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1/10. Familial paragangliomas: the emerging impact of molecular genetics on evaluation and management.

    HYPOTHESIS: Advancements in molecular genetics has direct impact on the evaluation and management of patients and family members with familial paragangliomas (FP). BACKGROUND: Familial paragangliomas. in contrast to sporadic cases, are commonly multiple, bilateral, and present at an earlier age. Familial tumors are inherited in an autosomal dominant pattern with genomic imprinting of the paternal allele. Mapping studies have identified regions on chromosome 11q as harboring the genetic defect responsible for paraganglioma formation. methods: A multigenerational family with five affected females with head and neck paragangliomas underwent clinical and genetic evaluation. Genetic mapping was performed with microsatellite markers froin chromosome 11q13 and q23. Nonaffected individuals were screened for carrying the affected haplotype. In addition, by using dna obtained from an amniotic fluid sample. in utero screening of a fetus was performed. RESULTS: The most common complaints were hearing loss and neck masses that usually manifested by age 25. Genetic mapping identified loci 11q13 and q23 as sites likely responsible for tumorogenesis. Three unaffected family members, including a fetus, were identified as carriers of the affected haplotype. The genetic findings were used to design a screening protocol for family members at risk for developing glomus tumors. CONCLUSIONS: Genetic screening of unaffected family members can identify individuals harboring the mutated allele. Identification of family members at risk for developing FP by molecular genetic techniques may lead to early detection of head and neck paragangliomas and may directly impact morbidity from glomus tumors and their treatment.
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ranking = 1
keywords = microsatellite
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2/10. Evidence for a recessive inheritance of Turcot's syndrome caused by compound heterozygous mutations within the PMS2 gene.

    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.
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ranking = 19.307217508431
keywords = microsatellite instability, microsatellite, instability
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3/10. Novel germline mutation (300-305delAGTTGA) in the human MSH2 gene in hereditary non-polyposis colorectal cancer (HNPCC).

    Hereditary non-polyposis colorectal cancer (HNPCC) is a common hereditary syndrome characterized by the high incidence and early onset of colorectal cancer. The majority of the HNPCC families carry germline mutations in either the MSH2 or the MLH1 mismatch repair gene. A 46 year-old female patient whose family history fulfilled the Amsterdam criteria for HNPCC was diagnosed with undifferentiated adenocarcinoma of the transverse colon. Recognizing the Lynch 2 syndrome (the existance of multiple HNPCC related cancers in a pedigree), we used polymerase chain reaction followed by direct sequencing to screen the coding regions of both the MSH2 and the MLH1 genes for germline mutations in dna from the patient. We detected a novel germline mutation (300-305delAGTTGA) in exon 2 of human MSH2. We noted microsatellite instability in four microsatellite loci. immunohistochemistry showed a lack of expression of the MSH2 gene product in the tumor, suggesting that the mutation is a disease-causing mutation. copyright Wiley-Liss, Inc.
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ranking = 20.253922465253
keywords = microsatellite instability, microsatellite, instability
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4/10. Molecular pathologic analysis enhances the diagnosis and management of muir-torre syndrome and gives insight into its underlying molecular pathogenesis.

    The muir-torre syndrome (MTS) is an autosomal dominantly inherited disorder, characterized by visceral malignancies and sebaceous skin lesions. In a subset of MTS families the disease is due to an underlying dna mismatch-repair defect. We have identified a MTS family whose spectrum of reported neoplasia included adenocarcinomas of numerous gastrointestinal sites, carcinomas of the endometrium, ovary and breast, papillary transitional cell carcinoma of the ureter, a range of cutaneous tumors, as well as keratoacanthomas. All tumors were tested for microsatellite instability and immunohistochemically stained for expression of MLH1 and MSH2 proteins. All tumors were found to be microsatellite unstable and lacking in MSH2 protein expression. The subsequent mutation detection focused on hMSH2, and a germline mutation was identified (CAA-->TAA, Gln-->STOP, codon 337). This mutation was subsequently found in a family member with a single skin lesion only. We propose that the combination of immunohistologic and microsatellite instability analysis can be exploited to screen individuals with characteristic skin lesions even before development of visceral tumors and to direct the subsequent germline mutation search. The profile of microsatellite instability and the genes rendered dysfunctional differed between tumor samples, suggesting that the molecular pathogenesis varied between lesions, despite a common germline mutation.
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ranking = 58.761767395759
keywords = microsatellite instability, microsatellite, instability
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5/10. Different phenotypes in muir-torre syndrome: clinical and biomolecular characterization in two Italian families.

