Familial erythrocytosis 2 and von Hippel-Lindau disease in the same pediatric patient / Eritrocitosis familiar 2 y enfermedad de von Hippel-Lindau en el mismo paciente

Abstract Background: Patients with familial erythrocytosis type 2 have no increased risk of von Hippel-Lindau-associated tumors, although mutations in the VHL gene cause both pathologies. Case report: We present a case of a compound heterozygote patient with von Hippel-Lindau disease and familial erythrocytosis type 2. One of the mutations found in our patient, c.416C>G (p.Ser139Cys) of the VHL gene, has not been previously reported. This case is the second one reported where von Hippel-Lindau disease and familial erythrocytosis type 2 coexist in the same individual. Conclusions: Despite the low frequency of familial erythrocytosis type 2 in patients with von Hippel-Lindau disease, the possibility of this diagnosis should be considered to avoid unnecessary invasive studies to explain the polyglobulia in these patients and guarantee an adequate follow-up and vigilance of both diseases.

Resumen Introducción: Los pacientes con eritrocitosis familiar tipo 2 no muestran un riesgo incrementado de desarrollar tumores asociados con la enfermedad de von Hippel-Lindau, a pesar de que ambas afecciones están causadas por variantes patogénicas en el gen VHL. Caso clínico: Se presenta el caso de un paciente heterocigoto compuesto con enfermedad de von Hippel-Lindau y eritrocitosis familiar tipo 2. Una de las variantes patogénicas en el paciente, VHL c.416C>G (p.Ser139Cys), no ha sido previamente reportada. Este es el segundo reporte de caso en que la enfermedad de von Hippel-Lindau y la eritrocitosis familiar tipo 2 coexisten en el mismo individuo. Conclusiones: A pesar de la baja frecuencia de la eritrocitosis familiar tipo 2 en pacientes con enfermedad de von Hippel-Lindau, la posibilidad del diagnóstico debe considerarse con el fin de evitar estudios invasivos innecesarios para explicar la presencia de poliglobulia en estos pacientes y para garantizar un adecuado seguimiento y una correcta vigilancia de ambas enfermedades.

Síndrome de Li Fraumeni: análisis clínico de un caso y revisión de la literatura / Li-Fraumeni syndrome: clinical case study and literature survey / Síndrome de Li Fraumeni: análise clínica de um caso e uma revisão da literatura

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

Cáncer ginecológico hereditario en la era de la medicina genómica

Cancer is a genetic disease caused by accumulation of sporadic genetic changes in the tumor tissue, generally after the age of 50. However, 10% to 30% of cases occur before the age of 50, some have a family history of cancer and may have inherited genetic changes that are transmitted from generation to generation and are present since conception. The number of genes identified is more than 80 related to approximately 200 genetic syndromes of predisposition to cancer. The importance of detecting these syndromes in patients and their families is because it allows an accurate diagnosis and prediction of risks and specific controls for each person and family, avoiding illness and death in many cases.

El cáncer es una enfermedad genética producto de la acumulación de cambios genéticos esporádicos en el tejido tumoral. Generalmente se presenta después de los 50 años. Sin embargo, un 10% a 30% de los casos ocurren antes de los 50 años, algunos tienen historia familiar de cáncer y podrían presentar cambios genéticos hereditarios que se transmiten de generación en generación y están presentes desde la concepción. El número de genes que se han identificado son más de 80 relacionados con aproximadamente 200 síndromes genéticos de predisposición al cáncer. La importancia de detectar estos síndromes en los pacientes y familias se debe a que nos permite hacer un diagnóstico preciso, predicción de los riesgos y controles específicos para cada persona y familia, evitando la enfermedad y muerte en muchos casos.

