Biallelic germline mutations of mismatch-repair genes: A possible cause for multiple pediatric malignancies

BACKGROUND. Heterozygous defects in mismatch-repair (MMR) genes cause hereditary nonpolyposis colorectal cancer (HNPCC). In this syndrome, tumors typically arise from age 25 years onward. Case reports have shown that homozygosity or compound heterozygosity for MMR gene mutations can cause multiple tumors in childhood, sometimes combined with neurofibromatosis type I (NF1)-like features. Therefore, the authors studied the role of homozygosity or compound heterozygosity (CZ) for MMR gene defects in children with multiple primary tumors. METHODS. A database that contained all pediatric oncology patients who were seen between 1982 and 2003 at the author's institution was queried to identify patients aged <16 years with more than 1 tumor for whom tissue of at least 1 tumor was available. On isolated DNA, microsatellite instability (MSI) and immunohistochemistry of MMR proteins were assessed. RESULTS. In total, 15 patients with more than 1 tumor were identified. Abnormal test results were obtained in 2 of them, including 1 patient who was diagnosed at age 4 years with a glioblastoma (MSI-stable; no human mutL homolog 1 [MLH1] or postmeiotic segregation increased, Saccharomyces cerevisiae 2 [PMS2] expression) and a Wilms tumor (high MSI; no MLH1 or PMS2 expression). Apart from >6 cafe-au-lait spots, he had no other signs of NF1. The patient had CZ identified for a pathogenic MLH1 mutation (593delAG frameshift) and an unclassified MLH1 variant (Met35Asn). There was strong evidence that this unclassified variant was a pathogenic mutation. The second patient was diagnosed with a non-Hodgkin lymphoma (no tissue available) and an anaplastic oligodendroglioma (low MSI; no MSH6 expression) at age 4 years and 6 years, respectively. His brother had died of a medulloblastoma at age 6 years (low MSI, no MSH6 expression). Both boys had cafe-au-lait spots. Further genetic testing was not possible. CONCLUSIONS. Carriage of biallelic MMR gene defects can be associated with multiple malignancies in childhood that may differ from the standard spectrum of HNPCC tumor types. In 15 pediatric patients with multiple malignancies, the authors identified 1 clear case and 1 possible case of biallelic MMR gene defect. Recognition of the inherited nature of the tumors in these patients is important for counseling these patients and their families.