Risk-reducing hysterectomy and bilateral salpingo-oophorectomy in female heterozygotes of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report.

PURPOSE: To determine impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) on gynecological cancer incidence and death in heterozygotes of pathogenic MMR (path_MMR) variants. METHODS: The Prospective Lynch Syndrome Database was used to investigate the effects of gynecological risk-reducing surgery (RRS) at different ages. RESULTS: Risk-reducing hysterectomy at 25 years of age prevents endometrial cancer before 50 years in 15%, 18%, 13%, and 0% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 heterozygotes and death in 2%, 2%, 1%, and 0%, respectively. Risk-reducing BSO at 25 years of age prevents ovarian cancer before 50 years in 6%, 11%, 2%, and 0% and death in 1%, 2%, 0%, and 0%, respectively. Risk-reducing hysterectomy at 40 years prevents endometrial cancer by 50 years in 13%, 16%, 11%, and 0% and death in 1%, 2%, 1%, and 0%, respectively. BSO at 40 years prevents ovarian cancer before 50 years in 4%, 8%, 0%, and 0%, and death in 1%, 1%, 0%, and 0%, respectively. CONCLUSION: Little benefit is gained by performing RRS before 40 years of age and premenopausal BSO in path_MSH6 and path_PMS2 heterozygotes has no measurable benefit for mortality. These findings may aid decision making for women with LS who are considering RRS.

Correction: Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.

PURPOSE: Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer. METHODS: We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years. RESULTS: There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer. CONCLUSION: Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.

Evaluation of MLH1 variants of unclear significance.

Inactivating mutations in the MLH1 gene cause the cancer predisposition Lynch syndrome, but for small coding genetic variants it is mostly unclear if they are inactivating or not. Nine such MLH1 variants have been identified in South American colorectal cancer (CRC) patients (p.Tyr97Asp, p.His112Gln, p.Pro141Ala, p.Arg265Pro, p.Asn338Ser, p.Ile501del, p.Arg575Lys, p.Lys618del, p.Leu676Pro), and evidence of pathogenicity or neutrality was not available for the majority of these variants. We therefore performed biochemical laboratory testing of the variant proteins and compared the results to protein in silico predictions on structure and conservation. Additionally, we collected all available clinical information of the families to come to a conclusion concerning their pathogenic potential and facilitate clinical diagnosis in the affected families. We provide evidence that four of the alterations are causative for Lynch syndrome, four are likely neutral and one shows compromised activity which can currently not be classified with respect to its pathogenic potential. The work demonstrates that biochemical testing, corroborated by congruent evolutionary and structural information, can serve to reliably classify uncertain variants when other data are insufficient.

Germline Mutations in PALB2, BRCA1, and RAD51C, Which Regulate DNA Recombination Repair, in Patients With Gastric Cancer.

Up to 10% of cases of gastric cancer are familial, but so far, only mutations in CDH1 have been associated with gastric cancer risk. To identify genetic variants that affect risk for gastric cancer, we collected blood samples from 28 patients with hereditary diffuse gastric cancer (HDGC) not associated with mutations in CDH1 and performed whole-exome sequence analysis. We then analyzed sequences of candidate genes in 333 independent HDGC and non-HDGC cases. We identified 11 cases with mutations in PALB2, BRCA1, or RAD51C genes, which regulate homologous DNA recombination. We found these mutations in 2 of 31 patients with HDGC (6.5%) and 9 of 331 patients with sporadic gastric cancer (2.8%). Most of these mutations had been previously associated with other types of tumors and partially co-segregated with gastric cancer in our study. Tumors that developed in patients with these mutations had a mutation signature associated with somatic homologous recombination deficiency. Our findings indicate that defects in homologous recombination increase risk for gastric cancer.

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.

Genetic and epigenetic characteristics of patients with colorectal cancer from Uruguay.

