Microsatellite instability analysis in hereditary non-polyposis colon cancer using the Bethesda consensus panel of microsatellite markers in the absence of proband normal tissue

BACKGROUND: Hereditary non-polyposis colon cancer (HNPCC) is an autosomal dominant syndrome predisposing to the early development of various cancers including those of colon, rectum, endometrium, ovarium, small bowel, stomach and urinary tract. HNPCC is caused by germline mutations in the DNA mismatch repair genes, mostly hMSH2 or hMLH1. In this study, we report the analysis for genetic counseling of three first-degree relatives (the mother and two sisters) of a male who died of colorectal adenocarcinoma at the age of 23. The family fulfilled strict Amsterdam-I criteria (AC-I) with the presence of extracolonic tumors in the extended pedigree. We overcame the difficulty of having a proband post-mortem non-tumor tissue sample for MSI testing by studying the alleles carried by his progenitors. METHODS: Tumor MSI testing is described as initial screening in both primary and metastasis tumor tissue blocks, using the reference panel of 5 microsatellite markers standardized by the National Cancer Institute (NCI) for the screening of HNPCC (BAT-25, BAT-26, D2S123, D5S346 and D17S250). Subsequent mutation analysis of the hMLH1 and hMSH2 genes was performed. RESULTS: Three of five microsatellite markers (BAT-25, BAT-26 and D5S346) presented different alleles in the proband's tumor as compared to those inherited from his parents. The tumor was classified as high frequency microsatellite instability (MSI-H). We identified in the HNPCC family a novel germline missense (c.1864C>A) mutation in exon 12 of hMSH2 gene, leading to a proline 622 to threonine (p.Pro622Thr) amino acid substitution. CONCLUSION: This approach allowed us to establish the tumor MSI status using the NCI recommended panel in the absence of proband's non-tumor tissue and before sequencing the obligate carrier. According to the Human Gene Mutation Database (HGMD) and the International Society for Gastrointestinal Hereditary Tumors (InSiGHT) Database this is the first report of this mutation

A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America

Background: Genetic counselling and testing for Lynch syndrome (LS) have recently been introduced in several Latin America countries. We aimed to characterize the clinical, molecular and mismatch repair (MMR) variants spectrum of patients with suspected LS in Latin America. Methods: Eleven LS hereditary cancer registries and 34 published LS databases were used to identify unrelated families that fulfilled the Amsterdam II (AMSII) criteria and/or the Bethesda guidelines or suggestive of a dominant colorectal (CRC) inheritance syndrome. Results: We performed a thorough investigation of 15 countries and identified 6 countries where germline genetic testing for LS is available and 3 countries where tumor testing is used in the LS diagnosis. The spectrum of pathogenic MMR variants included MLH1 up to 54%, MSH2 up to 43%, MSH6 up to 10%, PMS2 up to 3% and EPCAM up to 0.8%. The Latin America MMR spectrum is broad with a total of 220 different variants which 80% were private and 20% were recurrent. Frequent regions included exons 11 of MLH1 (15%), exon 3 and 7 of MSH2 (17 and 15%, respectively), exon 4 of MSH6 (65%), exons 11 and 13 of PMS2 (31% and 23%, respectively). Sixteen international founder variants in MLH1, MSH2 and MSH6 were identified and 41 (19%) variants have not previously been reported, thus representing novel genetic variants in the MMR genes. The AMSII criteria was the most used clinical criteria to identify pathogenic MMR carriers although microsatellite instability, immunohistochemistry and family history are still the primary methods in several countries where no genetic testing for LS is available yet. Conclusion: The Latin America LS pathogenic MMR variants spectrum included new variants, frequently altered genetic regions and potential founder effects, emphasizing the relevance implementing Lynch syndrome genetic testing and counseling in all of Latin America countries.Radium Hospital Foundation (Oslo, Norway) in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript, Helse Sør-Øst (Norway) in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript, the French Association Recherche contre le Cancer (ARC) in the analysis, and interpretation of data, the Groupement des Entreprises Françaises dans la Lutte contre le Cancer (Gefluc) in the analysis, and interpretation of data, the Association Nationale de la Recherche et de la Technologie (ANRT, CIFRE PhD fellowship to H.T.) in the analysis, and interpretation of data and by the OpenHealth Institute in the analysis, and interpretation of data. Barretos Cancer Hospital received financial support by FINEP-CT-INFRA (02/2010)info:eu-repo/semantics/publishedVersio

Bases moleculares e importancia clínica de los excepcionales fenotipos de grupo sanguíneo P y P K Molecular bases and clinical importance of the exceptional phenotypes of blood group P and PK

