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1.
Acta Gastroenterol Belg ; 83(3): 399-405, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33094586

RESUMO

BACKGROUND AND STUDY AIMS: The most important causes of hereditary colorectal cancer are Lynch syndrome (LS) and the adenomatous polyposis syndromes (familial adenomatous poly- posis syndrome or FAP, attenuated FAP or AFAP and MUTYH associated polyposis syndrome or MAP). The aim of this study was to investigate whether all patients with a hereditary syndrome within one center receive uniform advice regarding surveillance and treatment. PATIENTS AND METHODS: A retrospective analysis was performed of all electronic patient health records of patients with LS, FAP, AFAP and MAP who received genetic counselling or were followed by a health care specialist at the University Hospital in Ghent. RESULTS: Data from 122 patients were collected. For all patients, recommendations from the medical genetics department were highly consistent. Adherence to their recommendations was good within the center for the management of colon polyps. There was a lack of consistency in the screening and surveillance advice for other tumors in departments other than gastroenterology. Only 33 patients had systematic follow-up consultations to check results and organize surveillance. CONCLUSION: Previously, small studies have suggested that patients with hereditary gastrointestinal cancer syndromes infrequently have surveillance as specified in the guidelines. This study shows almost uniform recommendations and good adherence for surveillance of the colon, but incomplete or contradictory advice for surveillance of other organs. The need for an integrated approach from a multidisciplinary team will only increase in the future, because more families with hereditary cancer are likely to be found due to the increased use of next generation sequencing in cancer diagnostics.


Assuntos
Polipose Adenomatosa do Colo , Neoplasias do Colo , Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais , Polipose Adenomatosa do Colo/diagnóstico , Polipose Adenomatosa do Colo/epidemiologia , Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Humanos , Estudos Retrospectivos
2.
PLoS One ; 15(7): e0235038, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32609729

RESUMO

Lynch syndrome (LS) is an autosomal dominant condition caused by pathogenic variants in mismatch repair (MMR) genes that predispose individuals to different malignancies, such as colorectal cancer (CRC) and endometrial cancer. Current guidelines recommended testing for LS in individuals with newly diagnosed CRC to reduce cancer morbidity and mortality in relatives. Economic evaluations in support of such approach, however, are not available in Italy. We developed a decision-analytic model to analyze the cost-effectiveness of LS screening from the perspective of the Italian National Health System. Three testing strategies: the sequencing of all MMR genes without prior tumor analysis (Strategy 1), a sequential IHC and MS-MLPA analysis (Strategy 2), and an age-targeted strategy with a revised Bethesda criteria assessment before IHC and methylation-specific MLPA for patients ≥ than 70 years old (Strategy 3) were analyzed and compared to the "no testing" strategy. Quality Adjusted Life Years (QALYs) in relatives after colonoscopy, aspirin prophylaxis and an intensive gynecological surveillance were estimated through a Markov model. Assuming a CRC incidence rate of 0.09% and a share of patients affected by LS equal to 2.81%, the number of detected pathogenic variants among CRC cases ranges, in a given year, between 910 and 1167 depending on the testing strategy employed. The testing strategies investigated, provided one-time to the entire eligible population (CRC patients), were associated with an overall cost ranging between €1,753,059.93-€10,388,000.00. The incremental cost-effectiveness ratios of the Markov model ranged from €941.24 /QALY to €1,681.93 /QALY, thus supporting that "universal testing" versus "no testing" is cost-effective, but not necessarily in comparison with age-targeted strategies. This is the first economic evaluation on different testing strategies for LS in Italy. The results might support the introduction of cost-effective recommendations for LS screening in Italy.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais/diagnóstico , Testes Genéticos/economia , Neoplasias Colorretais/economia , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose/economia , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Análise Custo-Benefício , Reparo de Erro de Pareamento de DNA , Testes Genéticos/métodos , Humanos , Itália/epidemiologia , Proteína 1 Homóloga a MutL/genética , Linhagem , Probabilidade , Anos de Vida Ajustados por Qualidade de Vida
3.
Medicine (Baltimore) ; 99(19): e20124, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32384491