Carcinoma de ovario en paciente con mutación del gen BRCA1. Diagnóstico tras biopsia de adenopatía cervical, en el contexto de un síndrome paraneoplásico cutáneo / Ovarian carcinoma in a patient with a BRCA1 gene mutation. Diagnosis after biopsy of cervical adenopathy, in the context of a cutaneous paraneoplastic syndrome

RESUMEN El cáncer epitelial de ovario representa uno de los tumores ginecológicos más letales ya que más del 75% de las pacientes son diagnosticadas en estadío avanzado. Aún no se ha demostrado que la realización de pruebas y exámenes pélvicos rutinarios haya reducido la mortalidad, no existiendo actualmente, un cribado eficaz para su diagnóstico precoz. Aunque la sintomatología metastásica extraperitoneal más común es el derrame pleural, las linfadenopatías neoplásicas a nivel supraclavicular aparecen hasta en el 4% de casos, generalmente asociándose a un mal pronóstico. La identificación de una adenopatía supraclavicular se relaciona hasta en un 58-83% de los casos, con el hallazgo de una tumoración maligna. Por otro lado, la dermatomiositis del adulto puede tener un origen paraneoplásico en un 15-25% de las ocasiones, siendo el cáncer de mama y de ovario la etiología más frecuente en la población femenina. Las pacientes portadoras de mutaciones en los genes BRCA 1 y 2 tienen un aumento del riesgo de padecer neoplasias de mama y ovario. En aquellas afectas de un cáncer de ovario y portadoras de una mutación en los genes BRCA, no se debería plantear una cirugía profiláctica de rutina sobre la mama, al menos en los primeros 5 años tras el diagnóstico de la neoplasia ovárica. Presentamos el caso de una paciente portadora de una mutación germinal del gen BRCA 1, que debuta con un cáncer de ovario, tras el estudio de una adenopatía neoplásica de cuello, biopsiada en el contexto de un síndrome paraneoplásico cutáneo.

ABSTRACT Epithelial ovarian cancer represents one of the most lethal gynecological tumors, since more than 75% of affected women are diagnosed at an advanced stage. However, studies have not demonstrated yet that performing routine pelvic exams and tests had reduced mortality in ovarian cancer, and currently there is no effective screening for early diagnosis. The most common extraperitoneal metastatic symptomatology of ovarian cancer is pleural effusion, but there are other, like neoplastic lymphadenopathies at supraclavicular level, described in up to 4% of cases and generally related to a poor prognosis. The identification of a supraclavicular adenopathy is associated with the finding of a malignant tumor in 58-83% of the cases. On the other hand, adult dermatomyositis can have a paraneoplastic origin in 15-25% of patients, being breast and ovarian cancer the most frequent etiology in the female population. Patients with BRCA 1 and 2 genes mutations have an increased risk of breast and ovarian malignancies. In those affected by an ovarian cancer and carriers of a mutation in the BRCA genes, routine prophylactic surgery should not be considered on the breast, at least in the first 5 years after the diagnosis of ovarian neoplasia. We present the case of a patient with a germinal mutation of the BRCA 1 gene, who debuts with an ovarian cancer, after the study of a neoplastic adenopathy of neck, biopsied in the context of a cutaneous paraneoplastic syndrome.

Indicação de testagem genética para câncer de mama e ovário hereditários no Hospital São Lucas da PUCRS / The indication of genetic counselling for hereditary breast and ovarian cancer syndrome at Hospital São Lucas da PUCRS

Introdução: O câncer de mama e ovário hereditário ("hereditary breast and ovarian cancer", HBOC) associa-se a mutações herdadas nos genes BRCA1/2. Nesses casos, o aconselhamento genético é mandatório, e a investigação do indivíduo tem como base características pessoais, a história familiar e as características da neoplasia. Uma vez que o diagnóstico HBOC é estabelecido através de testagem genética, existem protocolos bem estabelecidos para manejo do paciente e familiares em risco com objetivo de reduzir risco de câncer nos indivíduos não afetados e personalizar o tratamento nos pacientes já com diagnóstico de neoplasia. Métodos: Esse é um estudo observacional, transversal, de prevalência. Foi realizada uma revisão pelo banco de dados do "Projeto Amazona III" em todas pacientes incluídas do Hospital São Lucas de Porto Alegre. O objetivo do atual estudo foi avaliar as pacientes com critérios de indicação de testagem genética para HBOC através de 2 critérios. Para discussão, foram pesquisados artigos científicos dos últimos 12 anos. Resultados: Dentre os 112 participantes do estudo, 23% preenchiam critérios para testagem genética da Síndrome HBOC. Conclusão: Esse estudo revelou que um expressivo número (23%) de pacientes incluídas no Projeto Amazona III no Hospital São Lucas da PUCRS apresenta critérios para testagem da síndrome HBOC, considerando apenas 2 critérios indicadores de testagem. Além disso, 27% das pacientes apresentavam história familiar de até terceiro grau de câncer de mamãe/ ou ovário, necessitando de aconselhamento genético. A não identificação dessas pacientes significa em diagnósticos de câncer evitáveis.