    The muir-torre syndrome (MTS) is an autosomal dominant genodermatosis characterized by the presence of sebaceous gland tumours, with or without keratoacanthomas, associated with visceral malignancies. We describe and characterize two families in which the ample phenotypic variability of MTS was evident. After clinical evaluation, the skin and visceral tumours of one member of a family with 'classic' MTS and one member of a family with a 'peculiar' MTS phenotype without sebaceous lesions, but with only multiple keratoacanthomas, were analysed for microsatellite instability (MSI) and by immunohistochemistry. Tumours of both individuals showed MSI, with a concomitant lack of MSH2 immunostaining in all evaluated skin and visceral lesions; moreover, in the proband of family 2 a constitutional mutation (C-->T substitution leading to a stop codon) in the MSH2 gene was identified. We conclude that the diagnosis of MTS, which is mainly clinical, should take into account an ample phenotypic variability, which includes both cases with typical cancer aggregation in families and cases characterized by the association of visceral malignancies with multiple keratoacanthomas (without sebaceous lesions), without an apparent family history of cancer.
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ranking = 19.253922465253
keywords = microsatellite instability, microsatellite, instability
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6/10. Two PMS2 mutations in a Turcot syndrome family with small bowel cancers.

    We report the clinicopathological, genetic, and immunohistochemical characterization of an atypical Turcot syndrome (TS) family with small bowel cancer. The tumor family history of a patient with cafe-au-lait spots (CALS) and early onset adenomas, duodenal cancer, and glioblastoma was positive for colonic adenoma (mother), jejunal (maternal grandfather), lung (father), and colorectal (paternal uncle) cancers. PMS2 genetic testing identified the nonsense 1951C>T (Q643X) and the missense 161C>T (S46I) mutations. PMS2 expression was absent in the proband's duodenal cancer with high microsatellite instability. The normal cells also displayed no PMS2 expression and some degree of instability. Our findings point out the association between PMS2 and TS, and support the hypothesis that patients with a few polyps, small bowel tumors with a very early onset, glioblastoma, and CALS should be considered as a variant of hereditary nonpolyposis colorectal cancer. A recessive model of inheritance caused by compound heterozygous mutations was consistent with the observed severe clinical phenotype and has important implications for predicting cancer risk in both the proband and his relatives.
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ranking = 19.307217508431
keywords = microsatellite instability, microsatellite, instability
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7/10. Attenuated familial adenomatous polyposis and muir-torre syndrome linked to compound biallelic constitutional MYH gene mutations.

