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Colorectal cancer (CRC) is one of the most common cancers in Latin America and the Caribbean, with the highest rates reported for Uruguay, Brazil and Argentina. We provide a global snapshot of the CRC patterns, how screening is performed, and compared/contrasted to the genetic profile of Lynch syndrome (LS) in the region. From the literature, we find that only nine (20%) of the Latin America and the Caribbean countries have developed guidelines for early detection of CRC, and also with a low adherence. We describe a genetic profile of LS, including a total of 2,685 suspected families, where confirmed LS ranged from 8% in Uruguay and Argentina to 60% in Peru. Among confirmed LS, path_MLH1 variants were most commonly identified in Peru (82%), Mexico (80%), Chile (60%), and path_MSH2/EPCAM variants were most frequently identified in Colombia (80%) and Argentina (47%). Path_MSH6 and path_PMS2 variants were less common, but they showed important presence in Brazil (15%) and Chile (10%), respectively. Important differences exist at identifying LS families in Latin American countries, where the spectrum of path_MLH1 and path_MSH2 variants are those most frequently identified. Our findings have an impact on the evaluation of the patients and their relatives at risk for LS, derived from the gene affected. Although the awareness of hereditary cancer and genetic testing has improved in the last decade, it is remains deficient, with 39%–80% of the families not being identified for LS among those who actually met both the clinical criteria for LS and showed MMR deficiency. Radium Hospital Foundation (Oslo, Norway)

RESUMEN Este articulo analiza el rol de las imagenes en diferentes sindromes neoplasicos hereditarios, incluyendo mama, colon y neoplasias endocrinas multiples. Las mujeres con mutaciones geneticas asociadas a mayor susceptibilidad de desarrollar cancer de mama pueden optar a la vigilancia con imagenes desde edades tempranas, detectando asi precozmente la enfermedad. En este grupo de mujeres, la mamografia ha mostrado un bajo rendimiento, mientras que la resonancia mamaria se ha establecido como el principal metodo de screening. El cancer colorrectal es una patologia muy frecuente en nuestra poblacion. Un 2-5% constituyen sindromes hereditarios, de los cuales el mas frecuente es el Sindrome de Lynch o cancer colorrectal hereditario no poliposico, seguido de la Poliposis Adenomatosa Familiar y otras poliposis. La importancia de detectar estos sindromes esta en identificar los individuos en riesgo, y realizar metodos de tamizaje apropiados para una deteccion precoz del cancer. Las Neoplasias Endocrinas Multiples incluyen entre sus manifestaciones los tumores paratiroideos, los feocromocitomas, los tumores gastroenteropancreaticos y el cancer medular de tiroides. Estas lesiones presentan caracteristicas fisiologicas como expresion de receptores o hiperfuncion celular que permiten obtener imagenes con tecnicas de Medicina Nuclear que actualmente se denominan Imagenes Moleculares.

Esta revisión tiene como objetivo dar a conocer los aspectos genéticos, clínicos y diagnósticos del síndrome de Lynch, además de brindar la información más relevante acerca de la asesoría genética en estos pacientes y las recomendaciones actuales para su seguimiento. This review aims to present the genetic, clinical and diagnostic aspects of Lynch syndrome, as well as providing the most relevant information about genetic counseling in these patients and the current recommendations for their surveillance.