Colorectal cancer (CRC), the 3rd most frequent cancer worldwide, affects both men and women. This pathology arises from the progressive accumulation of genetic and epigenetic alterations. In this study, KRAS, NRAS, PIK3CA, and BRAF gene mutations, mismatch repair (MMR) genes methylation profile, microsatellite instability (MSI) and CpG Island Methylator Phenotype (CIMP) status were assessed. The associations of these molecular features with clinicopathological data were also investigated. A hundred and eight unselected CRC samples and their histological and clinical data, were gathered between 2017 and 2020. The prevalence of KRAS, NRAS and BRAF gene mutations was similar to that described in other populations. 28.7% of tumors were KRAS-mutated, mostly in men, distal location, with a CIMP-negative status. BRAFV600E frequency was 6.5% and associated with MSI (p = 0.048), MLH1-methylated (p < 0.001) and CIMP-High (p < 0.001) status. We also confirmed that BRAFV600E tumors were more prevalent in older women and proximal location. A striking different result was the lack of most common variants in the PIK3CA gene. A complete absence of PIK3CA-mutated tumors in a population has not been previously reported. Among MMR genes, the only with an aberrant methylation pattern was MLH1 gene. Its frequency was 9.25%, lower than previously reported. Methylated tumors were most frequent in patients older than 70 years old and proximal tumor location. Finally, CIMP-High status was mainly observed in moderately differentiated tumors with a rate of 15.7%. Our findings were consistent with previous reports in other populations, but also showed some features unique to our cohort. This study is the first to report the analysis of a large number molecular biomarkers of CRC in Uruguay and one of the few performed in Latin-America.

Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment: a report from the prospective Lynch syndrome database.

Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time. Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender. Findings: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers. Interpretation: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. Funding: We acknowledge funding from the Norwegian Cancer Society, contract 194751-2017.

Uptake of hysterectomy and bilateral salpingo-oophorectomy in carriers of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report.

PURPOSE: This study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery [RRS]) in carriers of pathogenic MMR (path_MMR) variants. METHODS: The Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30-69 years. RESULTS: Overall, 144, 79, and 517 carriers underwent risk-reducing hysterectomy, BSO, or both combined, respectively. Two-thirds of procedures before 50 years of age were combined hysterectomy and BSO, and 81% of all procedures included BSO. Risk-reducing hysterectomy was performed before age 50 years in 28%, 25%, 15%, and 9%, and BSO in 26%, 25%, 14% and 13% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 carriers, respectively. Before 50 years of age, 107 of 188 (57%) BSO and 126 of 204 (62%) hysterectomies were performed in women without any prior cancer, and only 5% (20/392) were performed simultaneously with colorectal cancer (CRC) surgery. CONCLUSION: Uptake of RRS before 50 years of age was low, and RRS was rarely undertaken in association with surgical treatment of CRC. Uptake of RRS aligned poorly with gene- and age-associated risk estimates for endometrial or ovarian cancer that were published recently from PLSD and did not correspond well with current clinical guidelines. The reasons should be clarified. Decision-making on opting for or against RRS and its timing should be better aligned with predicted risk and mortality for endometrial and ovarian cancer in Lynch syndrome to improve outcomes.

A snapshot of current genetic testing practice in Lynch syndrome: The results of a representative survey of 33 Latin American existing centres/registries.

We aimed to assess the current genetics practice to manage patients with Lynch syndrome (LS) across Latin America. A Latin American LS survey was sent out to 52 centres/registries, comprising a total of 12 countries from the region. Overall, 33 centres completed the survey, of which the oldest LS registry was established in 1992 in Sao Paulo (Brazil), and the youngest this year in San Jose (Costa Rica). In total, 87% (26/30) of the participating centres/registries belonging to the nine countries are performing genetic testing. Overall, 1352 suspected families were sequenced. Pathogenic variants were identified in 34% of the families, with slightly differing distribution of variants between females and males. Path_MLH1 variants were identified in 39% of females and 50% of males (p = 0.023), while path_MSH2 were identified in 37% of females and males, followed by path_PMS2 in 11% of females and 8% of males, path_MSH6 in 13% of females and 3% of males (p < 0.001) and path_EPCAM in 0.3% of females and 2% of males. In Latin America, 9 of 12 (75%) participating countries had implemented healthcare for LS. LS screening is inconsistently applied within Latin America healthcare systems because of structural differences in the healthcare systems between the countries.

Aggressive mutation in a familial adenomatous polyposis syndrome family: when phenotype guides clinical surveillance.

Familial adenomatous polyposis (FAP) is an autosomal dominant genetic condition, caused by mutations in the adenomatous polyposis coli (APC) tumor suppressor gene. Desmoid tumors (DTs) are seen in 15% to 20% of FAP patients. Specific location of mutation serves as a guide to predict colonic and extra colonic manifestations and their aggressiveness. A severe FAP-phenotypic family was registered in a genetic counselling high-risk Uruguayan hereditary cancer clinic. Proband's DNA was analysed by NGS, detecting a pathogenic mutation in APC gene. All willing family members were counselled and encouraged to be tested. Here we report a kindred formed by 16 individuals with a very severe FAP phenotype. A two-base deletion mutation: c.4393_4394delAG in APC gene and a consequent premature stop codon was detected. DTs were diagnosed in 6 individuals, ranging from 2 to 25 years of age. The causes of death were diverse: gastric cancer, rectal cancer and desmoid tumor. The already described genotype-phenotype correlation has proved its worth in this family, as clinical features reflect the mutation location at 3' end of APC gene. The inheritable and lethal nature of the disease needs a tailored follow up approach in order to reduce mortality, optimize local tumor control, and preserve patients' quality of life.