Objectives: The primary objective is to examine the necessity of genetic testing for Hereditary Breast and Ovarian Cancer (HBOC) syndrome as a preventive measure. Basically, HBOC genetically inherited disorder arising out of mutations in the BRCA1 and BRCA2 genes. The HBOC diagnosis can be conducted through genetic testing. The investigation in these cases is carried out on the basis of individual characteristics, family history and features of the cancer. There are well-established protocols to manage patients and family members whom carry these mutations and to personalize the treatment for the patients already diagnosed with cancer. Methods: This is an observational, cross-sectional, and prevalence study. We conducted a review applying the database of the "Projeto Amazona III" on patients enrolled at the Hospital São Lucas de Porto Alegre (HSL-PUCRS). The purpose of the study was to evaluate patients that fall within the criteria for HBOC genetic testing. We considered only two criteria. We also analyzed the relevant scientific articles of the past 12 years to discuss the subject. Results: 23% of the 112 participants of the study met with the criteria for HBOC genetic testing. Conclusion: This study revealed that a significant number (23%) of the patients enrolled in the "Projeto Amazona III" at the HSL-PUCRS have the two criteria for HBOC genetic testing. Furthermore, 27% of the patients required genetic testing since they had a third-degree family history of breast cancer or ovarian cancer. The failure to identify these patients leads to the absence of the diagnosis of preventable cancer.

Principais tópicos em oncogenética / Main subjects in oncogenetics

Introdução: O câncer é um distúrbio genético no qual ocorre a perda do controle da proliferação celular. De maneira geral, podemos dividir os casos de câncer em esporádicos (mutações somáticas restritas ao tumor), que são a maioria, e hereditários (mutações germinativas presentes em todas as células do indivíduo), que em conjunto correspondem a aproximadamente a 10% de todos os casos. É importante compreender o papel da Oncogenética na identificação de pacientes com risco aumentado para desenvolvimento de câncer para possibilitar medidas de detecção precoce, de prevenção e de tratamento, diferenciadas das recomendadas para a população em geral. Métodos: Foi realizada revisão da literatura através dos sites de busca PubMed e Scielo, bem como através de literatura e Guidelines pertinentes à área da Oncogenética. Resultados: A indicação de investigação genética molecular deve ser baseada em uma suspeita de câncer hereditário, sugerida pela história de câncer do paciente e de sua família. Os critérios de indicação variam para as diversas síndromes hereditárias. Assim, torna-se importante o aconselhamento genético pré e pós-teste, a fim de direcionar a investigação mais indicada para cada caso e permitir que o paciente possa realizar escolhas informadas e adaptar-se ao risco e/ou à condição que esse diagnóstico traz à sua vida. Conclusão: A fim de tornar a oncogenética acessível à população em risco, é necessário capacitar mais profissionais no aconselhamento genético, buscar um maior acesso aos exames moleculares especialmente no serviço público de saúde, garantir a qualidade dos testes realizados por diferentes centros e a adequada interpretação de seus resultados.

Introduction: Cancer is a genetic disorder in which occurs a loss of control of cell proliferation. In general, we can divide cancer cases into sporadic (tumor-restricted somatic mutations), which are the majority, and hereditary (germ mutations present in all the cells of the individual), which together account for approximately 10% of all cases. It is important to understand the role of Oncogenetics in identifying patients at increased risk for cancer development in order to enable early detection, prevention and treatment measures, unlike those recommended for the general population. Methods: A review of the literature was performed through PubMed and Scielo databases, as well as through literature and guidelines considered relevant to the area of Oncogenetics. Results: The indication of molecular genetic research should be based on a suspected hereditary cancer, suggested by the patient's and his family's cancer history. The indication criteria vary for the various hereditary syndromes. Thus, pre and post-test genetic counseling becomes important in order to direct the most appropriate investigation for each case, allowing the patient to make informed decisions and to adapt to the risk and / or to the condition this diagnosis brings to his / her life. Conclusion: In order to make Oncogenetics accessible to the population at risk, it is necessary to train more professionals in genetic counseling, to seek greater access to molecular tests, especially in the public health service, to ensure the quality of the tests carried out by different centers and also to provide adequate interpretation of the results.