RESUMO

Recent studies have suggested an increased risk of prostate cancer in men with Lynch syndrome driven by germline mutations in mismatch repair (MMR) genes. However, the incidence and clinical implication of MMR deficiency in sporadic prostate cancers remain poorly understood. We immunohistochemically stained for MLH1, MSH2, MSH6, and PMS2 in a set of tissue microarray consisting of 220 radical prostatectomy specimens and evaluated the relationship between loss of their expression and available clinicopathological features. MLH1, MSH2, MSH6, and PMS2 were lost in 2 (0.9%), 6 (2.7%), 37 (16.8%), and 27 (12.3%) prostate cancers, respectively. Loss of at least 1 MMR protein was identified in 50 (22.7%) cases. There were no statistically significant associations between MMR deficiency and patient age, family history of prostate cancer, Gleason score, or pT/pN stage. Nonetheless, the levels of preoperative prostate-specific antigen (PSA) were significantly (P = .015) higher in patients with MMR deficiency (mean ±â€ŠSD: 9.12 ±â€Š9.01 ng/mL) than in those without abnormal MMR (5.76 ±â€Š3.17 ng/mL). There were 15 (6.8%) cases showing loss of at least 2 MMR proteins, which was not significantly associated with PSA level or tumor grade/stage. Additionally, 5 and 2 cases showed losses of at least 3 MMR proteins and all 4 proteins, respectively. Kaplan-Meier analysis revealed no significant associations between loss of MLH1 (P = .373), MSH2 (P = .348), MSH6 (P = .946), or PMS2 (P = .681), or at least 1 (P = .477), 2 (P = .486), or 3 (P = .352) MMR proteins and biochemical recurrence. Further analyses of the data on programmed death-ligand 1 (PD-L1) expression previously stained in the same set of tissue microarray demonstrated associations between loss of ≥2 MMR proteins and a higher rate of PD-L1 expression in cancer cells (17.2% vs 5.2%; P = .033) as well as between cases showing both loss of ≥1 MMR protein(s) and PD-L1 expression in tumor-infiltrating immune cells vs a higher risk of biochemical recurrence (P = .045). MMR protein loss was seen in a subset of prostate cancers. Interestingly, it was associated with significantly higher levels of PSA. Moreover, immunohistochemical detection of MMR proteins together with other proteins, such as PD-L1, might be helpful in predicting tumor recurrence following radical prostatectomy.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/fisiologia , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/genética , Fatores Etários , Idoso , Antígeno B7-H1/biossíntese , Biomarcadores Tumorais , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Proteínas de Ligação a DNA/biossíntese , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/biossíntese , Proteína 1 Homóloga a MutL/biossíntese , Proteína 2 Homóloga a MutS/biossíntese , Gradação de Tumores , Recidiva Local de Neoplasia , Antígeno Prostático Específico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Análise Serial de Proteínas
4.
J. coloproctol. (Rio J., Impr.) ; 40(1): 73-78, Jan.-Mar. 2020. tab
Artigo em Inglês | LILACS | ID: biblio-1090835

RESUMO

Abstract Introduction: Colorectal carcinoma is the third most prevalent neoplasm in the world, and the second cause of death by cancer. The most part of these neoplasms are sporadic by somatic mutations, but around 15% are hereditary, such as Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC). Despite being the same tumor, it has differences between these two contexts as well as different prognosis. In Lynch syndrome cases, the survival of these individuals was greater than that observed in sporadic cases. Methods: This review focuses on the different characteristics and development of colorectal carcinoma in sporadic and Lynch syndrome cases, in order to conclude what may motivate the greater survival in the tumors associated with this syndrome. Results: Although the histopathological features drive into a worse prognosis, the colorectal carcinoma in the Lynch Syndrome presents a greater survival comparing to sporadic colorectal carcinoma. Discussion: The greater survival in the colorectal carcinoma in the HNPCC compared to the sporadic carcinomas has been linked to factors such as high microsatellite instability, diploid predominance, earlier screening for colo-rectal carcinoma, deficient DNA repair mechanism, low p53 mutation rate, and presence of lymphoid aggregates involving the neoplasm. Conclusion: Further studies should be conducted to provide new insights about survival of colorectal carcinoma in Lynch syndrome, as well as the therapeutic alternatives for this neoplasia.


Resumo Introdução: O carcinoma colorretal é a terceira neoplasia mais prevalente no mundo, bem como a segunda causa de morte por câncer. A maioria destas neoplasias são esporádicas, devidas a mutações somáticas, mas cerca de 15% são hereditárias como a síndrome de Lynch ou Hereditary Nonpolyposis Colorectal Cancer (HNPCC). Apesar de ser a mesma neoplasia, esta apresenta características clinico-patológicas e moleculares distintas, bem como diferentes prognósticos. Nos casos de síndrome de Lynch, a sobrevida parece ser maior quando comparada com os carcinomas esporádicos. Métodos: Realizamos uma revisão bibliográfica sobre as diferentes características e desenvolvimentos do carcinoma colorretal esporádico e no contexto da síndrome de Lynch, para concluir o que causa a maior sobrevida no caso das neoplasias associadas a esta síndrome. Resultados: Apesar das características histopatológicas apontarem para um pior prognóstico, o HNPCC apresenta uma maior sobrevida em relação ao carcinoma colorretal esporádico. Discussão: A maior sobrevivência nos carcinomas colorretais associados ao HNPCC em comparação com os carcinomas colorretais esporádicos tem sido atribuída a fatores como a elevada instabilidade microssatélite, a predominância diploide, a realização de rastreio para o carcinoma colorretal mais precoce, deficiente mecanismo de reparação de DNA, menor taxa de mutação da p53 e existência de agregados linfoides a envolver a neoplasia. Conclusão: Consideramos que deve ser encorajado o estudo mais aprofundado dos fatores que levam à maior sobrevida do carcinoma colorretal na síndrome de Lynch, bem como de alternativas terapêuticas para esta neoplasia.