Tamizaje para cáncer de mama con resonancia magnética en mujeres portadoras de mutaciones BRCA y no-BRCA / Magnetic resonance imaging breast cancer screening in women who are carriers of BRCA and non-BRCA gene mutations / Rastreamento de câncer de mama com ressonância magnética em mulheres com mutações BRCA e não BRCA

Introducción: la predisposición hereditaria causada por mutaciones patogénicas de la línea germinal (MPG) explica hasta el 10% de los cánceres de mama. Para reducir su impacto en mujeres mutadas se han propuesto diferentes estrategias, tales como las cirugías reductoras de riesgo o el screening con resonancia magnética (RM) de mamas. Métodos: en este estudio observacional retrospectivo se analizaron los registros de mujeres portadoras de MPG para evaluar las diferentes acciones tomadas luego del test genético. A las pacientes no mastectomizadas se les recomendó ingresar a un programa anual de cribado con RM y se evaluó el porcentaje de adherencia al plan, el número de biopsias efectuadas y el número de cánceres de mama detectados. Resultados: se incluyeron 134 mujeres con MPG, con una distribución en tercios iguales de los genes BRCA1, BRCA2 y genes no-BRCA. Entre las mutadas con indicación de seguimiento, 64% ingresaron al programa de cribado con RM. Las razones que llevaron a las mujeres a no ingresar al programa de seguimiento fueron: la oposición del médico tratante (53%), oposición de la paciente (38%), y falta de recursos (9%). Se realizaron seis biopsias por hallazgos en la RM entre las cuales se detectó un cáncer de mama. La incidencia de cáncer fue de 11 cada 1.000 mujeres-años de riesgo. Conclusiones: nuestro programa de seguimiento con RM de pacientes mutadas logró captar un porcentaje alto de candidatas. Una proporción significativa de las mujeres no ingresó debido la desaprobación del médico tratante o de la propia paciente. La evidencia obtenida revela una necesidad imperiosa de reforzar los programas educativos que destaquen la importancia del seguimiento con RM de las pacientes de alto riesgo en nuestro país.

Summary: Introduction: genetic propensity caused by germline pathogenic mutations explain up to 10% of breast cancer cases. Different strategies have been proposed to reduce its impact on women who are carriers of mutations, such as risk-reducing surgeries or breast magnetic resonance screening. Method: observational, retrospective study analyzing the medical records of women who are carriers of germline pathogenic mutations to assess the different measures taken after the genetic test. Non-mastectomized patients were advised to join an annual MRI screening program and the percentage of adherence to plan was evaluated, along with biopsies performed and the number of breast cancer cases detected. Results: 134 women carriers of germline pathogenic mutations were included in the study, with equal distributions in thirds for BRCA1, BRCA2 and non-BRCA genes. 64% of carriers of mutations who were subject to follow-up checkups joined the RMI screening program. The reasons why women failed to join the follow-up program were: the treating physician objected to the program (53%), the patients opposed to program (38%) and lack of resources (9%). Six biopsies were performed as a consequence of findings in the RMI, and one case of breast cancer was detected. Cancer incidence was 11 out of 1000 women - risk years. Conclusions: our RMI follow-up program for women who are carriers of mutations managed to attract a high percentage of candidates. A significant amount of women failed to join the program because of their treating physician's or their own disapproval. Evidence obtained reveals the dramatic need to reinforce educational programs that emphasize on the importance of RMI follow-up of high risk patients in our country.

