Early onset brain tumor and lymphoma in MSH2-deficient children.

摘要: To the Editor: Homozygous germline mutations of MLH1 have been reported so far in three families with hereditary nonpolyposis colorectal cancer (HNPCC [MIM 114500]) and shown to be associated leukemia or lymphoma, CNS tumors, neurofibromatosis type I phenotype (Ricciardone et al. 1999; Wang Vilkki 2001). More recently, first case a homozygous mutation MSH2 was described child multiple cafe-au-lait spots (Whiteside 2002). We report here incidental discovery new deficiency, which is remarkable because presentation family association an early-onset brain tumor. The proband (III.2) her husband (III.1), French origin, were seen for genetic counseling dramatic context death their two children (fig. 1). Individual IV.1 died at age 15 mo from T mediastinal lymphoma; brother (IV.2) 4 years temporal glioblastoma. Their mother father, 29 32 years, respectively, had no personal history cancer. Although several second-degree relatives parents developed cancers 1), did not fulfill criteria Mendelian predisposition The development tumor lymphoma sibs led us consider initially hypothesis Li-Fraumeni syndrome (LFS) this family. Since DNA available affected children, we analyzed TP53 gene both unaffected parents. Sequencing analysis revealed mutation. Stimulated by our recent finding LFS complete heterozygous deletion (unpublished data), completed searching similar defect using quantitative multiplex PCR short fluorescent fragments (QMPSF) (Charbonnier 2000, QMPSF performed father (III.1) demonstrated that affected, but, surprise, exon 3 corresponding control amplicon. Therefore, analyzed, QMPSF, 16 exons MSH2, showed presence, genomic removing 1–6 2A). then sequenced identified 1-bp codon 153 within 2B). In absence constitutional glioblastoma individual IV.2. As figure 2C, detected only mutant maternal allele, strongly suggested IV.2 received his allele harboring deletion. Haplotype locus confirmed presence parental alleles tumor, ruling out somatic loss heterozygosity (data shown). Screening microsatellite instability (MSI), as recommended Boland (1998), replication error (RER) glioblastoma. Figure 1 Partial pedigree Filled symbols denote subjects; open asymptomatic oblique line deceased. Numbers beside are subject identifiers. ages individuals indicated. For ... Figure 2 Detection alterations. A, Heterozygous (individual III.1) QMPSF. electropherogram (red) superposed on (blue). Y-axis displays ... This shows deficiency humans can result tumors. Homozygous who medulloblastoma (Wang 1999) glioma (Vilkki Compound PMS2 gene, rarely involved HNPCC, sisters tumors (De Rosa 2000). These studies, together present report, indicate MMR predisposes primary neuroepithelial Turcot (MIM 276300) originally defined malignant familial polyposis colon, but molecular studies subsequently distinguished entities, resulting APC mutations, respectively (Hamilton 1995; Paraf 1997). It tempting speculate, elsewhere 2000), that, some syndrome, neoplasms childhood may due deficiency. We surprised could detect RER MSH2-deficient tumor. interesting MSI also nontumoral patient Whiteside (2002), contrast MLH1-deficient subjects (1999) (2001). This suggest least certain tissues, lead tumorigenesis through mechanism distinct repair postreplicative mismatches affecting repetitive sequences. Indeed, like its bacterial homolog, MutS, has play additional roles recombination, since these proteins prevent exchange between divergent sequences (Modrich Lahue 1996). Furthermore, recently recombinative complexes during S phase (Zink 2002). As previous 2002), presented study suggestive although young explain generation. different genes must considered hematological malignancies, even HNPCC.