Assuntos
Neoplasias Colorretais , Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia
5.
Gastroenterology ; 158(5): 1326-1333, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31926173

RESUMO

BACKGROUND & AIMS: Lynch syndrome is caused by variants in DNA mismatch repair (MMR) genes and associated with an increased risk of colorectal cancer (CRC). In patients with Lynch syndrome, CRCs can develop via different pathways. We studied associations between Lynch syndrome-associated variants in MMR genes and risks of adenoma and CRC and somatic mutations in APC and CTNNB1 in tumors in an international cohort of patients. METHODS: We combined clinical and molecular data from 3 studies. We obtained clinical data from 2747 patients with Lynch syndrome associated with variants in MLH1, MSH2, or MSH6 from Germany, the Netherlands, and Finland who received at least 2 surveillance colonoscopies and were followed for a median time of 7.8 years for development of adenomas or CRC. We performed DNA sequence analyses of 48 colorectal tumors (from 16 patients with mutations in MLH1, 29 patients with mutations in MSH2, and 3 with mutations in MSH6) for somatic mutations in APC and CTNNB1. RESULTS: Risk of advanced adenoma in 10 years was 17.8% in patients with pathogenic variants in MSH2 vs 7.7% in MLH1 (P < .001). Higher proportions of patients with pathogenic variants in MLH1 or MSH2 developed CRC in 10 years (11.3% and 11.4%) than patients with pathogenic variants in MSH6 (4.7%) (P = .001 and P = .003 for MLH1 and MSH2 vs MSH6, respectively). Somatic mutations in APC were found in 75% of tumors from patients with pathogenic variants in MSH2 vs 11% in MLH1 (P = .015). Somatic mutations in CTNNB1 were found in 50% of tumors from patients with pathogenic variants in MLH1 vs 7% in MSH2 (P = .002). None of the 3 tumors with pathogenic variants in MSH6 had a mutation in CTNNB1, but all had mutations in APC. CONCLUSIONS: In an analysis of clinical and DNA sequence data from patients with Lynch syndrome from 3 countries, we associated pathogenic variants in MMR genes with risk of adenoma and CRC, and somatic mutations in APC and CTNNB1 in colorectal tumors. If these findings are confirmed, surveillance guidelines might be adjusted based on MMR gene variants.


Assuntos
Adenoma/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Proteínas de Ligação a DNA/genética , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Adenoma/diagnóstico , Adenoma/genética , Proteína da Polipose Adenomatosa do Colo/genética , Adulto , Colonoscopia , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA , Análise Mutacional de DNA , Feminino , Finlândia/epidemiologia , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Países Baixos/epidemiologia , Estudos Prospectivos , beta Catenina/genética
6.
Jpn J Clin Oncol ; 50(1): 80-88, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31665498

RESUMO

BACKGROUND: The prevalence of Lynch syndrome and the use of universal tumor screening to identify Lynch syndrome among unselected patients with upper urinary tract urothelial carcinoma, which is associated with Lynch syndrome, have not been closely investigated yet. METHODS: A total of 166 tumors from 164 upper urinary tract urothelial carcinoma patients were tested for microsatellite instability and expression of mismatch repair proteins (MLH1, MHS2, MSH6 and PMS2) by immunohistochemistry. Genetic testing was performed for patients suspected of having Lynch syndrome. Clinicopathological factors, including familial and personal cancer history associated with mismatch repair deficiency, were evaluated. RESULTS: The frequency of high-level microsatellite instability and loss of at least one mismatch repair protein was 2.4% (4/164); the microsatellite instability and immunohistochemistry results showed complete concordance. Of these four patients, three were genetically proven to have Lynch syndrome, while the remaining one was highly suggestive for Lynch syndrome based on their personal cancer history. Univariate analysis showed that age<70 years (P = 0.04), ureter as the tumor location (P = 0.052), previous history/synchronous diagnosis of colorectal cancer (P < 0.01) and fulfillment of the criteria per the revised Bethesda guideline (P < 0.01) tended to be or were significantly associated with high-level microsatellite instability/mismatch repair loss. CONCLUSIONS: The prevalence of Lynch syndrome among unselected upper urinary tract urothelial carcinoma patients was at least 1.8% in our study population. The screening efficacies of the microsatellite instability test and immunohistochemistry appear equivalent. Universal tumor screening may be a valid approach; however, selective screening methods that consider factors associated with mismatch repair loss/high-level microsatellite instability tumors require further investigation.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Instabilidade de Microssatélites , Neoplasias Urológicas/epidemiologia , Neoplasias Urológicas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas , Carcinoma de Células de Transição/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Detecção Precoce de Câncer/métodos , Feminino , Testes Genéticos , Humanos , Imuno-Histoquímica , Japão/epidemiologia , Masculino , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/genética , Síndromes Neoplásicas Hereditárias , Prevalência , Sistema Urinário/patologia , Neoplasias Urológicas/complicações
7.
Genes Chromosomes Cancer ; 59(2): 111-118, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31433521