Introdução: a predisposição hereditária causada por mutações germinativas patogênicas (GMP) explica até 10% dos cânceres de mama. Para reduzir seu impacto em mulheres com mutações, diferentes estratégias têm sido propostas, como cirurgias de redução de risco ou ressonância magnética (RM) das mamas. Métodos: neste estudo observacional retrospectivo, os registros de mulheres portadoras de MPG foram analisados para avaliar as diferentes ações tomadas após o teste genético. Pacientes não mastectomizadas foram recomendadas a entrar em um programa anual de triagem por ressonância magnética e foram avaliados o percentual de adesão ao plano, o número de biópsias realizadas e o número de cânceres de mama detectados. Resultados: foram incluídas 134 mulheres com MPG, com uma distribuição de terços iguais dos genes BRCA1, BRCA2 e não-BRCA. Entre as mulheres com mutações com indicação de acompanhamento, 64% entraram no programa de triagem por ressonância magnética. Os motivos que levaram as mulheres a não ingressarem ao programa de acompanhamento foram: oposição do médico assistente (53%), oposição da paciente (38%) e falta de recursos (9%). Seis biópsias foram realizadas devido a achados de ressonância magnética, entre os quais foi detectado um câncer de mama. A incidência de câncer foi de 11 por 1.000 mulheres-ano de risco. Conclusões: nosso programa de acompanhamento de ressonância magnética para pacientes com mutação conseguiu capturar uma alta porcentagem de candidatas. Uma proporção significativa de mulheres não entrou devido à falta de aprovação do médico assistente ou da própria paciente. As evidências obtidas revelam a necessidade urgente de reforçar programas educacionais que destaquem a importância do acompanhamento por RM de pacientes de alto risco no Uruguai.

Three new mutations in hereditary nonpolyposis colorectal cancer (Lynch syndrome II) in Uruguay.

Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common hereditary form of colorectal cancer (CRC). Our purpose is to describe three extended HNPCC families, each of which manifests novel germline mutations in Uruguay, a small country that is a study model for cancer investigation given its high cancer incidence and mortality rate. This is a study of three extended HNPCC families in which extensive genealogic information, medical history, and pathology findings are critically reviewed. DNA testing was performed for evidence of HNPCC mutations. The findings reveal three novel germline mutations, namely MLH1, with a deletion resulting in a frameshift and a premature stop codon (codon 228) in one of the families; in the second family, MSH2 exon 1, codon 61 at nucleotide 181, which results in immediate stop of translation; and in the third family, a mutation in MSH2 at exon 3: the amino acid at nucleotide 530, codon 117, causing a frameshift and a premature stop codon eight base pairs later. We conclude that it is important to study HNPCC mismatch repair genes because of emerging evidence for genotypic and phenotypic heterogeneity, which will harbor the potential to eventually translate this knowledge into specific screening and management protocols. Future projections for such mutations could even contribute to the emergence of molecular-based designer drugs developed through advances in genomics, proteomics, high-throughput screening, and bioinformatics, which would be effective therapeutically for these high-cancer risk patients.

Cáncer de mama y ovario hereditario en Uruguay: resultados del screening para mutaciones en genes de susceptibilidad por secuenciación de nueva generación / Hereditary breast and ovary cancer in Uruguay: screening results for mutations in susceptibility genes by new generation sequencing

Introducción: el cáncer de mama representa la primera causa de muerte por cáncer en mujeres de Uruguay. Se estima que cerca de 7% son causados por mutaciones en el ácido desoxirribonucleico germinal. Los costos de la secuenciación genética han descendido dramáticamente gracias a la aparición de la secuenciación de nueva generación (NGS). El cambio tecnológico abrió una nueva etapa en el estudio del cáncer hereditario en nuestro país. Objetivo: comunicar los resultados de la utilización de tecnología NGS y paneles multigénicos en familias uruguayas con alto riesgo de cáncer de mama hereditario. Pacientes y método: se secuenciaron 135 familias de alto riesgo que provenían de la consulta de consejería genética que funciona en el Grupo Colaborativo Uruguayo: Investigación de afecciones oncológicas hereditarias. Cuando la historia familiar sugería claramente un síndrome de cáncer de mama y ovario hereditario se efectuó secuenciación NGS exclusiva de los genes BRCA1 y 2; cuando el patrón familiar no configuraba claramente se utilizó un panel multigénico. Resultados: se efectuó NGS exclusiva de genes BRCA1 y 2 en 62 familias y un panel multigénico en 73 familias. Se identificaron en total 29 mutaciones patógenas (21 en genes BRCA y 8 en otros genes). Dos de ellas fueron noveles y tres pueden considerarse recurrentes en la población uruguaya. Conclusiones: este trabajo es el primero en Uruguay en reportar el resultado de esta nueva tecnología en el cáncer de mama hereditario. El hallazgo de 29 mutaciones patógenas nos ayuda a delinear el perfil mutacional de nuestro país.