Síndrome de Lynch: impacto de la caracterización de familias en base a estudios genéticos / Lynch syndrome: impact of the characterization of families based on genetic studies

El objetivo de este trabajo fue caracterizar demográfica y molecularmente las familias con diagnóstico de síndrome de Lynch en base a estudios genéticos. Se utilizó la base prospectiva del Registro de Epidemiología Molecular de Cáncer Colorrectal (REM-CCR) del Hospital Italiano de Buenos Aires (Clinical trials.gov NCT02781337). El criterio de inclusión fue que tuvieran hecho un estudio genético entre 1996 y 2017 (secuenciación y/o determinación de grandes rearreglos de al menos un gen reparador de error de apareamiento). Se analizaron 50 familias con los criterios de Amsterdam. En 23 (46%) se identificaron variantes patogénicas (n=19) y probablemente patogénicas (n=2). El 28.6% de las variantes patogénicas fueron originalmente descritas en esta serie, entre ellas la variante c.1911del en el exón 12 de MSH2 identificada en una familia con agregación de cáncer de mama. Fue identificada una mutación fundadora de Piamonte, Italia (c.2252_2253del). Los genes afectados incluyeron MSH2 (13 variantes) MLH1 (9 variantes) y PMS2 (1 variante). La tasa de detección de mutaciones fue del 46%. Entre las familias con mutación identificada (n=23), se detectó una edad mediana de inicio del cáncer menor (46 vs. 50 años, p=0.02) y mayor incidencia de tumores extra-colorrectales (90.5% vs. 45.8%, p <0.01), que las 27 sin mutaciones. La implementación de estudios genéticos permitió caracterizar variables demográficas en base a la identificación de mutaciones germinales asociadas al síndrome de Lynch, identificándose dos grupos diferenciados por la edad de afectación y la incidencia de tumores extracolónicos (AU)

The aim of this study was to characterize demographically and molecularly families diagnosed with Lynch syndrome based on genetic studies. Families with a genetic study performed between 1996 and 2017 (sequencing and/or determination of large rearrangements of a mismatch repair gene at least) were selected from the prospective database REM-CCR of Hospital Italiano de Buenos Aires (Clinical trials. Gov NCT02781337). Fifty families fulfilled Amsterdam criteria were analyzed. Pathogenic variants were found in 23 out of 50 (46%) families, being 21 pathogenic and 2 likely pathogenic. The 28.6% of the pathogenic variants were originally described in this series. Among them, the variant c.1911del in MSH2 in a family with breast cancer aggregation and a founder MLH1 mutation from Piedmont, Italy (c.2252_2253del) were identified. Affected genes include MSH2 (13 variants), MLH1 (9 variants), PMS2 (1 variant). Mutations detection rates was 46%. Those families with an identified mutation (n=23) had a lower median age of cancer onset (46 vs. 50 years, p=0.02) and a higher incidence of extra-colorectal tumors (90.5% vs. 45.8%, p<0.01) than those without identified mutations (n=27). The implementation of genetic studies allowed characterizing demographic variables based on the identification of germline mutations associated with Lynch syndrome. Two groups, Síndrome de Lynch: impacto de la caracterización de familias en base a estudios genéticos 3 differentiated by the age of cancer onset and the incidence of extracolonic tumors were characterized (AU)

Molecular diagnosis of hereditary nonpolyposis colorectal cancer (Lynch syndrome) / Diagnóstico molecular del cáncer colorrectal no polipósico hereditario (síndrome de Lynch)

Abstract Lynch syndrome is the most common cause of inherited colorectal cancer, totaling 5 to 8% of all the cases with high susceptibility to this type of cancer and extracolonic cancer. It is related to germinal mutations taking place at mismatch repair genes. The diagnosis of Lynch syndrome is essential for both monitoring patients with this disease and detecting asymptomatic carriers, in order to establish appropriate clinical monitoring, preventive management and genetic counseling. Although clinical criteria have been standardized by implementing Amsterdam I and II, as well as Bethesda guidelines, the detection rate of mutations in these genes only varies between 20% and 60%. The objective of this research was to review the state of the art regarding molecular diagnosis of Lynch syndrome; thus, a review of the literature published from 1995 to 2015 in PubMed database was performed by using the criteria "lynch syndrome molecular screening". 19 articles were selected and reviewed, and the relevant bibliography related to such articles was also reviewed. This paper presents different approaches proposed by several researchers on molecular algorithms to improve the efficiency of Lynch syndrome diagnosis.