RESUMO

Interpretation of missense variants remains a major challenge for genetic diagnosis, even in well-known genes such as the DNA-mismatch repair (MMR) genes involved in Lynch syndrome. We report the characterization of a variant in MSH2: c.1022T>C, which was identified in 20 apparently unrelated families living in the North of France. A total of 150 patients from 20 families were included in this study. Family segregation studies, tumor analyses and functional analyses at both the RNA and protein levels were performed. Founder effect was evaluated by haplotype analysis.We show that MSH2 c.1022T>C is a missense variant (p.Leu341Pro) that affects protein stability. This variant is frequent in the North of France (7.7% of pathogenic variations identified in MMR genes), and is located on an ancestral haplotype. It is associated with a high risk of a broad tumor spectrum including brain and cutaneous cancers. The MSH2 c.1022T>C variant is a pathogenic founder variation associated with a high risk of cancer. These findings have important implications for genetic counseling and management of variant carriers.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Proteína 2 Homóloga a MutS/genética , Adulto , Idoso , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Reparo de Erro de Pareamento de DNA , Éxons , Feminino , Efeito Fundador , França/epidemiologia , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Haplótipos , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Proteína 2 Homóloga a MutS/metabolismo , Mutação de Sentido Incorreto , Linhagem , Polimorfismo de Nucleotídeo Único
8.
Dis Colon Rectum ; 63(2): 152-159, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31842160

RESUMO

BACKGROUND: Obtaining an accurate pedigree is the first step in recognizing a patient with hereditary nonpolyposis colorectal cancer, or Lynch syndrome. However, lack of standardization of the degree of relationship included in the pedigrees generally limits obtaining a complete and/or accurate pedigree. DESIGN: This study analyzed the extent of pedigree required to screen for colorectal cancer and to diagnose Lynch syndrome. SETTINGS: The study was conducted at 2 tertiary care centers. PATIENTS: A detailed family history was obtained from patients undergoing surgery for colorectal cancer from 2003 to 2016. A simplified pedigree that included only first-degree relatives was obtained and compared with the extended pedigree. MAIN OUTCOME MEASURES: The eligibility of the 2 pedigrees was assessed for each proband. The proportion of patients who would be missed using a simplified rather than an extended pedigree was calculated based on the American Cancer Society guidelines for recommending screening for colorectal cancer, on the revised Bethesda guidelines and the revised suspected hereditary nonpolyposis colorectal cancer criteria for screening for hereditary colorectal cancer, and on the Amsterdam II criteria for diagnosis of Lynch syndrome. RESULTS: The study examined 2015 families, including 41,826 individuals. Use of simplified and extended pedigrees was comparable in screening for colorectal cancer, with ratios of 183 of 185 (98.9%) for American Cancer Society guidelines, 295 of 295 (100%) for revised Bethesda guidelines, and 60 of 60 (100%) for revised suspected hereditary nonpolyposis colorectal cancer criteria. However, the use of simplified pedigrees missed a definitive diagnosis of Lynch syndrome in 6 of 10 patients fulfilling Amsterdam II criteria based on extended pedigrees. The mean ages at diagnosis of the 4 probands included and the 6 missed using simplified pedigrees differed significantly (60.8 vs 38.2 y). LIMITATIONS: The study was limited by its recall bias, cross-sectional nature, lack of germline testing, and potential inapplicability to the general population. CONCLUSIONS: A simplified pedigree is acceptable for selecting candidates to screen for hereditary colorectal cancer, whereas an extended pedigree is still required for a more precise diagnosis of Lynch syndrome, especially in younger patients. See Video Abstract at http://links.lww.com/DCR/B97. EXTENSIÓN DE PEDIGREE REQUERIDO EN LA DETECCIÓN Y DIAGNÓSTICO DE CÁNCER COLORRECTAL HEREDITARIO SIN POLIPOSIS: COMPARACIÓN DE LOS PEDIGREES SIMPLIFICADO Y EL EXTENDIDO: La obtención de un Pedigree exacto es el primer paso para reconocer un paciente con cáncer colorrectal hereditario sin poliposis o síndrome de Lynch. Sin embargo, la falta de estandarización del grado de relación incluido en los Pedigrees generalmente limita la obtención de un Pedigree completo y / o preciso.Este estudio analizó el grado de Pedigree requerido para detectar el cáncer colorrectal y diagnosticar el síndrome de Lynch.Se obtuvo una historia familiar detallada de pacientes sometidos a cirugía por cáncer colorrectal desde 2003 hasta 2016. Se obtuvo también un Pedigree simplificado que incluía solo familiares de primer grado y se comparó con el Pedigree extendido.La elegibilidad de los dos Pedigrees se evaluó para cada sujeto de prueba (proband). La proporción de pacientes que se perderían usando un Pedigree simplificado en lugar de extendido se calculó en base a las guías de la Sociedad Americana del Cáncer y sus recomendaciones en la detección de cáncer colorrectal, en las pautas revisadas de Bethesda y en los criterios revisados de cáncer colorrectal hereditario sin poliposis para la detección hereditaria de cáncer colorrectal y según las normas de Amsterdam II para el diagnóstico del síndrome de Lynch.El estudio examinó a 2.015 familias, incluidas 41.826 personas. El uso de Pedigree simplificado y extendido fue comparable en la detección del cáncer colorrectal, con proporciones de 183/185 (98,9%) comparadas con las recomendaciones de la American Cancer Society, 295/295 (100%) para las pautas revisadas de Bethesda y 60/60 (100%) para los criterios revisados de sospecha de cáncer colorrectal hereditario sin poliposis. Sin embargo, el uso de Pedigree simplificado omitió un diagnóstico definitivo del síndrome de Lynch en 6 de diez pacientes que cumplían las normas de Amsterdam II basados en Pedigrees extendidos. Las edades medias al diagnóstico de los cuatro sujetos de prueba incluidos y los seis perdidos usando el Pedigree simplificado diferían significativamente (60.8 vs. 38.2 años).Un Pedigre simplificado es aceptable en la selección de candidatos para la detección de cáncer colorrectal hereditario, mientras que aún se requiere un Pedigree extendido para un diagnóstico más preciso de síndrome de Lynch, especialmente en pacientes más jóvenes. Consulte Video Resumen en http://links.lww.com/DCR/B97. (Traducción-Dr. Edgar Xavier Delgadillo).