Introduction: breast cancer is women's first cause of death in Uruguay. According to estimations, around 7% of cases result from germinal mutations by deoxyribonucleic acid. The cost of genetic sequencing has dramatically dropped thanks to the arrival of next-generation sequencing (NGS). This technological change opened a new era in the study of hereditary cancer in our country. Objective:to communicate the results of using NGS technology and multigenic panels in Uruguayan families with high risk of hereditary breast cancer. Method: 135 high risk families referred by the genetic counselling consultation that is provided at the Uruguayan Collaborative Group (Hereditary Oncological Conditions Research) were sequenced. When the family history clearly suggested hereditary breast and ovary cancer was a possibility, exclusive NGS sequencing was done for BRCA1 and BRCA2 genes; when the family pattern was not clear to this respect, multigenic panels were used. Results: exclusive NGS sequencing for BRCA1 and BRCA2 genes was done in 62 families, and multigenic panels were used in 73 families. 29 pathogenic mutations were identified (21 in BRCA genes and 8 in other genes). Two of them were new to the disease and three could be considered recurrent in the Uruguayan population. Conclusions:this study is the first one in Uruguay to report the results of this new technology in hereditary breast cancer. The finding of 29 pathogenic mutations contributes to outlining the mutational profile of our country.

Introdução: o câncer de mama é a primeira causa de morte por câncer em mulheres no Uruguai. Estima-se que aproximadamente 7% sejam causados por mutações no ácido desoxirribonucleico germinal. Os custos da sequenciação genética diminuíram dramaticamente graças ao aparecimento da sequenciação de nova geração (NGS). Esta nova tecnologia deu inicio a uma nueva etapa no estudo do câncer hereditário no nosso país. Objetivo: comunicar os resultados da utilização de tecnologia NGS e painéis mutagênicos em famílias uruguaias com alto risco de câncer de mama hereditário. Pacientes e método: 135 famílias de alto risco originárias do aconselhamento genético que funciona no Grupo Colaborativo Uruguaio: Pesquisa de afecções oncológicas hereditárias foram sequenciadas. Quando a história familiar sugeria uma síndrome de câncer de mama e ovário hereditários fez-se a secuenciacao NGS exclusivamente dos genes BRCA1 e 2; quando o padrão familiar não era claro foi utilizado um painel multigênico. Resultados: realizou-se NGS exclusivamente de genes BRCA1 e 2 em 62 famílias e um painel multigênico em 73 famílias. Foram identificadas 29 mutações patogênicas (21 em genes BRCA e 8 em outros genes). Duas eram novas e três podem ser consideradas como recorrentes na população uruguaia. Conclusões: este trabalho é o primeiro que apresenta os resultados desta nova tecnologia aplicada ao câncer de mama hereditário no Uruguai. O achado de 29 mutações patogênicas ajuda a definir o perfil mutacional do nosso país.

Evaluation of MLH1 I219V polymorphism in unrelated South American individuals suspected of having Lynch syndrome.

BACKGROUND: Some single-nucleotide polymorphisms are associated with higher risk of colorectal cancer development and are suggested to explain part of the genetic contribution to Lynch syndrome. AIM: To evaluate the mutL homolog 1 (MLH1) I219V polymorphism in 124 unrelated South American individuals suspected of having Lynch syndrome, based on frequency, association with pathogenic MLH1 and mutS homolog 2 (MSH2) mutation and clinical features. MATERIALS AND METHODS: DNA was obtained from peripheral blood and polymerase chain reaction (PCR) was performed, followed by direct sequencing. RESULTS: The Val allelic of the I219V polymorphism was found in 51.61% (64/124) of the individuals, with an allelic frequency of 0.3. MLH1 or MHS2 pathogenic mutations were found in 32.81% (21/64) and in 23.33% (14/60) of Val-carriers and non-carriers, respectively. CONCLUSION: The Val-carrying genotype was frequent in the studied population; however, it does not appear to exert any modifier effect on MLH1 or MSH2 pathogenic mutations and the development of colorectal cancer.

Comités de Tumores en Uruguay: ¿cuál es el estado de situación diez años después? / Committees on Cancer in Uruguay. What is the state of situation after 10 years?

Introducción: en los últimos años hemos asistido a una escalada en la complejidad del diagnóstico y tratamiento del paciente con cáncer. Se ha comprobado que la evaluación multidisciplinaria de los pacientes oncológicos puede cambiar significativamente la conducta terapéutica. El enfoque multidisciplinario puede incluso reducir la mortalidad, mejorar la calidad de vida y reducir los costos de salud evitando intervenciones o análisis innecesarios. En Uruguay se decretó, enel año 2002, la obligatoriedad de los Comités de Tumores en todo el país.Objetivo: analizar la realidad de los Comités de Tumores en Uruguay diez años después de este decreto y ejemplificar en un tipo de tumor específico, el cáncer de recto, la conducta de una cohorte de especialistas de diferentes sectores del país. Material y método: del 2 de mayo de 2011 al 30 de junio de 2011 se efectuó una encuesta anónima a especialistas en oncología y cirugía.Resultados: se encuestó a un total de 40 oncólogos y 23 cirujanos. Todos coincidieron en la importancia que tienen los Comités de Tumores en la toma de decisiones; 66,7% reportaron su existencia en los sitios de trabajo, 69% cuando se trataba del ámbito laboral público y 45,2% en el privado; 2/63 (3,1%) conocía la integración recomendada de los Comités de Tumores. Al interrogar a los encuestados sobre el tratamiento frente a pacientes portadores de cáncer de recto estadio II o III, 100% de los oncólogos optó por comenzar conneoadyuvancia, mientras que entre los cirujanos, 65,2% eligió neoadyuvancia.Conclusiones: en nuestro sistema de salud, a diez años de legislada la existencia de los Comités de Tumores, esta modalidad de asistencia multidisciplinaria de los pacientes concáncer no se ha desarrollado aún en la forma recomendada.