Resumen El síndrome de Lynch es la causa más frecuente de cáncer colorectal (CCR) hereditario y representa el 5-8% de los casos con alta susceptibilidad a CCR y cánceres extracolónicos. Este síndrome se relaciona con mutaciones germinales en genes de reparación de malos apareamientos (MMR); su diagnóstico es fundamental, tanto para el seguimiento de los afectados como para la detección de portadores asintomáticos, y tiene el propósito de instaurar un adecuado seguimiento, un manejo preventivo y un asesoramiento genético. Si bien los criterios clínicos han sido estandarizados con la implementación de las guías de Amsterdam I y II y Bethesda, la tasa de detección de mutaciones en estos genes solo varía entre 20% y 60%. El objetivo de esta investigación fue revisar el estado del arte con relación al diagnóstico molecular del síndrome de Lynch, para lo cual se realizó una revisión de la literatura publicada entre 1995 y 2015 en la base de datos PubMed usando como criterio de revisión: "Lynch syndrome molecular screening". Se escogieron y revisaron 19 artículos y además se revisó y escogió la bibliografía pertinente de los artículos. Se presentan propuestas de varios autores sobre los algoritmos moleculares para mejorar la eficiencia del diagnóstico del síndrome de Lynch.

Pediatric inherited cancer predisposition syndromes and TP53 germ-line mutation / 临床儿科杂志

Pediatric inherited cancer predisposition syndromes are a group of diseases caused by germ-line mutation of cancer related genes. The patients are susceptible to cancers. TP53 germ-line mutation is the most commonly seen mutant gene in cancers that accounts for 20%-30%of all germ-line mutations of inherited cancers. TP53 gene mutation screening could help clinicians to better manage the patients and their family members.

Molecular Characterization of the NF2 Gene in Korean Patients with Neurofibromatosis Type 2: A Report of Four Novel Mutations / 대한진단검사의학회지

BACKGROUND: Neurofibromatosis type 2 (NF2) is an autosomal dominant syndrome caused by the NF2 tumor suppressor gene. However, the NF2 mutation characteristics in Korean patients are not sufficiently understood. In this study, we conducted a comprehensive mutational analysis in 7 Korean NF2 patients by performing direct sequencing and gene-dosage assessment. METHODS: We analyzed all exons and flanking regions of NF2 by direct sequencing and screened the deletions or duplications involving NF2 by multiplex ligation-dependent probe amplification. RESULTS: Four novel NF2 mutations, including 2 splice-site mutations (c.364-1G>A and c.886-3C>G), 1 frameshift mutation (c.524delA), and 1 missense mutation (c.397T>C; p.Cys133Arg), were identified in our patients. No large deletion or duplication was identified in our series. Subsequently, we identified an abnormal splicing product by using reverse transcription-PCR and direct sequencing in 2 patients with a novel splice-site mutation. The missense mutation c.397T>C was predicted to have harmful effects on protein function. CONCLUSIONS: The detection rate of NF2 mutations in Korean patients (57%) is similar to those in other populations. Our results provided a greater insight into the mutational spectrum of the NF2 gene in Korean subjects.

Population prevalence of hereditary breast cancer phenotypes and implementation of a genetic cancer risk assessment program in southern Brazil

