RESUMEN
Lynch syndrome (LS), Lynch-like syndrome (LLS) and familial colorectal cancer type X (FCCX) are different entities of familial cancer predisposition leading to an increased risk of colorectal cancer (CRC). The aim of this prospective study was to characterise and to compare the risks for adenoma and CRC in these three risk groups. Data was taken from the registry of the German Consortium for Familial Intestinal Cancer. Patients were prospectively followed up in an intensified colonoscopic surveillance programme that included annual examinations. Cumulative risks for adenoma and CRC were calculated separately for LS, LLS and FCCX, and then for males and females. Multivariate Cox regression was used to analyse the independent contributions of risk group, mismatch repair gene (within LS), sex and previous adenoma. The study population comprised 1448 individuals (103 FCCX, 481 LLS and 864 LS). The risks were similar for colorectal adenomas, but different for first and metachronous CRC between the three risk groups. CRC risk was highest in LS, followed by LLS and lowest in FCCX. Male sex and a prevalent adenoma in the index colonoscopy were associated with a higher risk for incident adenoma and CRC. In patients with LS, CRC risks were particularly higher in female MSH2 than MLH1 carriers. Our study may support the development of risk-adapted surveillance policies in LS, LLS and FCCX.
Asunto(s)
Adenoma/patología , Biomarcadores de Tumor/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/clasificación , Neoplasias Colorrectales Hereditarias sin Poliposis/complicaciones , Neoplasias Colorrectales/patología , Adenoma/etiología , Adenoma/metabolismo , Adulto , Anciano , Neoplasias Colorrectales/etiología , Neoplasias Colorrectales/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL/genética , Proteína 2 Homóloga a MutS/genética , Mutación , Pronóstico , Estudios Prospectivos , Factores de RiesgoRESUMEN
BACKGROUND: The risk of cancers is well characterized in Lynch syndrome (LS) families but has been less studied in familial colorectal cancer type X (FCCTX) families. METHODS: In this article, we compare the risk estimates of first and second colorectal cancers (CRCs) in 168 FCTTX and 780 LS families recruited through the Colon Cancer Family Registry as well as the risk of cancer-related deaths and disease-free survival (DFS) after a first CRC. Our methodology is based on a survival analysis approach, developed specifically to model the occurrence of successive cancers (ie, first and second CRCs) in the presence of competing risk events (ie, death from any causes). RESULTS: We found an excess risk of first and second CRC in individuals with LS compared to FCCTX family members. However, for an average age at first CRC of 60 years in FCCTX families and 50 years in LS families, the DFS rates were comparable in men but lower in women from FCCTX vs LS families, eg , 75.1% (95% confidence interval [CI] = 69.0% to 80.9%) vs 78.9% (95% CI = 76.3% to 81.3%) for the 10-year DFS. The 10-year risk of cancer-related death was higher in FCCTX families vs LS families, eg, 15.4% in men (95% CI = 10.9% to 19.8%) and 19.3% in women (95% CI = 13.6% to 24.7%) vs 8.9% (95% CI = 7.5% to 11.4%) and 8.7% (95% CI = 7.1% to 10.8%), respectively. CONCLUSIONS: Individuals with CRCs arising in the context of FCCTX do not experience the same improved DFS and overall survival of those with LS, and that difference may be relevant in management decisions.
Asunto(s)
Neoplasias del Colon/mortalidad , Neoplasias Colorrectales Hereditarias sin Poliposis/mortalidad , Neoplasias Colorrectales/mortalidad , Modelos Estadísticos , Adulto , Anciano , Neoplasias del Colon/clasificación , Neoplasias del Colon/patología , Neoplasias Colorrectales/clasificación , Neoplasias Colorrectales/patología , Neoplasias Colorrectales Hereditarias sin Poliposis/clasificación , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sistema de RegistrosRESUMEN
BACKGROUND: Lynch syndrome is a hereditary cancer syndrome associated with high risks of colorectal and endometrial cancer that is caused by pathogenic variants in the mismatch repair genes (MLH1, MSH2, MSH6, PMS2, EPCAM). Accurate classification of variants identified in these genes as pathogenic or benign enables informed medical management decisions. Previously, we developed a clinical History Weighting Algorithm (HWA) for the classification of variants of uncertain significance (VUSs) in BRCA1 and BRCA2. The BRCA1/2 HWA is based on the premise that pathogenic variants in these genes will be identified more often in individuals with strong personal and/or family histories of breast and/or ovarian cancer, while the identification of benign variants should be independent of cancer history. Here we report the development of a similar HWA to allow for classification of VUSs in genes associated with Lynch syndrome using data collected through both syndrome-specific and pan-cancer panel testing. METHODS: Upon completion of algorithm development, the HWA was tested using simulated variants constructed from 79,214 probands, as well as 379 true variants. Positive (PPV) and negative predictive values (NPV) were calculated on a per gene basis. RESULTS: 25,500 pathogenic and 50,500 benign simulated variants were analyzed using the HWA and the PPVs and NPVs for each gene were greater than 0.997 and 0.999, respectively. The HWA was also evaluated using 100 trials for each of the 379 true variants. PPVs of >0.998 and NPVs of >0.999 were obtained for all genes. CONCLUSIONS: We have developed and implemented a HWA to aid in the classification of VUSs in genes associated with Lynch syndrome. The work presented here demonstrates that this HWA is able to classify MLH1, MSH2, and MSH6 VUSs as either benign or pathogenic with high accuracy.
Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/clasificación , Proteínas de Unión al ADN/genética , Homólogo 1 de la Proteína MutL/genética , Proteína 2 Homóloga a MutS/genética , Mutación , Algoritmos , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Reparación de la Incompatibilidad de ADN , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Pruebas Genéticas , HumanosRESUMEN
PURPOSE: The Korean Hereditary Tumor Registry, the first and one of the largest registries of hereditary tumors in Korea, has registered about 500 families with hereditary cancer syndromes. This study evaluates the temporal changes in clinicopathologic features and surgical patterns of Lynch syndrome (LS) patients. MATERIALS AND METHODS: Data on 182 unrelated LS patients were collected retrospectively. The patients were divided into the period 1 group (registered in 1990-2004) and 2 (registered in 2005-2014). The clinical characteristics of the two groups were compared to identify changes over time. RESULTS: The period 1 group included 76 patients; the period 2 group, 106 patients. The mean ages at diagnosis were 45.1 years (range, 13 to 85 years) for group 1 and 49.7 years (range, 20 to 84 years) for group 2 (p=0.015). The TNM stage at diagnosis did not differ significantly-period 1 group: stage 0-I (n=18, 23.7%), II (n=37, 48.7%), III (n=19, 25.0%), and IV (n=2, 2.6%); period 2 group: stage 0-I (n=30, 28.3%), II (n=35, 33.0%), III (n=37, 34.9%), and IV (n=4, 3.8%). Extended resection was more frequently performed (55/76, 72.4%) in the period 1 group than period 2 (49/106, 46.2%) (p=0.001). CONCLUSION: Colorectal cancer in patients with LS registered at the Korean Hereditary Tumor Registry is still diagnosed at an advanced stage, more than two decades after registry's establishment. Segmental resection was more frequently performed in the past decade. A prompt nationwide effort to raise public awareness of hereditary colorectal cancer and to support hereditary cancer registries is required in Korea.
Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis , Neoplasias Colorrectales , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/clasificación , Neoplasias Colorrectales/fisiopatología , Neoplasias Colorrectales Hereditarias sin Poliposis/clasificación , Neoplasias Colorrectales Hereditarias sin Poliposis/fisiopatología , Humanos , Persona de Mediana Edad , Sistema de Registros , República de Corea , Adulto JovenRESUMEN
In the current German S3 guidelines for colorectal carcinoma (CRC), morphologically based tumor grading is extended by molecular grading for poorly differentiated and undifferentiated carcinomas, as well as for special morphological subtypes. These CRC are classified as low-grade when microsatellite instability (MSI) is found. In routine diagnostics, immunohistochemistry for hMLH1 and hMSH2, capturing MSI-CRC with high sensitivity and specificity, can be used as an inexpensive substitute for molecular MSI-testing. In patients with positive Bethesda criteria, a stepwise immunohistochemical and molecular diagnostic scheme is proposed. The detection of a BRAF mutation in tumors with hMLH1 loss allows distinguishing between sporadic and HNPCC-associated MSI-CRC. For rectal cancer the residual tumor classification (R-status) is completed by the circumferential resection margin classification (CRM).