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/cirurgia , Adenocarcinoma , Adulto , Idoso , Neoplasias Colorretais/patologia , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Estudos Transversais , Feminino , Humanos , Masculino , Programas de Rastreamento/métodos , Anamnese , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Linhagem , Prevalência
9.
Genet Med ; 21(10): 2390-2400, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30918358

RESUMO

PURPOSE: There are no internationally agreed upon clinical guidelines as to which women with gynecological cancer would benefit from Lynch syndrome screening or how best to manage the risk of gynecological cancer in women with Lynch syndrome. The Manchester International Consensus Group was convened in April 2017 to address this unmet need. The aim of the Group was to develop clear and comprehensive clinical guidance regarding the management of the gynecological sequelae of Lynch syndrome based on existing evidence and expert opinion from medical professionals and patients. METHODS: Stakeholders from Europe and North America worked together over a two-day workshop to achieve consensus on best practice. RESULTS: Guidance was developed in four key areas: (1) whether women with gynecological cancer should be screened for Lynch syndrome and (2) how this should be done, (3) whether there was a role for gynecological surveillance in women at risk of Lynch syndrome, and (4) what preventive measures should be recommended for women with Lynch syndrome to reduce their risk of gynecological cancer. CONCLUSION: This document provides comprehensive clinical guidance that can be referenced by both patients and clinicians so that women with Lynch syndrome can expect and receive appropriate standards of care.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/terapia , Neoplasias do Endométrio/terapia , Neoplasias dos Genitais Femininos/terapia , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Consenso , Detecção Precoce de Câncer , Neoplasias do Endométrio/epidemiologia , Europa (Continente) , Feminino , Neoplasias dos Genitais Femininos/epidemiologia , Humanos , Programas de Rastreamento , América do Norte , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/terapia
10.
Am J Surg ; 218(5): 928-933, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-30904142

RESUMO

BACKGROUND: Lynch syndrome (LS) has a 80% lifetime risk of developing colorectal cancer and metachronous cancer. No studies have examined the quality adjusted life expectancy after SEG or TAC for LS patients, which this study was aiming for. If TAC offers a higher quality adjusted life year (QALY) to SEG in LS patients, preoperative diagnosis of LS is critical as it alters the recommended surgical procedure. METHODS: A Markov decision tree was constructed using Treeage software to compare QALY of LS patients following SEG or TAC. Probabilities, cost, and utility were obtained from literature. Cost-effectiveness analyses were performed. RESULTS: TAC dominates SEG as both the life-saving and cost-saving strategy. TAC dominated SEG on QALY (17.80 vs 17.13 QALY) for a cohort of LS patients diagnosed at an average of 30 year old and followed every 2 years after initial surgery. CONCLUSIONS: We conclude that TAC as the primary surgical option for LS patients diagnosed with Stage I-III colon cancer is cost-effective. Further cost-effectiveness study is recommended to include extra-colonic malignancies in LS patients.


Assuntos
Colectomia/métodos , Neoplasias Colorretais Hereditárias sem Polipose/cirurgia , Abdome/cirurgia , Colectomia/estatística & dados numéricos , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/economia , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Análise Custo-Benefício , Árvores de Decisões , Humanos , Cadeias de Markov , Método de Monte Carlo , Qualidade de Vida
11.
Fam Cancer ; 18(2): 211-219, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30627969