    Attenuated familial adenomatous polyposis and muir-torre syndrome linked to compound biallelic constitutional MYH gene mutations.Peculiar dermatologic manifestations are present in several heritable gastrointestinal disorders. muir-torre syndrome (MTS) is a genodermatosis whose peculiar feature is the presence of sebaceous gland tumors associated with visceral malignancies. We describe one patient in whom multiple sebaceous gland tumors were associated with early onset colon and thyroid cancers and attenuated polyposis coli. Her family history was positive for colonic adenomas. She had a daughter presenting with yellow papules in the forehead region developed in the late infancy. skin and visceral neoplasms were tested for microsatellite instability and immunohistochemical status of mismatch repair (MMR), APC and MYH proteins. The proband colon and skin tumors were microsatellite stable and showed normal expression of MMR proteins. Cytoplasmic expression of MYH protein was revealed in colonic cancer cells. Compound heterozygosity due to biallelic mutations in MYH, R168H and 379delC, was identified in the proband. The 11-year-old daughter was carrier of the monoallelic constitutional mutation 379delC in the MYH gene; in the sister, the R168H MYH gene mutation was detected. This report presents an interesting case of association between MYH-associated polyposis and sebaceous gland tumors. These findings suggest that patients with MTS phenotype that include colonic polyposis should be screened for MYH gene mutations.
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ranking = 20.253922465253
keywords = microsatellite instability, microsatellite, instability
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8/10. Cytogenetic instability in a family with gastric cancer recurrence.

    An index case with a congenital malformation syndrome enabled detection of a family that had a previous history of spontaneous abortuses and recurrence of neoplasia through three generations. cytogenetic analysis performed on lymphocytes from 11 subjects in the second and third generation showed karyotypic alterations in both tumor bearers and apparently normal subjects. Chromosome variations consisted of: spontaneous chromosome fragility; chromosome translocations; polymorphisms in the heterochromatic regions in chromosomes Y, #1, #16, #22. The inheritance pattern of all chromosome rearrangements and heteromorphisms observed was established starting with the second generation, and the contribution of specific individuals was identified. Although the relationship between chromosomal instability and predisposition to gastric cancer does not appear to be coincidental, no specific chromosome alteration in normal somatic cells was shared by all members of the family who developed or are at risk of developing tumors.
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ranking = 0.26647521588869
keywords = instability
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9/10. mosaicism in the C-banded region of chromosome 1 in cancer families.

    Chromosome 1 C-band length mosaicism was detected in lymphocytes from six tumor patients and one healthy subject belonging to three families with a high incidence of cancer. In all cases the variant cell population showed a decreased amount of C-heterochromatin in one chromosome, whereas the C-banded pattern of the homolog was identical to that of the nonvariant cell population. A family tendency to unequal mitotic crossing over, possibly leading to C-band heteromorphism, may explain the high frequency of detection of C-heterochromatin mosaicism in cancer family members (seven of 13 cases studied). The possible role of heterochromatin in inducing cancer has been widely discussed. The special feature of the acquired C-band variants vis-a-vis the inherited ones is that they mark intrinsic genetic instability that may result, through multiple mechanisms, in increased susceptibility to malignancy.
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ranking = 0.053295043177739
keywords = instability
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10/10. Drastic genetic instability of tumors and normal tissues in Turcot syndrome.

    Turcot syndrome is characterized by an association of malignant brain tumors and colon cancer developing in the patient's teens. Since the mechanism of carcinogenesis in Turcot syndrome is still unclear, we analysed genetic changes in tumors from a Turcot patient with no family history of the condition. All tumors, including one astrocytoma, three colon carcinomas, and two colon adenomas, exhibited severe replication error (RER), and all colon tumors showed somatic mutations at repeated regions of TGFbetaRII, E2F-4, hMSH3, and/or hMSH6 genes. Somatic APC mutations were detected in three of three colon carcinomas, and somatic p53 mutations were detected in the astrocytoma and two of three colon carcinomas, both of which showed two mutations without allele loss. We also found that normal colon mucosa, normal skin fibroblasts and normal brain tissue from this patient showed respective high frequencies of RER, in contrast to usual HNPCC patients in which RER was very rare in normal tissues. These results suggest that extreme dna instability in normal tissues causes the early development of multiple cancer in Turcot syndrome. A missense mutation (GAG to AAG) at codon 705 of hPMS2 gene was detected in one allele of this patient, which was inherited from his mother without tumors. Additional unknown germline mutation may contribute to the genetic instability in normal tissues.
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ranking = 0.31977025906643
keywords = instability
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