Resumen: El síndrome de Li-Fraumeni (SLF) es una enfermedad hereditaria autosómica dominante con elevada penetrancia, que se caracteriza por la aparición precoz de múltiples tumores en un individuo y una marcada agregación familiar. Aproximadamente el 70% de los pacientes que cumplen criterios clínicos para su diagnóstico son portadores de la mutación germinal del gen TP53 localizado en el cromosoma 17p13. El gen TP53 es un supresor tumoral que cumple una importante función en el control de la estabilidad genómica. Se estima que el riesgo de desarrollar cáncer es del 50 % para las mujeres a los 31 años de edad y para los hombres a los 46 años y cerca del 100 % para ambos sexos a los 70 años. El curso clínico de la enfermedad es similar que en pacientes sin SLF a excepción de la edad más temprana al diagnóstico. Presentamos el caso de una paciente de 31 años a la que se diagnostica un condrosarcoma pelviano tratado con cirugía y al momento de la recidiva, aproximadamente 8 meses después, un cáncer de mama localizado. En otro miembro de su familia se había identificado la mutación 375G>C en el gen TP53 mediante secuenciación Sanger, la cual fue detectada posteriormente en nuestra paciente. Se discuten aspectos particulares del manejo como la minimización de la exposición a la radioterapia (por reportes de tumores malignos en zonas irradiadas) y el especial manejo de la repercusión del diagnóstico a nivel de los otros integrantes de la familia. Abstract: The Li-Fraumeni syndrome (SLF) is a highly penetrant condition with an autosomal dominant inheritance pattern, characterized by an early onset of multiple tumors in a subject and a marked familial occurrence. About 70 % of patients meeting clinical criteria for diagnosis of the disease carry the germline mutation of TP53 gene located in chromosome 17p13. TP53 is a tumor suppressor gene known for its major role in genome stability control. It has been estimated that risk of cancer development is 50 % for women at the age of 31 and for men at the age of 46 and nearly 100 % for both men and women at 70 years of age. Except at earlier ages of diagnosis, the clinical course of the disease for healthy patients and for patients suffering SLF shows similarities. We present the case of a 31-year-old patient diagnosed both with pelvic chondrosarcoma treated surgically and localized breast cancer during relapse, about 8 months later. By Sanger sequencing, mutation 375G>C had been identified in TP53 gene in another family member, and said mutation was later detected in our patient. We discuss particular aspects of treatment procedures, such as minimizing radiotherapy exposure (due to reports of malignancies in radiated areas) and the special management of diagnosis implications for other family members. Resumo: A síndrome de Li-Fraumeni (SLF) é uma doença hereditária autorexistente dominante com pena de penetração, que caracteriza a aparição precoz de múltiplos tumores em um indivíduo e uma coletânea familiar. Aproximadamente o 70% dos pacientes com critérios clínicos para o diagnóstico em crianças portadores da mutação germinal do gen TP53 localizado no cromosoma 17p13. El gen TP53 é um tumor tumoral que cumple uma função importante no controle da estabilização genómica. Se estima que o riesgo do desengate faz dos 50% para as mulheres aos 31 anos de idade e para os 40 anos e cerca de 100% para ambos os sexos aos 70 anos. O curso clínico da doença é semelhante ao que ocorre com a SLF a exceção da doença mais tem sido diagnosticada. Presentamos o caso de um paciente de 31 años que diagnostica um paciente de pélvico com relato ao momento da recidiva, aproximadamente 8 meses depois, em um lugar de mama próximo. En otio miembro de la familia se habiocuident to the mutación 375G> C en el gen TP53 por secuenciación Sanger, a cual fue detectada em recente paciente. A discussão foi feita sobre os aspectos do tratamento com a minimização da exposição à radioterapia (por tumores malignos em zonas irradiadas) e o especial manejo da repercussão do diagnóstico a nível dos otros integrantes da familia

El cáncer colorrectal hereditario no asociado a poliposis, también llamado síndrome de Lynch, es reconocido como un síndrome hereditario de patrón autosómico dominante de penetrancia incompleta, en el cual hay mutación en los genes reparadores del ADN. De 2 a 3 % de todos los tumores colorrectales se originan por este síndrome hereditario que predispone a su desarrollo. El síndrome Lynch, el más frecuente de los síndromes genéticos, incrementa, además del riesgo de desarrollar cáncer de colon, el de cáncer metacrónico y otros tipos de cáncer no colorrectal como los de endometrio, de intestino delgado, de uréter o de la pelvis renal. Por lo tanto, es indispensable reconocerlo e identificar a los individuos en riesgo de presentarlo para prevenir, diagnosticar y tratar de manera precoz la aparición de estas neoplasias, y poder disminuir las tasas de morbilidad y mortalidad asociadas. Hereditary nonpolyposis colorectal cancer, also known as Lynch syndrome is recognized as an autosomal dominant hereditary syndrome of incomplete penetrance characterized by mutations in DNA repair genes. It is the most frequent of all the hereditary syndromes, and increases the likelihood of developing colorectal cancer, thus representing 2-3% of all colorectal cancers (CRC). This syndrome predisposes to metachronous (CRC) and other extracolonic cancers, as endometrium, small bowel, ureter and renal pelvis, among others. Therefore, it is necessary to recognize this syndrome and identify individuals with HNPCRC to prevent, diagnose and provide, if possible, early treatment in an effort to decrease its morbidity and mortality.