RESUMO

Lynch syndrome is one of the most common hereditary cancer predisposition syndromes and is associated with increased risks of colorectal and endometrial cancer, as well as multiple other cancer types. While the mechanism of mismatch repair deficiency and microsatellite instability and its role in Lynch-associated carcinogenesis has been known for some time, there have been significant advances recently in diagnostic testing and the understanding of the molecular pathogenesis of Lynch tumors. There is also an increased awareness that the clinical phenotype and cancer risk varies by specific mismatch repair mutation, which in turn has implications on surveillance strategies for patients. Even the treatment of Lynch-associated cancers has changed with the addition of immunotherapy for advanced disease. This progress report aims to review some of the many advances in epidemiology, molecular pathogenesis, diagnosis, clinical phenotype, cancer surveillance, treatment, and chemo- and immune-prevention strategies in the Lynch syndrome field over the past 5 years.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Colectomia/tendências , Neoplasias Colorretais Hereditárias sem Polipose/terapia , Testes Genéticos/tendências , Conduta Expectante/tendências , Quimioterapia Adjuvante/métodos , Quimioterapia Adjuvante/tendências , Colectomia/métodos , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Predisposição Genética para Doença , Testes Genéticos/métodos , Humanos , Instabilidade de Microssatélites , Mutação , Fenótipo , Prevalência , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Conduta Expectante/métodos
12.
Dig Liver Dis ; 51(2): 299-303, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30448460

RESUMO

BACKGROUND AND AIMS: Lynch syndrome (LS) is associated with an increased risk of small bowel tumors but routine screening is not recommended in international guidelines. The aim of our study was to determinate the prevalence of duodenal tumors in a French cohort of LS patients. METHODS: Patients carrying a germline pathogenic variant in a MMR gene, supported by our local network, in which at least one upper endoscopy had been performed, were included. We registered the occurrence of duodenal lesions in those patients. RESULTS: 154 LS patients were identified including respectively 85 MSH2 and 41 MLH1 mutated patients respectively. Seven out of 154 (4.5%) had at least one duodenal lesion. Median age at diagnosis was 58 years (range: 49-73). The twelve lesions locations were: descending duodenum (n = 7), genu inferius (n = 2), duodenal bulb (n = 1), ampulla (n = 1), fourth duodenum (n = 1). Three lesions were invasive adenocarcinomas. The incidence rate of duodenal lesions in patients with MSH2 or MLH1 pathogenic variants was respectively 7.1% (6 out of 85) and 2.4% (1 out of 41) emphasizing a trend toward increased risk of developing duodenal lesion in MSH2 mutated patients: OR: 5.17, IC95% (0.8-60.07), p = 0.1307. CONCLUSION: Regarding this high prevalence rate, especially in MSH2 patients, regular duodenal screening during upper endoscopy should be considered in routine in LS patients.


Assuntos
Adenocarcinoma , Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Duodenais , Duodeno/patologia , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Adenocarcinoma/epidemiologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Estudos de Coortes , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Reparo do DNA , Enzimas Reparadoras do DNA , Neoplasias Duodenais/epidemiologia , Neoplasias Duodenais/genética , Neoplasias Duodenais/patologia , Endoscopia Gastrointestinal/métodos , Feminino , França/epidemiologia , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Subunidades Proteicas
13.
Fam Cancer ; 18(1): 67-73, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30019097

RESUMO

Past methods for estimating the population frequency of familial cancer syndromes have used cases and controls ignoring the familial nature of genetic disease. In this study we modified the capture-recapture method from ecology to estimate the number of families in central Ohio with Lynch syndrome (LS). We screened 1566 colorectal cancer cases and 545 endometrial cancer cases in central Ohio from 1999 to 2005 and identified 58 with LS. We screened an additional 3346 colorectal and 342 endometrial cancer cases from 2013 to 2016 and identified 149 with LS. We found 12 LS mutations shared between families observed in the first and second studies. We identified three individuals between studies who were closely related and eight who were more distantly related. We used identified family relationships and genetic test results to estimate family size and structure. Applying a modified capture-recapture method we estimate 1693 3-generation families in the area who have 288 unique LS causing mutations. Comprehensive colorectal and endometrial cancer screening will take about 20 years to identify 50% of families with LS. This is the first time that the capture-recapture method has been applied to estimate the burden of families with a specific heritable disease. Family structure reveals the potential extent of prevention and the time necessary to identify a proportion of families with LS.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Detecção Precoce de Câncer/métodos , Testes Genéticos/estatística & dados numéricos , Anamnese/estatística & dados numéricos , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/prevenção & controle , Efeitos Psicossociais da Doença , Detecção Precoce de Câncer/estatística & dados numéricos , Neoplasias do Endométrio/genética , Feminino , Humanos , Mutação , Ohio/epidemiologia
14.
Int J Cancer ; 145(1): 87-98, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30575961