In 2004, a population-based cohort (the Núcleo Mama Porto Alegre - NMPOA Cohort) was started in Porto Alegre, southern Brazil and within that cohort, a hereditary breast cancer study was initiated, aiming to determine the prevalence of hereditary breast cancer phenotypes and evaluate acceptance of a genetic cancer risk assessment (GCRA) program. Women from that cohort who reported a positive family history of cancer were referred to GCRA. Of the 9218 women enrolled, 1286 (13.9 percent) reported a family history of cancer. Of the 902 women who attended GCRA, 55 (8 percent) had an estimated lifetime risk of breast cancer ³ 20 percent and 214 (23.7 percent) had pedigrees suggestive of a breast cancer predisposition syndrome; an unexpectedly high number of these fulfilled criteria for Li-Fraumeni-like syndrome (122 families, 66.7 percent). The overall prevalence of a hereditary breast cancer phenotype was 6.2 percent (95 percentCI: 5.67-6.65). These findings identified a problem of significant magnitude in the region and indicate that genetic cancer risk evaluation should be undertaken in a considerable proportion of the women from this community. The large proportion of women who attended GCRA (72.3 percent) indicates that the program was well-accepted by the community, regardless of the potential cultural, economic and social barriers.

Clinical approach of hereditary cancer in gynecology / 대한산부인과학회지

Hereditary cancer syndrome is a genetic condition that causes and increases the risk for specific type of cancers. Recent advances in genetics have identified a number of genes associated with inherited susceptibility to cancer, and this rapid development of knowledge about cancer genetics have implications for all aspects of cancer management, including prevention, screening, and treatment. Hereditary patterns of cancer are often characterized by early age at onset, high penetrance, bilaterality in paired organs, vertical transmission through either parent, and an association with other types of tumors. Most representative hereditary cancer syndromes in gynecologic field are hereditary breast/ovarian cancer syndrome (HBOC), hereditary non-polyposis colorectal cancer (HNPCC), Li-Fraumeni syndrome, and Cowden syndrome. Several familial mutations of specific genes, such as BRCA1, 2, TP53, PTEN, MMR, CHEK2, are linked to hereditary cancer syndrome, which are responsible for hereditary gynecologic cancers. It would be very important for gynecologic doctors to know the inclusion criteria for the genetic assessment, taking family history, clinical evaluation, genetic testing, screening guideline and risk reduction strategies for women with hereditary high risk factor. The morbidity and mortality of gynecologic malignancies related to these syndromes could be reduced by the adequate clinical approach, although recent guidelines were developed with an acute awareness of the preliminary nature of much of our knowledge regarding the clinical application of the rapidly emerging field of molecular genetics, and with an appreciation for the need for flexibility when applying these guidelines to individual families.

A importância da suspeição clínica no diagnóstico e tratamento do câncer colorretal hereditário / The importance of clinical suspicion on the diagnosis and treatment of hereditary colorectal cancer

Neste trabalho relatamos o caso de um paciente portador de síndrome de Lynch (HNPCC) que desenvolveu câncer retal metacrônico em curto intervalo de tempo após tratamento do tumor primário (câncer de cólon direito). O objetivo deste relato de caso é salientar a importância da suspeição clínica no diagnóstico de câncer colorretal hereditário e suas implicações terapêuticas.

In this article we report the case of a patient with Lynch syndrome (HNPCC) who developed metachronic rectal cancer in a short time interval after the primary tumor had been treated (right colon cancer). The objective of this case report is to point out the importance of clinical suspicion in the diagnosis of hereditary colorectal cancer and its therapeutics implications.

Cáncer gástrico difuso hereditario (CGDH): presentación de una familia con una nueva mutación del gen CDH1 / Hereditary diffuse gastric Cancer (HDGC): presentation of a family with a new mutation of the CDH1 GENE

Introducción: el CGDH se hereda en forma autosómica dominante. Su sospecha se basa en los antecedentes familiares y su confirmación requiere estudios moleculares. En el 40% de las familias se logra identificar una mutación en el gen CDH1 de la caderina- E que permite discriminar a los portadores y no portadores. La prevención para los portadores de la mutación incluye la gastrectomía profiláctica o la vigilancia endoscópica cada 6 a 12 meses. Objetivo: presentar el caso de una familia con CGDH portadora de una mutación en gen CDH1 no previamente reportada. Caso: mujer de 28 años, gastrectomizada por cáncer gástrico de tipo difuso con antecedentes familiares de cáncer gástrico que mostraba un patrón de herencia autosómico dominante (afectación de 9 miembros en 5 generaciones). Con sospecha de CGDH se comenzó un plan de vigilancia endoscópica y se analizó el ADN purificado de la sangre periférica de la paciente afectada mediante la secuenciación directa del gen CDH1, en la cual se dentificó una mutación sin sentido (non-sense) en la posición 1913 G>A (W638X) del exón 12. Conclusión: la recolección detallada de los antecedentes familiares permitió sospechar una entidad hereditaria muy poco frecuente. Los estudios moleculares confirmaron el diagnóstico, lo que posibilitará la estimación del riesgo individual en los familiares consanguíneos.