Background Breast cancer is one of the most prevalent malignancies in the world. In Peru, breast cancer is the second cause of death among women. Five to ten percent of patients present a high genetic predisposition due to BRCA 1 and BRCA 2 germline mutations. Methods We performed a comprehensive analysis of BRCA 1 and BRCA 2 genes by Sanger sequencing and multiplex ligation‐dependent probe amplification (MLPA ) to detect large rearrangements in patients from 18 families, which met the criteria for hereditary breast cancer. Results In this series, we found four pathogenic mutations, three previously reported (BRCA 1 : c.302‐1G>C and c.815_824dup10; BRCA 2 : c.5946delT) and a duplication of adenines in exon 15 in BRCA 1 gene (c.4647_4648dupAA , ClinVar SCV 000256598.1). We also found two exonic and four intronic variants of unknown significance and 28 polymorphic variants. Conclusion This is the first report to determine the spectrum of mutations in the BRCA 1/BRCA 2 genes in Peruvian families selected by clinical and genetic criteria. The alteration rate in BRCA 1/BRCA 2 with proven pathogenic mutation was 22.2% (4 out 18) and this finding could be influenced by the reduced sample size or clinical criteria. In addition, we found three known BRCA 1/BRCA 2 mutations and a BRCA 1 c.4647_4648dupAA as a novel pathogenic mutation.

Introducción: El cáncer colorrectal (CCR) es la cuarta neoplasia más frecuente en el mundo y según el origen de las alteraciones en el genoma de las células, el CCR se clasifica en esporádico (~70%) y genético (~30%), éste último involucra a los síndromes hereditarios de predisposición al CCR. Objetivo: Describir los síndromes hereditarios de predisposición al CCR, polipósicos y no polipósicos, identificados en el consultorio de Oncogenética del INEN. Material y métodos: Estudio descriptivo observacional a partir del registro de atenciones en el consultorio de Oncogenética del INEN durante el periodo 2009 al 2013. Se incluyeron a los pacientes con antecedentes personales o familiares de CCR y/o con poliposis colónica que fueron referidos para la evaluación clínica genética al consultorio de Oncogenética del INEN. Resultados: El 59,3% fueron mujeres, 40,7% varones, 69,8% fueron menores de 50 años, 60,5% presentó un CCR único, 23,2% más de un CCR o un CCR asociado a otra neoplasia extracolónica y el 32,6% poseían antecedentes familiares de cáncer con patrón de herencia autosómico dominante. Según el diagnóstico clínico genético, el 93,1% de los casos incluidos correspondieron a síndromes hereditarios de predisposición al CCR, siendo el 33,8% síndromes de poliposis colónica, 23,3% síndromes de CCR hereditario no polipósico (CCRHNP) y el 36,0% casos probables de síndrome CCRHNP. Conclusiones: La evaluación clínica genética de los pacientes con antecedentes personales o familiares de CCR y/o con poliposis colónica permite identificar a los síndromes hereditarios de predisposición al CCR y brindar una adecuada asesoría genética al paciente y familiares en riesgo, estableciendo medidas de seguimiento y estrategias de prevención a fin de evitar la morbimortalidad por cáncer Background: Colorectal cancer (CRC) is the fourth most common cancer in the world and is classified according to their origin in sporadic CRC (~ 70%) and genetic CRC (~ 30%), this latter involves cases of familial aggregation and inherited syndromes that predispose to CRC. Objective: To describe inherited CRC predisposition syndromes, polyposic and non-polyposic, identified in the Oncogenetics Unit at National Institute of Cancer Disease (INEN). Material and methods: A descriptive observational record from the attentions of the Oncogenetics Unit at INEN during 2009 to 2013. We included patients with personal or familiar history of CRC and/or colonic polyposis who were referred for clinical assessment to the Oncogenetics Unit at INEN. Results: 59.3 % were female, 40.7 % male, 69.8% under 50 years old, 60.5% had a single CRC, 23.2% had more than one CRC or CRC associated with other extracolonic neoplasia and 32.6% had a familiar history of cancer with autosomal dominant inheritance. According to the clinical genetic diagnosis, 93.1% of the included cases were inherited syndromes that predispose to CRC, with 33.8% of colonic polyposis syndromes, 23.3% of hereditary nonpolyposis CRC syndromes (HNPCC) and 36.0% of CCRHNP probable cases. Conclusions: Clinical genetic evaluation of patients with personal or familiar history of CRC and/or colonic polyposis can identify inherited colorectal cancer predisposition syndromes and provide an appropriate genetic counseling to patients and relatives at risk, establishing guidelines to follow-up and prevention strategies to prevent morbidity and mortality by cancer.

