Molecular mechanisms of cancer predisposition in HNPCC/Lynch syndrome

Hereditary non-polyposis colorectal carcinoma (HNPCC; Lynch syndrome) is among the most common hereditary cancers in man and a model of cancers arising through deficient DNA mismatch repair (MMR). It is inherited in a dominant manner with predisposing germline mutations in the MMR genes, mainly MLH1, MSH2, MSH6 and PMS2. Both copies of the MMR gene need to be inactivated for cancer development. Since Lynch syndrome family members are born with one defective copy of one of the MMR genes in their germline, they only need to acquire a so called second hit to inactivate the MMR gene. Hence, they usually develop cancer at an early age. MMR gene inactivation leads to accumulation of mutations particularly in short repeat tracts, known as microsatellites, causing microsatellite instability (MSI). MSI is the hallmark of Lynch syndrome tumors, but is present in approximately 15% of sporadic tumors as well. There are several possible mechanisms of somatic inactivation (i.e. the second hit ) of MMR genes, for instance deletion of the wild-type copy, leading to loss of heterozygosity (LOH), methylation of promoter regions necessary for gene transcription, or mitotic recombination or gene conversion. In the Lynch syndrome tumors carrying germline mutations in the MMR gene, LOH was found to be the most frequent mechanism of somatic inactivation in the present study. We also studied MLH1/MSH2 deletion carriers and found that somatic mutations identical to the ones in the germline occurred frequently in colorectal cancers and were also present in extracolonic Lynch syndrome-associated tumors. Chromosome-specific marker analysis implied that gene conversion, rather than mitotic recombination or deletion of the respective gene locus accounted for wild-type inactivation. Lynch syndrome patients are predisposed to certain types of cancers, the most common ones being colorectal, endometrial and gastric cancer. Gastric cancer and uroepithelial tumors of bladder and ureter were observed to be true Lynch syndrome tumors with MMR deficiency as the driving force of tumorigenesis. Brain tumors and kidney carcinoma, on the other hand, were mostly MSS, implying the possibility of alternative routes of tumor development. These results present possible implications in clinical cancer surveillance. In about one-third of families suspected of Lynch syndrome, mutations in MMR genes are not found, and we therefore looked for alternative mechanisms of predisposition. According to our results, large genomic deletions, mainly in MSH2, and germline epimutations in MLH1, together explain a significant fraction of point mutation-negative families suspected of Lynch syndrome and are associated with characteristic clinical and family features. Our findings have important implications in the diagnosis and management of Lynch syndrome families.

Walter, Greta and Karl Loewenstein Collection. 1821-2004 Bulk: 1933-1989

This collection holds papers of members of the Loewenstein family, especially Walter and Karl Loewenstein. Among the papers here are examples of Walter Loewenstein's writing, documentation of life in Rietberg in Westphalia (Germany) during the late 1930s and early 1940s, and correspondence concerning the fate of several family members during this time. Papers relating to Karl Loewenstein focus on his wartime activities. The genealogy of the Brandenstein family is also represented here along with a few papers of other family members. The collection consists of unpublished manuscripts, correspondence, photographs, official and restitution documentation, notebooks and notes, genealogical research, and fliers.

Franks family papers, 1711-1821, [1965-1968].

Contains business correspondence, accounts and documents relating to Jacob Franks of New York, his two sons, Moses and David, a nephew, Isaac, and a John Franks of Halifax, possibly a member of the family.

Journal of a voyage to Brazil and residence there, during part of the years 1821, 1822, 1823

Maria Graham, escritora inglesa, nasceu perto de Papscastle em 19 d e junho de 1785 e morreu em Londres, em 28 de novembro de 1842. Casada com o capitão Thomas Graham comandante da fragata Doris fez em sua companhia a sua primeira viagem ao Brasil, em 1821, quando se dirigia ao Chile. Em 1824, já viúva, retornou ao Rio de Janeiro como preceptora de D. Maria da Glória, filha do Imperador D. Pedro I e de Dona Leopoldina. Permaneceu no país até setembro de 1825, quando retornou para Londres por motivos políticos. Mais tarde, casou-se com Augustus Earle Calcott e passou a assinar suas obras literárias como Lady Calcott. ‘Journal of a voyage to Brazil’ relata as viagens da autora ao Brasil. Descreve o país, seus habitantes e os costumes das diferentes classes sociais, principalmente em Pernambuco, na Bahia e no Rio de Janeiro. Constitui importante fonte de informações sobre a época da independência e uma das melhores publicações do século XIX. As ilustrações, com desenhos da autora, são excelentes. De acordo com Borba de Moraes ‘a Catholic University Library em Washington (Oliveira Lima Collection) possui um exemplar que pertenceu à própria autora, onde ela fez correções e anotações para uma segunda edição, mas que nunca chegou a ser publicada. Essas anotações são muito importantes, sobretudo para a história da revolução de Pernambuco e a atuação de Cochrane. Quanto aos acontecimentos de sua vinda ao Rio de Janeiro como preceptora de Dona Maria da Glória, existe um diário que foi publicado por Rodolfo Garcia com preciosas notas e prefácio no volume 60 dos Anais da Biblioteca Nacional do Rio de Janeiro, assim como uma biografia de D. Pedro I e correspondência entre Maria Graham e a Imperatriz’