Introduction: over the last years we have seen how diagnosis and treatment of patients with cancer has become more complex. It has been proved that multidisciplinary assessment of oncological patients may have a significant impact on the therapeutic conduct. Multidisciplinary approach may even reduce mortality rates, improve the quality of life and diminish health costs, avoiding unnecessary interventions or tests. In Uruguay, Committees on Cancer became mandatory in 2002.Objective: to analyze the reality of the Committees on Cancer in Uruguay 10 years after the decree that made them mandatory was approved, and to provide an example on a specific type of tumors - rectal cancer û about the conduct of a cohort of specialists from different sectors in the country. Method: an anonymous survey was conducted from 2 May 2011, through 30 June, 2011, among oncologyand surgery specialists.Results: 40 oncologists and 23 surgeons were surveyed. All of them agreed on the importance of Committees on Cancer in the making of decisions, 66.7% reported they existed at their work sites, 69% when it came to the public employments sector and 45.2% in the private sector; 2 out of 63 (3.1%) were aware of the membersthat formed said committees. When questioned about treatment for patients with stage II or III rectal cancer, 100% of the oncologists chose to start neoadjuvant therapy, while 65.2% surgeons chose neoadjuvant therapy. Conclusions: in our health system, 10 years after the Committees on Cancer became mandatory by law, thismultidisciplinary approach to cancer patients has not developed as recommended.

Introdução: nos últimos anos observamos um aumento importante da complexidade do diagnóstico e do tratamento do paciente com câncer. Foi comprovado que a avaliação multiprofissional dos pacientes oncológicos pode mudar significativamente a conduta terapêutica. Esse tipo de abordagem pode inclusive reduzir a mortalidade, melhorar a qualidade de vida e diminuir os gastos em saúde evitando intervenções ou análises desnecessárias. Em 2002 foi decretado no Uruguai a obrigatoriedade da existência dos Comitês de Tumoresem todo o país.Objetivo: analisar a realidade dos Comitês de Tumores no Uruguai dez anos depois do decreto e mostrarum exemplo com um tipo específico de tumor, o câncer de reto, da conduta de uma coorte de especialistas dediferentes setores do país.Material e método: foi realizado um inquérito anônimo com especialistas em oncologia e cirurgia no período 2 de maio de 2011 a 30 de junho de 2011.Resultados: Foram entrevistados 40 oncologistas e 23 cirurgiões. Todos estiveram de acordo sobre a importância dos Comitês de Tumores na tomada de decisões; 66,7% reportaron sua existência em seus lugares de trabalho sendo 69% quando se tratava do setor público e 45,2% no privado; 2/63 (3,1%) conhecia a composição recomendada dos Comitês de Tumores. Quando se perguntou aos entrevistados qual o tratamento para pacientes portadores de câncer de reto estadio II ou III, 100% dos oncologistas optou por começar comneoadjuvancia, enquanto 65,2% dos cirurgiões escolheu esse tratamento.Conclusões: no nosso sistema de saúde, dez anos depois que a existência dos Comitês de Tumores foi decretada, a assistência multiprofissional dos pacientescom câncer não está desenvolvida de acordo com as recomendações.