El síndrome de Li-Fraumeni se caracteriza por la aparición de tumores en múltiples órganos, generalmente a temprana edad. Esta condición hereditaria es causada por mutaciones germinales en el gen TP53 , que codifica el gen supresor tumoral p53 . Se presenta el caso de una paciente de 31 años con diagnóstico clínico y molecular de síndrome de Li-Fraumeni, que presentó dos tumores sincrónicos a los 31 años: un leiomiosarcoma de antebrazo y un tumor filoides de mama. Tenía el antecedente de un hijo con diagnóstico de carcinoma cortical suprarrenal a los tres años, que falleció a los cinco años debido a la enfermedad. Además, su abuela y su bisabuela maternas habían fallecido de cáncer gástrico a los 56 y 60 años, respectivamente, y la madre y una hermana de su abuelo materno presentaron cáncer de mama pasados los 60 y los 40 años de edad, respectivamente. Después de una asesoría genética, se ordenó hacer la secuenciación completa y el análisis de duplicaciones y deleciones en el gen TP53 . El estudio molecular en una muestra de ADN proveniente de linfocitos de sangre periférica reveló la mutación germinal c.527G>T (p.Cys176Phe) en el exón 5 del gen, mutación deletérea descrita anteriormente en tejidos tumorales. Hasta donde se sabe, este es el primer caso que se publica en Colombia de síndrome de Li-Fraumeni con diagnóstico molecular confirmado. El diagnóstico y el manejo del síndrome de Li-Fraumeni deben estar a cargo de un equipo multidisciplinario, y debe contarse con asesoría genética para el paciente y sus familiares. The Li-Fraumeni syndrome is characterized clinically by the appearance of tumors in multiple organs generally at an early age. This hereditary condition is caused by germinal mutations in the TP53 gene, which codifies for the tumoural suppressor gene p53 . We present the case of a patient aged 31 with clinical and molecular diagnosis of Li-Fraumeni syndrome who presented two synchronous tumors: a leiomyosarcoma on the forearm and a phyllodes breast tumour. She had a family history of cancer, including a son diagnosed with a cortical adrenal carcinoma when he was three years old, who died at five from the disease. Furthermore, her maternal grandmother and great-grandmother died of stomach cancer at 56 and 60 years old, respectively, while her other great-grandmother and a great aunt presented with breast cancer at the ages of 60 and 40, respectively. After genetic counseling, complete sequencing and analysis of duplications and deletions in the TP53 gene were ordered prior to diagnosis. The molecular analysis of a DNA sample taken from peripheral blood lymphocytes revealed the germinal mutation c.527G>T (p.Cys176Phe) on exon 5 of the TP53 gene, a deleterious mutation described previously in tumoural tissues. To our knowledge, this is the first published case in Colombia of Li-Fraumeni syndrome with confirmed molecular diagnosis. The diagnosis and management of Li-Fraumeni syndrome should be performed by a multidisciplinary team, and genetic counselling should be offered to patients and their relatives.

Hereditary breast and ovarian cancer syndrome (HBOC) represents 5–10% of all patients with breast cancer and is associated with high-risk pathogenic alleles in BRCA1/2 genes, but only for 25% of cases. We aimed to find new pathogenic alleles in a panel of 143 cancer-predisposing genes in 300 Mexican cancer patients with suspicion of HBOC and 27 high-risk patients with a severe family history of cancer, using massive parallel sequencing. We found pathogenic variants in 23 genes, including BRCA1/2. In the group of cancer patients 15% (46/300) had a pathogenic variant, 11% (33/300) harbored variants with unknown clinical significance (VUS) and 74% (221/300) were negative. The high-risk group had 22% (6/27) of patients with pathogenic variants, 4% (1/27) had VUS and 74% (20/27) were negative. The most recurrent mutations were the Mexican founder deletion of exons 9-12 and the variant p.G228fs in BRCA1, each found in 5 of 17 patients with alterations in this gene. Rare VUS with potential impact at the protein level were found in 21 genes. Our results show for the first time in the Mexican population a higher contribution of pathogenic alleles in other susceptibility cancer genes (54%) than in BRCA1/2 (46%), highlighting the high locus heterogeneity of HBOC and the necessity of expanding genetic tests for this disease to include broader gene panels.

Background: Brooke-Spiegler syndrome (BSS) is probably an underdiagnosed genodermatosis that predisposes for the development of cylindromas, spiradenomas and trichoepitheliomas mainly of the head and neck. Wide phenotypic variability regarding the number and type of lesions can be observed within a family. Mutations of the CYLD gene are identified in the vast majority of cases and play a key role in BSS pathogenesis. Main observations: Two first degree relatives with numerous erythematous telangiectatic nodules of the scalp present for decades, with recurring tendency regardless the multiple previous excisions. Histopathological review of the lesions revealed predominantly "spiradenocylindromas" in the proband and cylindromas in her sister. The suspicion of BSS was confirmed after detection of a new nonsense germline mutation of CYLD (c.1783C>T pGln 595*) in the proband. Conclusions: BSS diagnosis can be challenging and is based on clinical-pathological correlation, positive familial association and identification of CYLD mutations. CYLD exerts antineoplastic effects by downregulating intracellular NF-κB signalling pathways. The reported mutation affecting the ubiquitin-specific protease domain leads to a truncated and catalytically inactive enzyme. Despite the expanding list of CYLD mutations no firm genotype-phenotype correlation is known so far. Early recognition and treatment of BSS avoid disfiguring changes like "turban tumor". ( J Dermatol Case Rep . 2015; 9(3): 67-70)

