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 caf e 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. Fortytwo 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 5 0.0003).The frequency of MMRD was significantly lower in Toronto cohort (23%, p 5 0.03). Both evidence of CAL and consanguinity correlated with bMMRD (p 5 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.Biallelic mismatch repair deficiency (bMMRD) is an autosomal recessive cancer predisposition syndrome caused by a biallelic germline mutation in the DNA mismatch repair (MMR) genes. This is one of the most devastating cancer syndromes associated with high penetrance and mortality during childhood.1-3 The MMR genes which are known to cause this syndrome in humans are MLH1, MSH2, MSH6 and PMS2. In contrast to heterozygous carriers of mutations in these genes who are at risk to develop gastrointestinal and urogenital tumors as adults, 4,5 bMMRD is characterized by a broad spectrum of early onset tumors during childhood. The most common cancers affecting children are brain tumors followed by hematological malignancies and a variety of premalignant and malignant lesions of the gastrointestinal tract. High grade gliomas (HGG) are the most common CNS tumors associated with bMMRD and are the major cause of

Comprehensive Analysis of Hypermutation in Human Cancer

“…The cancer genome becomes a powerful new diagnostic aid for underlying germline susceptibility. For instance, if a young patient is found to have a hypermutant tumor with a signature similar to C1 (Figure 3), their family should be offered genetic counseling and testing for CMMRD, an underdiagnosed syndrome without clear warning signs (Amayiri et al, 2016; Durno et al, 2015). This is important to ensure surveillance and treatment options are appropriately customized.…”

Pembrolizumab: first experience with recurrent primary central nervous system (CNS) tumors

“…There may be selected subgroups of gliomas which may have higher MSI scores, perhaps due to mismatch repair mechanisms (MMR). A cohort of consanguineous pediatric gliomas has been reported, with an MMR mutation which may render them an ideal population for treatment with anti-PD1 therapy [30]. Mutational load has also been recognized as a predictor of response to anti-PD1 therapy.…”

Recommendations on surveillance and management of biallelic mismatch repair deficiency (BMMRD) syndrome: a consensus statement by the US Multi-Society Task Force on Colorectal Cancer

“…There is a high frequency of unrecognized BMMRD among young patients with high-grade gliomas in populations in which consanguinity is common. 36 As more patients with BMMRD undergo brain MRI, a central nervous system phenotype is emerging that includes agenesis of the corpus callosum, vascular changes, and gray matter heterotopias. [37][38][39] Prospective surveillance with systematic data collection of BMMRD patients undergoing MRI will add to our understanding of this disease.…”