Introduction: HDGC is a hereditary cancer syndrome with an autosomic dominant pattern. It may be clinically diagnosed by family background, and confirmed by genetic testing. In 40% of the families, a mutation in the CDH1 gene (E-cadherin) can be identified. Furthermore, the identification of the pathogenic mutation enables the segregate non-carriers (having population risk) and carriers. Prevention for the latter group includes prophylactic gastrectomy or surveillance endoscopy every 6 to 12 months. Objective: to present the case of an HDGC family with identified CDH1 mutation. CASE: 28 yearold woman who underwent gastrectomy for a diffuse ype gastric cancer. Her family background showed multiple gastric cancers with inherited autosomaldominant pattern (affectation of 9 members in 5 generations). Suspecting HDGC, a plan of surveillance endoscopy was iniciated, and a her DNA sample was sequenced for CDH1 gene finding a non-sense mutation in position 1913 G>A (W638X) of exon 12. Conclusion: the detailed recollection of the family background allowed to identify a rare inherited entity. The molecular testing confirmed the diagnosis and will allow future tailored counselling among relatives.

Hereditary cancer and genetic counseling

Hereditary syndromes cause approximately 5 to 10% of overall cancer cases. Cancer related with genetic syndromes are found elsewhere, including stomach, breast, colorectum, ovary, brain and so on. Because hereditary cancers are due to germline mutations, these patients have unique clinical features distinct from sporadic cancer. Generally these features include (i) early age-of onset of cancer, (ii) frequent association with synchronous or metachronous tumors, (iii) frequent bilateral involvement in paired organs (iv) frequent association with other site tumors or characteristic clinical manifestation specific to each genetic syndrome. Due to these differences, the management strategy for patients with hereditary cancer is quite different from that for sporadic cancer. Additionally, there are important screening and surveillance implications for family members. Genetic counselling is prerequisite to these families for risk assessment by pedigree analysis, and guidance to clinical or genetic testing. The genes responsible for these syndromes has recently identified, as a result, genetic testing has become important determining factor in clinical decisions.

A gestão quotidiana da herança indesejada: um estudo sociológico sobre o risco genético de câncer hereditário / Quotidian management of an undesired inheritance: a sociological study on genetic risk of hereditary cancer

Neste artigo, apresentam-se alguns dos dados obtidos em um estudo qualitativo sobre o quotidiano dos sujeitos em risco genético de câncer hereditário do cólon. A perspectiva analítica, que é possível esboçar a partir da análise dos relatos desses indivíduos remete para a importância das condições-limite de aceitação positiva do risco e que, actualmente, se exprime na tendência de diferentes projectos tecnológicos - de que a genética é um exemplo ? apelarem aos desejos individuais e colectivos de um futuro melhor. Outro dos traços estruturantes da gestão quotidiana do risco genético centra-se na experiência familiar do câncer, que permite accionar práticas preventivas indispensáveis ao controlo da doença. Esse saber acumulado e transmitido de geração em geração, por vezes oralmente, outras vezes através da experiência quotidiana com o sofrimento e a morte, ou na partilha das alegrias inerentes ao triunfo sobre o câncer configura-se como um dos pilares na gestão quotidiana da herança, indesejada.

This study presents some results obtained on a qualitative study about the everyday life of the individuals in genetic risk of hereditary cancer. The analytical perspective, which can be outlined on the basis of an analysis of the individuals' reports, points out the importance of the limiting conditions of risk acceptance. This is presently expressed in the tendency for the different technological projects -including genetics - to appeal to both individual and collective wishes for a better future. Another conclusion is that the daily management of genetic risk is centred on the family experience of cancer, which allows preventives practices, indispensable to control the disease, to be put into action. This knowledge, sometimes accumulated and transmitted orally from generation to generation, and other times obtained from experiencing pain and death on a daily basis, or even by sharing in the joy of triumphing over cancer represents one of the pillars of the daily management of an unwelcome inheritance.