BACKGROUND & AIMS: Hereditary diffuse gastric cancer (HDGC) families carry CDH1 heterozygous germline mutations; their tumors acquire complete CDH1 inactivation through "2nd-hit" mechanisms. Most frequently, this occurs via promoter hypermethylation (epigenetic modification), and less frequently via CDH1 mutations and loss of heterozygosity (LOH). We quantified the different 2nd hits in CDH1 occurring in neoplastic lesions from HDGC patients. METHODS: Samples were collected from 16 primary tumors and 12 metastases from 17 patients among 15 HDGC families; CDH1 mutations, LOH, and promoter hypermethylation were analyzed. E-cadherin protein expression and localization were determined by immunohistochemistry. RESULTS: Somatic CDH1 epigenetic and genetic alterations were detected in lesions from 80% of HDGC families and in 75% of all lesions analyzed (21/28). Of the 28 neoplastic lesions analyzed, promoter hypermethylation was found in 32.1%, LOH in 25%, both alterations in 17.9%, and no alterations in 25%. Half of the CDH1 2nd hits in primary tumors were epigenetic modifications, whereas a significantly greater percentage of 2nd hits in metastases were LOH (58.3%; P = .0274). Different neoplastic lesions from the same patient frequently displayed distinct 2nd-hit mechanisms. Different 2nd-hit mechanisms were also detected in the same tumor sample. CONCLUSION: The 2nd hit in CDH1 frequently occurs via epigenetic changes in HDGC primary tumors and LOH in metastases. Because of the concomitance and heterogeneity of these alterations in neoplastic lesions and the plasticity of hypermethylated promoters during tumor initiation and progression, drugs targeting only epigenetic alterations might not be effective, particularly in patients with metastatic HDGC.