RESUMO

Colorectal carcinomas that are mismatch repair (MMR)-deficient in the absence of MLH1 promoter methylation or germline mutations represent Lynch-like syndrome (LLS). Double somatic events inactivating MMR genes are involved in the etiology of LLS tumors. Our purpose was to define the clinical and broader molecular hallmarks of LLS tumors and the population incidence of LLS, which remain poorly characterized. We investigated 762 consecutive colorectal carcinomas operated in Central Finland in 2000-2010. LLS cases were identified by a stepwise protocol based on MMR protein expression, MLH1 methylation and MMR gene mutation status. LLS tumors were profiled for CpG Island Methylator Phenotype (CIMP) and somatic mutations in 578 cancer-relevant genes. Among 107 MMR-deficient tumors, 81 (76%) were attributable to MLH1 promoter methylation and 9 (8%) to germline mutations (Lynch syndrome, LS), leaving 14 LLS cases (13%) (3 remained unclassified). LLS carcinomas were diagnosed at a mean age of 65 years (vs. 44 years in LS, p < 0.001), had a proximal to distal ratio of 1:1, and all were BRAF V600E-negative. Two somatic events in MMR genes were identifiable in 11 tumors (79%). As novel findings, the tumors contained an average of 31 nonsynonymous somatic mutations/Mb and 13/14 were CIMP-positive. In conclusion, we establish the epidemiological, clinical and molecular characteristics of LLS in a population-based study design. Significantly more frequent CIMP-positivity and lower rates of somatic mutations make a distinction to LS. The absence of BRAF V600E mutation separates LLS colorectal carcinomas from MLH1-methylated colorectal carcinomas with CIMP-positive phenotype.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Adulto , Idoso , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA , Finlândia/epidemiologia , Humanos , Instabilidade de Microssatélites , Epidemiologia Molecular , Proteína 1 Homóloga a MutL/genética , Mutação , Estudos Retrospectivos
15.
Fam Cancer ; 18(2): 183-191, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30302651

RESUMO

Development of multiple colorectal cancers (CRCs), synchronously or metachronously, is associated with hereditary predisposition for cancer and accurate risk estimates of multiple tumour development are relevant to recommend rational surveillance programs. A cross-sectional study design was used to estimate the risks of synchronous CRC (SCRC) and metachronous CRC (MCRC) based on data from the National Danish Hereditary Nonpolyposis Register. In total, 7100 individuals from families within the subgroups Lynch syndrome, familial CRC (FCC) and moderate risk were used with estimates relative to a non-hereditary population control cohort. SCRC was diagnosed in 7.4% of the Lynch syndrome cases, in 4.2% of FCC cases and 2.5% of the moderate risk cases, which translated to relative risks of 1.9-5.6. The risk of MCRC was distinctively linked to Lynch syndrome with a life-time risk up to 70% and an incidence rate ratio of 5.0. The risk of SCRC was significantly increased in all subgroups of FCC and hereditary CRC, whereas the risk of MCRC was specifically linked to Lynch syndrome. These observations suggest that individuals with FCC or hereditary CRC should be carefully screened for second primary CRC at the time of diagnosis, whereas intensified surveillance for second primary CRC is motivated in Lynch syndrome with lower-intensity programs in families with yet unidentified genetic causes.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Predisposição Genética para Doença , Neoplasias Primárias Múltiplas/epidemiologia , Segunda Neoplasia Primária/epidemiologia , Adulto , Fatores Etários , Idade de Início , Idoso , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Estudos Transversais , Dinamarca/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/diagnóstico , Neoplasias Primárias Múltiplas/genética , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/genética , Sistema de Registros/estatística & dados numéricos , Medição de Risco
16.
Int J Cancer ; 145(2): 318-326, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-30303536

RESUMO

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.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Detecção Precoce de Câncer , Feminino , Fidelidade a Diretrizes , Humanos , América Latina/epidemiologia , Masculino , Guias de Prática Clínica como Assunto , Medição de Risco
17.
Int J Cancer ; 144(9): 2161-2168, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30521064

RESUMO

The prevalence of Lynch syndrome (LS) varies significantly in different populations, suggesting that ethnic features might play an important role. We enrolled 3330 consecutive Chinese patients who had surgical resection for newly diagnosed colorectal cancer. Universal screening for LS was implemented, including immunohistochemistry for mismatch repair (MMR) proteins, BRAFV600E mutation test and germline sequencing. Among the 3250 eligible patients, MMR protein deficiency (dMMR) was detected in 330 (10.2%) patients. Ninety-three patients (2.9%) were diagnosed with LS. Nine (9.7%) patients with LS fulfilled Amsterdam criteria II and 76 (81.7%) met the revised Bethesda guidelines. Only 15 (9.7%) patients with absence of MLH1 on IHC had BRAFV600E mutation. One third (33/99) of the MMR gene mutations have not been reported previously. The age of onset indicates risk of LS in patients with dMMR tumors. For patients older than 65 years, only 2 patients (5.7%) fulfilling revised Bethesda guidelines were diagnosed with LS. Selective sequencing of all cases with dMMR diagnosed at or below age 65 years and only of those dMMR cases older than 65 years who fulfill revised Bethesda guidelines results in 8.2% fewer cases requiring germline testing without missing any LS diagnoses. While the prevalence of LS in Chinese patients is similar to that of Western populations, the spectrum of constitutional mutations and frequency of BRAFV600E mutation is different. Patients older than 65 years who do not meet the revised Bethesda guidelines have a low risk of LS, suggesting germline sequencing might not be necessary in this population.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Programas de Rastreamento/métodos , Proteína 1 Homóloga a MutL/genética , Proteínas Proto-Oncogênicas B-raf/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , China/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Variações do Número de Cópias de DNA/genética , Feminino , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência
18.
Bull Cancer ; 106(7-8): 647-655, 2019.
Artigo em Francês | MEDLINE | ID: mdl-30527816