Manejo terapéutico actual de la oclusión intestinal maligna no quirúrgica / Current therapeutic handling of non-surgical malignant intestinal

Introducción: la oclusión intestinal (OI) es una complicación frecuente de los pacientes oncológicos en etapa terminal.Cuando no es posible la cirugía, el tratamiento es médico, sin embargo este aún no está protocolizado. Objetivo: analizar el tratamiento de pacientes con diagnóstico de oclusión intestinal maligna (OIM) fuera de sanción quirúrgica. Material y método: trabajo retrospectivo descriptivo de diezpacientes atendidos por la Unidad de Cuidados Paliativos del Servicio de Oncología del Hospital Central de las Fuerzas Armadas, diagnóstico de OIM desde el 1° de enero de 2009 al31 de diciembre de 2010. Resultados: separamos a los pacientes según resultado terapéutico: en quienes revirtió la OIM (6/10) y en quienes no revirtió la OIM (4/10). En el primer grupo la edad media fue de 55 años, la causa de oclusión en 5/6 pacientes fue íleo adinámico. El tratamiento terapéutico comenzó entre el primer y elsexto día de iniciado los síntomas. Todos los pacientes utilizaron dexametasona, metoclopramida, antiácidos y analgésicos, hioscina en 5/6 pacientes, neostigmina fue utilizada en dos pacientes con dolor mínimo, haloperidol y levomepromazina en dos pacientes en que predominaron los vómitos. Lasobrevida media fue de 39 días. En el segundo grupo la edad media fue de 75 años. La causa de OIM fue mecánica en 2/4 pacientes. Todos presentaban más de tres comorbilidades. Todos los pacientes utilizaron metoclopramida, dos de ellos haloperidol y tres dexametasona. Sobrevida media: nuevedías. Discusión: obtuvimos buenos resultados al iniciar tempranamenteun plan con corticoides, haloperidol, analgesia y neostigmina, que deberán ser validados en un estudio prospectivoy con mayor número de pacientes.

Introduction: intestinal or bowel obstruction (BO) is a common complication in terminal cancer patients.When surgery is not an option, therapeutic treatment applies, although there is still no agreed protocol for it.Objective: to analyse the medical treatment of patients with a diagnosis of malignant bowel obstruction when surgery is not an option. Method: retrospective, descriptive study of ten patients who were seen at the Palliative Center Unit of the Oncology Department at the Armed Forces Central Hospital and were diagnosed with malignant bowel obstruction from 1 January, 2009 through 31 December 2010. Results: we classified patients according to their therapeutic response: those whose malignant bowel obstruction evidenced reversion (6/10) and those whoseMBOevidenced no reversion (4/10). Average age in the first group was 55 years old, and an adynamic ileus caused the obstruction in 5 out of 6 patients . Therapeutic treatment was initiated between the first and sixth day after symptoms became evident. All patients received dexamethasone, metoclopramide, antacids and analgesics. Five patients also received hyoscine, neostigmine was used in two patients with minimal pain, haloperidoland levomepromazine was used in two patients with intense vomiting. Average survival was 39 days. In the secondgroup, average age was 75 years old. The cause for the MBO was mechanic in two out of the four patients. All patients presented over three comorbilities. All patients received metoclopramide, two of them haloperidol and dexamethasone was used in three patients. Average survival was 9 days Discussion: Good results were obtained thanks to the early initiation of treatment with corticoids, haloperidol, analgesics and neostigmine. These results need to be validated by a prospective study over a larger population.

Introdução: a oclusão intestinal (OI) é uma complicação freqüente dos pacientes oncológicos em fase terminal.Quando não é possível realizar uma cirurgia, o tratamento é médico, no entanto ainda não existe umprotocolo. Objetivo: analisar o tratamento de pacientes com diagnóstico de oclusão intestinal maligna (OIM) sem possibilidades cirúrgicas. Material e método: trabalho retrospectivo descritivo de dez pacientes atendidos na Unidade de Cuidados Paliativos do Serviço de Oncologia do Hospital Central das Forças Armadas com diagnóstico de OIM no período 1° de janeiro de 2009 ao 31 de dezembro de 2010. Resultados: separamos os pacientes por resultado terapêutico: com reversão da OIM (6/10) e sem reversão (4/10). No primeiro grupo a idade média foi de 55 anos, a causa da oclusão em5 dos 6 pacientes foi íleo adinâmico. O tratamento terapêutico começo entre o primeiro e o sexto dia depois do inicio dos sintomas. Todos los pacientesutilizaram dexametasona, metoclopramida, antiácidos e analgésicos, hioscina en 5dos 6 pacientes, neostigmina foi utilizada em dois pacientes com dor mínima,haloperidol e levomepromazinaemdois pacientes com predomínio de vômitos. La sobrevida média foi de 39 dias. No segundo grupo a idade média foi de 75 anos. A causa de OIM foi mecânica en 2 dos 4 pacientes. Todos tinham mais de três comorbidades. Todos os pacientes utilizaram metoclopramida, dois haloperidol e três dexametasona. Sobrevida média: nove dias. Discussão: obtivemos bons resultados quando o tratamento com um plano com corticóides, haloperidol, analgesia y neostigmina, foi iniciado precocemente; esestes resultados deveriam ser validados em um estudo prospectivo e com um número maior de pacientes.

