRD/polymerase-mutant cancers rapidly amass an excess of simultaneous mutations (∼600 mutations/cell division), reaching but not exceeding ∼20,000 exonic mutations in <6 months. This implies a threshold compatible with cancer-cell survival. We suggest a new mechanism of cancer progression in which mutations develop in a rapid burst after ablation of replication repair. © 2015 Nature America, Inc. All rights reserved. Source

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