Reise im innern von brasilien : auf allerhochsten befehl selner majestat des kaisers von osterreich, Franz des Esten, in den jahren 1817-1821 unternonmen und herausgegeben

O primeiro volume foi editado em 1832 e o segundo em 1837, após a morte do autor, fato que contribuiu para a pouco acurada nomenclatura em português verificada no segundo volume, conforme afirma Borba de Moraes. A grande importância do trabalho de Pohl residiu na descrição de Goiás, à época, uma parte do Brasil quase desconhecida para os cientistas estrangeiros. Seu texto contém descrições sobre a arquitetura colonial e do século XIX. Pohl também produziu um atlas que complementou, por meio de belas ilustrações, o trabalho contido nesses dois volumes. Estes, especialmente se acompanhados do atlas, são um trabalho mais raro do que os relativos às viagens de Martins

Collecção das Leis do Brazil de 1821

Parte 1 - Leis das Cortes Gerais Extraordinárias e Constituintes da Nação Portuguesa

Playing games with words cultural transfer in David Lynch's Blue Velvet

Eguíluz, Federico; Merino, Raquel; Olsen, Vickie; Pajares, Eterio; Santamaría, José Miguel (eds.)

Carta que ao Illustre Deputado em Cortes o Senhor Luiz Nicolao Fagundes Varella, escreveo hum zellozo patriota em 14 de dezembro de 1821, dada á luz por José Alves Ribeiro de Mendonça

Diccionario Bibliographico Portuguez / Innocencio Francisco da Silva, 1860. v. 4, p. 219.

Collecção dos breves pontificios, e leys regias, que forão expedidos, e publicadas desde o anno de 1741, sobre a liberdade das pessoas, bens, e commercio dos indios do Brasil : dos excessos que naquelle Estado obraram os regulares da companhia denominada de Jesu; das reprezentaçoens que Sua Magestade Fidelissima fez à Santa Séde Apostolica, sobre esta materia até a expedição do breve que ordenou a reforma dos sobreditos regulares

Brasil. [Leis etc]

Evidence for classification of c.1852_1853AA > GC in MLH1 as a neutral variant for Lynch syndrome

Background: Lynch syndrome (LS) is an autosomal dominant inherited cancer syndrome characterized by early onset cancers of the colorectum, endometrium and other tumours. A significant proportion of DNA variants in LS patients are unclassified. Reports on the pathogenicity of the c.1852_1853AA>GC (p.Lys618Ala) variant of the MLH1 gene are conflicting. In this study, we provide new evidence indicating that this variant has no significant implications for LS. Methods: The following approach was used to assess the clinical significance of the p.Lys618Ala variant: frequency in a control population, case-control comparison, co-occurrence of the p.Lys618Ala variant with a pathogenic mutation, co-segregation with the disease and microsatellite instability in tumours from carriers of the variant. We genotyped p.Lys618Ala in 1034 individuals (373 sporadic colorectal cancer [CRC] patients, 250 index subjects from families suspected of having LS [revised Bethesda guidelines] and 411 controls). Three well-characterized LS families that fulfilled the Amsterdam II Criteria and consisted of members with the p.Lys618Ala variant were included to assess co-occurrence and co-segregation. A subset of colorectal tumour DNA samples from 17 patients carrying the p.Lys618Ala variant was screened for microsatellite instability using five mononucleotide markers. Results: Twenty-seven individuals were heterozygous for the p.Lys618Ala variant; nine had sporadic CRC (2.41%), seven were suspected of having hereditary CRC (2.8%) and 11 were controls (2.68%). There were no significant associations in the case-control and case-case studies. The p.Lys618Ala variant was co-existent with pathogenic mutations in two unrelated LS families. In one family, the allele distribution of the pathogenic and unclassified variant was in trans, in the other family the pathogenic variant was detected in the MSH6 gene and only the deleterious variant co-segregated with the disease in both families. Only two positive cases of microsatellite instability (2/17, 11.8%) were detected in tumours from p.Lys618Ala carriers, indicating that this variant does not play a role in functional inactivation of MLH1 in CRC patients. Conclusions: The p.Lys618Ala variant should be considered a neutral variant for LS. These findings have implications for the clinical management of CRC probands and their relatives.