El melanoma cutáneo es el cáncer cuya incidencia presenta la mayor tasa de crecimiento en el mundo. Su tasa de mortalidad no ha disminuido pese a las terapias costosas empleadas para su diagnóstico y tratamiento. Puede presentarse bajo dos formas: esporádica y hereditaria. Esta última incluye a individuos con alto riesgo de desarrollar melanoma, variando su frecuencia según la población estudiada. El objetivo general del presente trabajo es contribuir al conocimiento de la predisposición hereditaria de padecer melanoma en Uruguay. Mediante la aplicación de un formulario de tamizaje se identificaron 14 familias con alto riesgo de padecer melanoma hereditario. Diecisiete pacientes integrantes de ellas dieron su consentimiento informado para investigar mutaciones de línea germinal en CDKN2A y CDK4. La detección de cambios genéticos se realizó mediante PCR-SSCP (Polymerase Chain Reaction - Single Stranded Conformational Polymorphism). Los fragmentos con un patrón de bandas de SSCP atípicos fueron analizados mediante secuenciación. Se identificaron dos mutaciones: una en el exón 2 de CDKN2A (E88X) en dos pacientes familiares de primer grado portadoras de melanomas múltiples y síndrome familiar de nevos atípicos (SFNA) y con historia familiar de melanoma y cáncer de páncreas. Esta mutación de línea germinal no ha sido descripta previamente en familias con melanoma. La otra mutación identificada (G101W) es una de las más frecuentes a nivel mundial. Ambas mutaciones fueron identificadas en pacientes con SFNA y múltiples melanomas en sus familias. La frecuencia de mutaciones encontrada concuerda con la documentada en estudios previos que utilizaron criterios de selección similares. Summary Cutaneous melanoma is the cancer whose incidence has the highest growing rates worldwide. Mortality rates have not decreased in spite of diagnostic and management therapies. There are two expressions of melanoma: sporadic and hereditary forms. The latest include persons with high risk to develop melanoma, whose frequency varies according to the studied population. The aim of this study is to analyze hereditary predisposition of melanoma in Uruguay. Fourteen families with high risk of hereditary melanoma were identified using a sift questionnaire. Search for germline mutations in CDKN2A and CDK4 was performed in 17 patients of these families who gave informed consent using PCR-SSCP (Polymerase Chain Reaction - Single Stranded Conformational Polymorphism). Fragments with atypical SSCP patterns were analyzed by sequenciation. Two mutations were identified; the first mutation in exon 2 of CDKN2A (E88X) in two first-degree relatives carriers of multiple melanomas and familial syndrome of atypical nevus (SFNA) with familial history of melanoma and pancreatic cancer (this germinal mutation has not been described in families with melanoma) and the second mutation (G101W) is one of the most frequent worldwide. Both mutations were identified in patients with SFNA and multiple melanoma within families. The frequency of these mutations is the same as reported in previous studies with similar selection criteria. Résumé Le mélanome cutané est le cancer dont l incidence présente le plus fort taux de croissance dans le monde entier. Son taux de mortalité n a pas diminué malgré les thérapies coûteuses employées pour son diagnostic et traitement. Il peut se présenter de deux façons différentes: sporadique et héréditaire. Celle-ci comprend des individus qui ont un grand risque de développer le mélanome, et sa fréquence varie selon la population étudiée. L objectif général du présent travail est de contribuer à la connaissance de la prédisposition héréditaire de souffrir de mélanome en Uruguay. Moyennant l application d un formulaire de tri, on a identifié 14 familles ayant un haut risque de souffrir de mélanome héréditaire. Dix-sept patient intégrants de celles-ci ont donné leur accord informé pour chercher des mutations de ligne germinale à CDKN2A y CDK4. La détection de changements génétiques a été réalisée moyennant PCR-SSCP (Polymérase Chain Reaction - Single Stranded Conformational Polymorphism). Les fragments avec un patron de bandes de SSCP atypiques ont été analysés moyennant un séquençage. On a identifié deux mutations: une dans l exon 2 de CDKN2A (E88X) chez deux patients parents au premier degré porteuses de mélanomes multiples et de syndrome familial de nævus atypiques (SFNA) et avec une histoire familiale de mélanome et de cancer au pancréas. Cette mutation de ligne germinale n a pas été préalablement décrite chez des familles avec mélanome. L autre mutation identifiée (G101W) est l une des plus fréquentes au niveau mondial. Les deux mutations ont été identifiées chez des patients avec SFNA et des multiples mélanomes dans leurs familles. La fréquence de mutations trouvée concorde avec celle documentée dans des études précédentes qui ont utilisé des critères similaires de sélection. Resumo O melanoma cutâneo é o tipo de câncer cuja incidência apresenta a maior taxa de crescimento no mundo. Apesar dos tratamentos caros empregados em seu diagnóstico y tratamento sua taxa de mortalidade não diminui. Pode apresentar-se de duas formas: esporádica e hereditária. Esta última inclui indivíduos com risco alto de desenvolver, sendo que sua freqüência varia segundo a população estudada. O objetivo geral deste trabalho é contribuir ao conhecimento da predisposição hereditária de desenvolver melanoma no Uruguai. Utilizando um formulário de triagem foram identificadas 14 famílias com risco alto de desenvolver melanoma hereditário. Dezessete pacientes integrantes destas famílias deram seu consentimento informado para pesquisar mutações na linha germinal em CDKN2A e CDK4. A detecção de alterações genéticas foi feita utilizando PCR-SSCP (Polymerase Chain Reaction-Single Stranded Conformational Polymorphism). Os fragmentos com um padrão de bandas de SSCP atípicos foram analisados por sequenciação. Foram identificadas duas mutações: uma no exon 2 de CDKN2A (E88X) em dois pacientes familiares em primeiro grau portadores de melanomas múltiplos e síndrome familiar de nevos atípicos (SFNA) e com história familiar de melanoma e câncer de pâncreas. Esta mutação da linha germinal ainda não tinha sido descrita em famílias com melanoma. A outra mutação identificada (G101W) é uma das mais freqüentes em todo o mundo. Ambas mutações foram identificadas em pacientes com SFNA e múltiplos melanomas em suas famílias. A freqüência de mutações encontrada está de acordo com a descrita em estudos anteriores que utilizaram critérios de seleção semelhantes.