Todas las células de los individuos con fenotipos "p" y "Pk" carecen de los antígenos glucídicos de grupo sanguíneo "públicos". Estos individuos forman anticuerpos "naturales" y "regulares" contra las estructuras faltantes (anti-P, anti-PP1 y anti-PP1Pk), que aglutinan y/o hemolisan los glóbulos rojos de todos los individuos, excepto aquellos con el mismo fenotipo. Por lo excepcional de estos cuadros (unos pocos individuos por millón) y su asociación con reacciones transfusionales hemolíticas graves y aborto espontáneo a repetición, estos individuos deben ser identificados y caracterizadosAll the cells of the individuals with phenotypes "p" y "Pk" lack the glucidic antigens of "public" blood groups. These subjects form natural and regular antibodies against the missing structures (anti-P, anti-PP1 y anti-PP1Pk) that agglutínate or hemolyze the red-blood cells of every individual, excepting those with the same phenotype. Due to the exceptional character of these pictures (a few individuals per million) and their association with severe transfusional hemolytic reactions and repeated miscarriages, these subjects should be identified and characterize

Uso prenatal de gammaglogulina endovenosa en gestante con severa isoinmuniación Rh(D) High dose of intravenous immunoglobulin for the treatment of senere Rh(D) alloinmunization

El uso prenatal de altas dosis de gammaglobulina endovenosa en la enfermedad hemolítica del feto y el recién nacido está indicado en situaciones donde se registran antecedentes obstétricos de jerarquía con compromiso fetal predecible y en edad gestacional precoz para realizar transfusión intrauterina. Se presenta el caso de una paciente de 28 años con antecedentes de 3 muertes fetales por enfermedad hemolítica Rh(D), la última en edad gestacional muy temprana, que alcanzó un recién nacido vivo con altas dosis de gammaglobulina endovenosa a partir de la 13ª semana. El trabajo interdisciplinario de los servicios tratantes garantizó el estricto control, seguimiento y exitoso tratamientoThe prenatal use of high dose intravenous immunoglobulin (IVIG) is indicated in cases of severe haemolytic disease of the fetus and newborn when low gestational age makes intrauterine transfusions technically difficult. We describe our experience with a patient with history of three fetal deaths from Rh (D) hemolytic disease, the last one at very low gestational age, who achieved an alive newborn after early treatment with IVIG from 13 weeks gestation. The interdisciplinary work guaranteed the strict control, follow-up and successful treatmen

BRCA1 and BRCA2 analysis of argentinean breast/ovarian cancer patients selected for age and family history highlights a role for novel mutations of putative south-American origin

Background: The spectrum of BRCA1/2 genetic variation in breast-ovarian cancer patients has been scarcely investigated outside Europe and North America, with few reports for South America, where Amerindian founder effects and recent multiracial immigration are predicted to result in high genetic diversity. We describe here the results of BRCA1/BRCA2 germline analysis in an Argentinean series of breast/ovarian cancer patients selected for young age at diagnosis or breast/ovarian cancer family history. Methods: The study series (134 patients) included 37 cases diagnosed within 40 years of age and no family history (any ethnicity, fully-sequenced), and 97 cases with at least 2 affected relatives (any age), of which 57 were non-Ashkenazi (fully-sequenced) and 40 Ashkenazi (tested only for the founder mutations c.66_67delAG and c.5263insC in BRCA1 and c.5946delT in BRCA2). Discussion: We found 24 deleterious mutations (BRCA1:16; BRCA2: 8) in 38/134 (28.3%) patients, of which 6/37 (16.2%) within the young age group, 15/57 (26.3%) within the non-Ahkenazi positive for family history; and 17/40 (42.5%) within the Ashkenazi. Seven pathogenetic mutations were novel, five in BRCA1: c.1502_1505delAATT, c.2626_2627delAA c.2686delA, c.2728 C > T, c.3758_3759delCT, two in BRCA2: c.7105insA, c.793 + 1delG. We also detected 72 variants of which 54 previously reported and 17 novel, 33 detected in an individual patient. Four missense variants of unknown clinical significance, identified in 5 patients, are predicted to affect protein function. While global and European variants contributed near 45% of the detected BRCA1/2 variation, the significant fraction of new variants (25/96, 26%) suggests the presence of a South American genetic component. This study, the first conducted in Argentinean patients, highlights a significant impact of novel BRCA1/2 mutations and genetic variants, which may be regarded as putatively South American, and confirms the important role of founder BRCA1 and BRCA2 mutations in Argentinean Ashkenazi Jews. © 2012 Solano et al.Fil: Solano, Angela Rosario. Universidad de Buenos Aires; Argentina. Centro de Internación E Investigación Clínica; ArgentinaFil: Aceto, Gitana Maria. University Of G. D'annunzio Chieti And Pescara;Fil: Delettieres, Dreanina. Centro de Internación E Investigación Clínica; ArgentinaFil: Veschi, Serena. University Of G. D'annunzio Chieti And Pescara;Fil: Neuman, Maria Isabel. Universidad de Buenos Aires; ArgentinaFil: Alonso, Eduardo. Instituto Universitario del Hospital Italiano de Buenos Aires; ArgentinaFil: Chialina, Sergio. Instituto Universitario del Hospital Italiano de Buenos Aires; ArgentinaFil: Chacón, Reinaldo Daniel. Universidad de Buenos Aires; ArgentinaFil: Renato, Mariani-Costantini. University Of G. D'annunzio Chieti And Pescara;Fil: Podesta, Ernesto Jorge. Universidad de Buenos Aires; Argentin