RESUMO

Lynch syndrome is a genetic condition defined by a germline mutation of an MMR (MisMatch Repair) gene leading to a defective DNA MMR system. Therefore, it is characterized by the predisposition to a spectrum of cancers, primarily colorectal cancer (CRC) and endometrial cancer (EC). Lynch syndrome-related CRC accounts for 3% of all CRC. Lynch syndrome also accounts for 2% of all EC. In case of Lynch syndrome, there is usually a familial history of cancer defined by the Amsterdam and Bethesda criteria. Diagnosis is made by tumor testing with (i) MMR immunohistochemistry and (ii) PCR for MSI (microsatellite instability), a genetic phenotype that characterizes these tumors. MSI can also be detected in sporadic tumors, through epigenetic events inactivating the MMR system. Progress in diagnosis and molecular biology has allowed for better identification of Lynch patients but also other rare genetic syndromes. MSI tumors can now benefit from new treatments such as immunotherapy which underlines the importance of their diagnosis. Finally, patients with Lynch syndrome as well as their relatives, undergo specific surveillance in order to prevent development of other cancers. This review will summarize the different aspects of Lynch syndrome and also focus on recent progress on the topic.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Algoritmos , Neoplasias Colorretais/genética , Neoplasias Colorretais/fisiopatologia , Neoplasias Colorretais/prevenção & controle , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/terapia , Reparo de Erro de Pareamento de DNA/genética , Neoplasias do Endométrio/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Técnicas de Diagnóstico Molecular , Risco
19.
Fam Cancer ; 18(1): 43-51, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29651783

RESUMO

Dissemination of information on a genetically increased risk should according to guidelines primarily be family-mediated. Incomplete and incorrect information spread has, however, been documented and implies missed possibilities for prevention. In Denmark, the national HNPCC register has been granted an exception to send unsolicited letters with information on hereditary colorectal cancer and an invitation to genetic counseling to members of families with familial and hereditary colorectal cancer. To evaluate this approach, we investigated reactions and attitudes to unsolicited letters in 708 members of families with genetic predisposition and in 1600 individuals from the general population. Support for information letters was expressed by 78% of the family members and by 82% of the general population. Regarding route of information, 90% of family members preferred a letter to no information, 66% preferred information from the hospital rather than from family members and 40% preferred to obtain information from a close family member. Our results suggest that use of unsolicited information letters from the health care system may be a feasible and highly acceptable strategy to disseminate information to families at high risk of colorectal cancer.


Assuntos
Atitude Frente a Saúde , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Aconselhamento Genético/organização & administração , Disseminação de Informação/métodos , Sistema de Registros/normas , Adulto , Idoso , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/prevenção & controle , Dinamarca/epidemiologia , Detecção Precoce de Câncer , Família , Estudos de Viabilidade , Feminino , Aconselhamento Genético/normas , Predisposição Genética para Doença , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Educação de Pacientes como Assunto , Projetos Piloto , Serviços Postais , Guias de Prática Clínica como Assunto , Fatores de Risco
20.
Appl Immunohistochem Mol Morphol ; 27(6): e54-e62, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-29985199

RESUMO

Colorectal cancer (CRC) has many subtypes with different prognoses and response to treatment. Patients must be characterized to access the most appropriate treatment and improve outcomes. An increasing number of biomarkers are required for characterization but are not in routine use. We investigated whether CRC can be stratified routinely within a small district general hospital to inform clinical decision making at local multidisciplinary team meeting/tumor board level. We evaluated mismatch repair (MMR) and EGFR signaling pathways using predominantly in-house immunohistochemical (IHC) tests (MSH2, MSH6, MLH1, PMS2, BRAF-V600E, Her2, PTEN, cMET) as well as send away PCR/NGS tests (NRAS, KRAS, and BRAF). We demonstrated that many of the tests required for personalized treatment of CRC can be done locally and timely. Send away tests need to be requested shortly after cut-up and this needs to be firmly established in the tissue pathways for the results to be considered at multidisciplinary team meeting/tumor board. We have shown that MMR IHC combined with BRAFV600E IHC is practical and easy to perform in a small district general hospital, has full concordance with DNA-based tests and satisfies the latest NICE requirements for the identification of potential Lynch syndrome patients. We provide a framework for the interpretation and presentation of test results. It is a practical classification that clinical pathologists can use to communicate effectively with the clinical team. It is broadly based on molecular subtyping, firmly focused on treatment decisions and dependent on the panel of molecular tests currently available.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Tomada de Decisão Clínica , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Centros Comunitários de Saúde , Reparo do DNA , Proteínas de Ligação a DNA/metabolismo , Testes Diagnósticos de Rotina , Receptores ErbB/genética , Receptores ErbB/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Hospitais Gerais , Humanos , Imuno-Histoquímica , Mutação/genética , Medicina de Precisão , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Transdução de Sinais , Reino Unido/epidemiologia
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