Introducción: El gen p53 codifica para una proteína de 53 KD con importante función reguladora en procesos celulares como la proliferación, la muerte celular y la preservación del material genético. Se le conoce como el "guardián del genoma" y frecuentemente se encuentra mutado en casi el 50% de los carcinomas humanos. Se han identificado variantes en su secuencia o polimorfismos genéticos (en diferentes regiones del gen), varios estudios han mostrado una asociación entre el riesgo de desarrollar cáncer mamario y la presencia de estas variantes. El objetivo del presente estudio de casos y controles fue analizar la asociación de los genotipos y las frecuencias alélicas de tres de los polimorfismos del gen p53 con el riesgo de desarrollar cáncer mamario familiar en una población colombiana. Los polimorfismos estudiados fueron: en el exón 4 del gen que corresponde al codón 72 de la proteína, donde puede haber una arginina o una prolina (Arg72Pro); en el intrón 3 (duplicación de 16pb) y en el intrón 6, donde puede encontrarse una guanina o una adenina (G/A). Materiales y métodos: Se analizaron 186 pacientes con cáncer mamario familiar y 186 individuos como controles, las frecuencias alélicas y genotípicas se determinaron por análisis de RFLPs y se midió la fuerza de asociación mediante la razón de disparidad (Odds ratio: OR), con una significancia de la asociación utilizando el intervalo de confianza del 95% y con el programa estadístico SPSS 11,5. Resultados: Las frecuencias genotípicas del codón 72 en la población estudiada fueron: 61,3% para Arg/Arg, 32,3% para Pro/Arg y 6,5% para Pro/Pro en los casos y 44,1, 45,7 y 10,2% respectivamente en los controles. La frecuencia alélica obtenida para arginina en los casos fue 77,4 y 67,0% en los controles (P=0,004). Se obtuvo un OR=2,19 con un IC de 95% (1,33-3,63). La frecuencia de los genotipos del intrón 6 fueron entre casos y controles W/W (75,3 frente a 82,3%), W/M (24,2 frente a 15,6%) y M/M (0,5 frente a 2,2%) mientras que los valores de las frecuencias genotípicas del intrón 3 en los casos fueron: 90,3% para W/W, 8,6% para W/M y 1,1% para M/M y en los controles 98,9% para W/W y 0,5% para W/M y M/M. Las frecuencias alélicas para el alelo silvestre (W) fueron en los casos 94,6% y en los controles 99,2%. Se obtuvo un OR=17,86 con un IC del 95% (2,25-141,84). Conclusiones: Los resultados obtenidos en la población colombiana estudiada muestran una importante asociación entre el genotipo Arg/Arg del codón 72 (dos veces más) y el genotipo W/M intrón 3 (18 veces más) del gen p53 con el riesgo de desarrollar cáncer mamario familiar. Introduction: Gen p53 codifies a 53 KD protein, an important regulator of cell processes such as proliferation, cellular death (apoptosis), and the preservation of the genetic material. It is known as the "guardian of the genoma" and is frequently encountered in a mutated stated in as much as 50% of the human carcinomas. Variants in its sequence, or genetic polymorphism (in various regions of the gen), have been identified, and diverse studies have shown an association of the risk of developing breast cancer with the presence of such variants. The purpose of this cases-controls study was to analyze the association of the genotypes and the allelic frequencies of three of the polymorphisms of gen p53 with the risk of developing familial mammary cancer in a population group in Colombia. Polymorphisms studied were: in the gen´s exon 4, corresponding to codon 72 of the protein, where there may be an aginine or a proline (Arg72Pro); in the intron 3 (duplication of 16pb); and in the intron 6, where there could be found a guanine or an adenine (G/A). Materials and methods: 186 patients with familial breast cancer were studied, with 186 subjects as controls, determining the allelic and genotype frequencies by RFLPS analyses and measurement the force of association by the Odds Ratio (OR), with a significance of the association utilizing a Confidence Interval (CI) of 95% and the statistical program SPSS 11.5. Results. The genotype frequencies of codon 72 in the study population were: 61.3% for Arg/Arg, 32.3% for Pro/Arg, and 6.5% for Pro/Pro in the cases studied, and 44.1%, 45.7% and 10.2%, respectively, for the control subjects. The allelic frequency obtained for arginine in the cases studied were 77.4%, and 67.0% in the control subjects (P=0.004). An OR=2.19 with a 95% CI (1.33-3.63) was observed. The frequency of the genotypes of intron 6 were between the cases and the W/W controls (75.3% versus 82.3%), W/M (24.2% versus 15.6%), and M/M (0.5% versus 2.2%), while the values of the genotype intron 3 frequencies in the cases were: 90.3% for W/W, 8.6% for W/M, and 1.1% for M/M, and in the controls: 98.9% for W/W and 0.5% for W/M and M/M. The allelic frequencies for the silvester allelo (W) were 94.6% in the cases and 99.2% in the controls. An OR=17.86 with a 95% CI (2.25-141.84) was achieved. Conclusions: Our results in the Colombian population group studied show an important association of the Arg/Arg genotype of codon 72 (2 x) and the W/M intron 3 genotype (18 x) of gen p53 with the risk of developing familial mammary cancer.