Sedación paliativa: experiencia en una unidad de cuidados paliativos de Montevideo / Palliative sedation: experience at a Palliative Care Unit in Montevideo

Introducción: la sedación paliativa es una maniobra terapéutica usada con cierta frecuencia en los pacientes al final de la vida y constituye una buena práctica médica cuando está bienindicada. Objetivos: analizar la prevalencia, las indicaciones, dosis y el proceso de sedación en la unidad de cuidados paliativos (UCP) del Hospital Central des las Fuerzas Armadas deMontevideo y compararlo con estudios internacionales. Material y método: es un estudio descriptivo y retrospectivo de 274 pacientes tratados en forma consecutiva por la UCP desde 1° de diciembre de 2006 hasta el 30 de junio de 2008. Resultados: la edad media fue de 65 años. Los motivos de sedación fueron: delirio 35/58 (60,3), dolor 26/58 (44,8), disnea 10/58 (17,2), convulsiones 2/58 (3,4), vómitos 1/58 (1,7). Los fármacos utilizados en la sedación fueron: midazolam en 56/58 (96,5) yhaloperidol en 23/58 (39,6). El intervalo entre el inicio de la sedación y el fallecimiento fue de 2,6 días. En 100 de los casos hubo consentimiento implícito, explícito o delegado.Conclusiones: la sedación paliativa es un procedimiento terapéutico destinado al alivio de los síntomas refractarios que pueden aparecer en el contexto del enfermo al final de la vida. Se deben cumplir los siguientes requisitos: síntoma refractario, enfermedad terminal y consentimiento, y en lo posible estar avalada por una segunda opinión médica. La sedación paliativa no es eutanasia y las diferencias están en el objetivo, el proceso y el resultado.

Introduction: palliative sedation is a therapeutic maneuver often used in patients at the end of life stage, and itconstitutes a good medical practice when well applied. Objective: to analyze prevalence, medical indicationsand the sedation process at the Palliative Care Unit (UCP) of the Armed Forces Central Hospital in Montevideo, and to compare it with other international studies. Methods: this is a descriptive and retrospective studycovering 274 patients who were treated consecutively at the UCP from December 1, 2006 through June 30, 2008. Results: average age was 65 years old. Causes for sedation were: delirium 35/58 (60.3), pain 26/58 (44.8), dyspnea 10/58 (17,2), seizure 2/58 (3,4), and vomits 1/58 (1.7). Drugs used for sedation were: midazolam in 56/58 (96.5) and haloperidol in 23/58 (39,6). The interval between the initiation of sedation and death was 2.6 days.Consent was implicit, explicit or delegated in 100 of cases. Conclusions: palliative sedation is a therapeutic procedure for relieving refractory symptoms that may arise indying patients at the end of life stage. The following conditions are required in order for it to be applied: refractory symptom, terminal illness and consent, and as long as possible, the decision must be supported by a second medical opinion. Palliative sedation is different from euthanasia, and the differences lie in the objective, the process and the result.

Introdução: a sedação paliativa é uma manobra terapêutica usada com certa frequência em pacientes no final da vidasendo uma boa prática médica quando está bem indicada. Objetivos: analisar a prevalência, as indicações, dose e o processo de sedação na unidade de cuidados paliativos (UCP) do Hospital Central das Forças Armadas de Montevidéu e compará-lo com estudos internacionais. Material e método: é um estudo descritivo e retrospectivode 274 pacientes tratados consecutivamente pela UCP no período entre 1° de dezembro de 2006 a 30 dejunho de 2008. Resultados: a idade média foi 65 anos. Os motivos desedação foram: delírio 35/58 (60,3), dor 26/58 (44,8), dispnéia 10/58 (17,2), convulsões 2/58 (3,4), vômitos 1/58 (1,7). Os medicamentos utilizados na sedação foram: midazolam em 56/58 (96,5) e haloperidol em 23/58 (39,6).Ol intervalo entre o início da sedação e o falecimento foi de 2,6 dias. Em 100 de los casos houve consentimento implícito, explícito ou delegado. Conclusões: a sedação paliativa é um procedimentoterapêutico destinado a aliviar os sintomas refratários que podem aparecer no final da vida. Deve-se cumprir com os seguintes requisitos: sintoma refratário, enfermidade terminale consentimento, e na medida do possível, contar com uma segunda opinião médica. A sedação paliativanão é eutanásia e as diferenças estão no objetivo, no processo e no resultado.