title: Evidence for a recessive inheritance of Turcot's syndrome caused by compound heterozygous mutations within the PMS2 gene.
abstract: Turcot's syndrome is a genetic disease characterized by the concurrence of primary brain tumors and colon cancers and/or multiple colorectal adenomas. We report a Turcot family with no parental consanguinity, in which two affected sisters, with no history of tumors in their parents, died of a brain tumor and of a colorectal tumor, respectively, at a very early age. The proband had a severe microsatellite instability (MIN) phenotype in both tumor and normal colon mucosa, and mutations in the TGFbeta-RII and APC genes in the colorectal tumor. We identified two germline mutations within the PMS2 gene: a G deletion (1221delG) in exon 11 and a four-base-pair deletion (2361delCTTC) in exon 14, both of which were inherited from the patient's unaffected parents. These results represent the first evidence that two germline frameshift mutations in PMS2, an MMR gene which is only rarely involved in HNPCC, are not pathogenic per se, but become so when occurring together in a compound heterozygote. The compound heterozygosity for two mutations in the PMS2 gene has implications for the role of protein PMS2 in the mismatch repair mechanism, as well as for the presymptomatic molecular diagnosis of at-risk family members. Furthermore, our data support and enlarge the notion that high DNA instability in normal tissues might trigger the development of cancer in this syndrome.
authors.affiliation: Dipartimento di Biochimica e Biotecnologie Mediche, CEINGE-Biotecnologie Avanzate, Università di Napoli Federico II, Italy.
authors.forename: M
authors.initials: M
authors.lastname: De Rosa
authors.forename: C
authors.initials: C
authors.lastname: Fasano
authors.forename: L
authors.initials: L
authors.lastname: Panariello
authors.forename: M I
authors.initials: MI
authors.lastname: Scarano
authors.forename: G
authors.initials: G
authors.lastname: Belli
authors.forename: A
authors.initials: A
authors.lastname: Iannelli
authors.forename: F
authors.initials: F
authors.lastname: Ciciliano
authors.forename: P
authors.initials: P
authors.lastname: Izzo
mesh_terms: D000236:Adenoma / Q000235:genetics*; D000251:Adenosine Triphosphatases; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000235:genetics*; D003062:Codon / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics; D003111:Colonic Polyps / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics*; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D005260:Female; D005808:Genes, Recessive; D006579:Heterozygote; D006801:Humans; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics*; D009447:Neuroblastoma / Q000235:genetics*; D009837:Oligodendroglioma / Q000235:genetics*; D010296:Parietal Lobe; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational; D011506:Proteins / Q000235:genetics* / Q000502:physiology; D012004:Rectal Neoplasms / Q000235:genetics; D017384:Sequence Deletion; D012811:Sigmoid Neoplasms / Q000235:genetics; D013577:Syndrome; D013728:Terminator Regions, Genetic / Q000235:genetics*
chemical_list: D003062:Codon; D004268:DNA-Binding Proteins; D011506:Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D045643:DNA Repair Enzymes