Una proporción de los cánceres colorrectales presentan algún tipo de predisposición genética que es posible reconocer en la práctica clínica. Desde los clásicos patrones hereditarios dominantes de la poliposis adenomatosa familiar o el cáncer de colon hereditario no asociado a poliposis, pasando por la transmisión recesiva mostrada por la poliposis asociada al gen MYH, hasta llegar a los novedosos síndromes de la "vía serrada" o los alelos de baja penetrancia, el descubrimiento de nuevos genes y el mejor conocimiento de los mecanismos de acción de los ya conocidos, están permitiendo comprender nuevos aspectos de la carcinogénesis colorrectal que arrojan nueva luz sobre algunas de las observaciones de patrones de agregación familiar al cáncer de colon que permanecían inexplicadas. A proportion of colorectal cancers shows some type of genetic predisposition that can be recognised in clinical practice. From the classical dominant inheritance pattern of familial adenomatous polyposis or hereditary non-polyposis colorectal cancer, through the recessive transmission of the MYH associated polyposis, to the new syndromes of the "serrated pathway" or low-penetrance alleles, the discovery of new genes and a deeper understanding of the mechanisms of action of already-known ones are enabling us to understand new aspects of the colorectal carcinogenesis. This is throwing a new light on some of the observed familial aggregation patterns which had remained unexplained.

Una proporción de los cánceres colorrectales presentan algún tipo de predisposición genética que es posible reconocer en la práctica clínica. Desde los clásicos patrones hereditarios dominantes de la poliposis adenomatosa familiar o el cáncer de colon hereditario no asociado a poliposis, pasando por la transmisión recesiva mostrada por la poliposis asociada al gen MYH, hasta llegar a los novedosos síndromes de la "vía serrada" o los alelos de baja penetrancia, el descubrimiento de nuevos genes y el mejor conocimiento de los mecanismos de acción de los ya conocidos, están permitiendo comprender nuevos aspectos de la carcinogénesis colorrectal que arrojan nueva luz sobre algunas de las observaciones de patrones de agregación familiar al cáncer de colon que permanecían inexplicadas.

Germinal mutations in the base excision repair (BER) gene MUTYH (MYH) have recently been described in association with predisposition to multiple colorectal adenomas and cancer. In contrast to the classic dominant condition of familial adenomatous polyposis (FAP) due to germinal mutations in the APC gene, the MYH polyposis is an autosomal recessive disease. The identification of individuals affected by MYH polyposis brings new and important implications for the diagnostic, screening, genetic counseling, follow up and therapeutic options in these patients. In this study, screening for germinal mutations in the MYH gene was performed in 53 Portuguese individuals with multiple colorectal adenomas or classic adenomatous polyposis, in whom no mutation had been identified in the APC gene. The results revealed the presence of biallelic germline MYH mutations in 21 patients. In addition, we here report 3 mutations (c.340T>C [p.Y114H]; c.503G>A [p.R168H]; and c.1186_1187insGG [p.E396fsX437]) which, to our knowledge, have not been previously described. © 2004 Wiley-Liss, Inc.

El cáncer colorrectal hereditario no asociado a poliposis, también llamado síndrome de Lynch, es reconocido como un síndrome hereditario de patrón autosómico dominante de penetrancia incompleta, en el cual hay mutación en los genes reparadores del ADN. De 2 a 3 % de todos los tumores colorrectales se originan por este síndrome hereditario que predispone a su desarrollo. El síndrome Lynch, el más frecuente de los síndromes genéticos, incrementa, además del riesgo de desarrollar cáncer de colon, el de cáncer metacrónico y otros tipos de cáncer no colorrectal como los de endometrio, de intestino delgado, de uréter o de la pelvis renal. Por lo tanto, es indispensable reconocerlo e identificar a los individuos en riesgo de presentarlo para prevenir, diagnosticar y tratar de manera precoz la aparición de estas neoplasias, y poder disminuir las tasas de morbilidad y mortalidad asociadas. Hereditary nonpolyposis colorectal cancer, also known as Lynch syndrome is recognized as an autosomal dominant hereditary syndrome of incomplete penetrance characterized by mutations in DNA repair genes. It is the most frequent of all the hereditary syndromes, and increases the likelihood of developing colorectal cancer, thus representing 2-3% of all colorectal cancers (CRC). This syndrome predisposes to metachronous (CRC) and other extracolonic cancers, as endometrium, small bowel, ureter and renal pelvis, among others. Therefore, it is necessary to recognize this syndrome and identify individuals with HNPCRC to prevent, diagnose and provide, if possible, early treatment in an effort to decrease its morbidity and mortality.