Asunto(s)
Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Adhesión a Directriz , Proteínas Adaptadoras Transductoras de Señales/genética , Transformación Celular Neoplásica/patología , Colon/patología , Neoplasias Colorrectales/clasificación , Neoplasias Colorrectales Hereditarias sin Poliposis/clasificación , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Análisis Mutacional de ADN , Reparación del ADN/genética , Humanos , Inmunohistoquímica , Inestabilidad de Microsatélites , Homólogo 1 de la Proteína MutL , Proteínas MutL , Clasificación del Tumor , Proteínas de Neoplasias/genética , Neoplasia Residual/clasificación , Neoplasia Residual/genética , Neoplasia Residual/patología , Proteínas Nucleares/genética , Valor Predictivo de las Pruebas , Pronóstico , Proteínas Proto-Oncogénicas B-raf/genética , Recto/patologíaRESUMEN
Women with Lynch syndrome (LS) are at increased risk for the development of epithelial ovarian cancer (OC). Analogous to previous studies on BRCA1/2 mutation carriers, there is evidence to suggest a histotype-specific association in LS-associated OCs (LS-OC). Whereas the diagnosis of high-grade serous carcinoma is an indication for BRCA1/2 germline testing, in contrast, there are no screening guidelines in place for triaging OC patients for LS testing based on histotype. We performed a centralized pathology review of tumor subtype on 20 germline mutation-confirmed LS-OCs, on the basis of morphologic assessment of hematoxylin and eosin-stained slides, with confirmation by immunohistochemistry when necessary. Results from mismatch-repair immunohistochemistry (MMR-IHC) and microsatellite instability (MSI) phenotype status were documented, and detailed pedigrees were analyzed to determine whether previously proposed clinical criteria would have selected these patients for genetic testing. Review of pathology revealed all LS-OCs to be either pure endometrioid carcinoma (14 cases), mixed carcinoma with an endometrioid component (4 cases), or clear cell carcinoma (2 cases). No high-grade or low-grade serous carcinomas or mucinous carcinomas of intestinal type were identified. Tumor-infiltrating lymphocytes were prominent (≥40 per 10 high-powered fields) in 2 cases only. With the exception of 1 case, all tumors tested for MMR-IHC or MSI had an MMR-deficient phenotype. Within this cohort, 50%, 55%, 65%, and 85% of patients would have been selected for genetic workup by Amsterdam II, revised Bethesda Guidelines, SGO 10% to 25%, and SGO 5% to 10% criteria, respectively, with <60% of index or sentinel cases detected by any of these schemas. To further support a subtype-driven screening strategy, MMR-IHC reflex testing was performed on all consecutive non-serous OCs diagnosed at 1 academic hospital over a 2-year period; MMR deficiency was identified in 10/48 (21%) cases, all with endometrioid or clear cell histology. We conclude that there is a strong association between endometrioid and clear cell ovarian carcinomas and hereditary predisposition due to MMR gene mutation. These findings have implications for the role of tumor subtype in screening patients with OC for further genetic testing and support reflex MMR-IHC and/or MSI testing for newly diagnosed cases of endometrioid or clear cell ovarian carcinoma.
Asunto(s)
Carcinoma Endometrioide/patología , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Detección Precoz del Cáncer/métodos , Neoplasias Ováricas/patología , Adulto , Anciano , Proteína BRCA1/genética , Proteína BRCA2/genética , Biopsia , Canadá , Carcinoma Endometrioide/química , Carcinoma Endometrioide/clasificación , Carcinoma Endometrioide/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/química , Neoplasias Colorrectales Hereditarias sin Poliposis/clasificación , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Reparación de la Incompatibilidad de ADN , Análisis Mutacional de ADN , Femenino , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Mutación de Línea Germinal , Herencia , Humanos , Inmunohistoquímica , Linfocitos Infiltrantes de Tumor/patología , Inestabilidad de Microsatélites , Persona de Mediana Edad , Clasificación del Tumor , Neoplasias Ováricas/química , Neoplasias Ováricas/clasificación , Neoplasias Ováricas/genética , Linaje , Fenotipo , Valor Predictivo de las Pruebas , Sistema de RegistrosRESUMEN
In a fraction of families fulfilling the Amsterdam criteria for hereditary non-polyposis colorectal cancer, colorectal cancers are microsatellite stable and DNA mismatch repair gene (MMR) mutations are not found. These families were designated as familial colorectal cancer type X (FCCTX). We aimed to characterise a group of FCCTX families defined by the Amsterdam criteria and MSS tumours at clinical and molecular level. Twenty-four tumours from 15 FCCTX families were analysed for loss of known tumour suppressor gene (TSG) loci (APC, TP53, SMAD4 and DCC), MGMT and MMR genes promoter methylation, and also APC and KRAS somatic mutations. FCCTX families presented specific clinical features: absence of endometrial tumours, high adenoma/carcinoma ratio (1.91) and prevalence of rectal cancers (13/27, 48%). New molecular features were found: the majority of FCCTX tumours (13/18; 72%) presented TSG loss. TSG loss positive tumours presented frequent APC and KRAS somatic mutations and MGMT methylation [10/13 (77%), 7/13 (54%) and 6/11 (54%), respectively]. In TSG loss negative tumours (5/18; 28%), the same molecular events were found in 2/5 (40%), 2/5 (40%) and 1/3 (33%) tumours, respectively. Transition mutations in KRAS were more frequent among MGMT methylated tumours than in unmethylated [5/8 (63%) vs. 1/10 (10%), P = 0.03]. Although sharing similar clinical features, at least two different molecular entities should exist among FCCTX families, one whose tumours present frequent TSG loss, APC and KRAS somatic mutations, and MGMT promoter methylation, and a second, lesser predominant, with no evidence of TSG loss and rarely presenting promoter methylation.
Asunto(s)
Adenoma/genética , Carcinoma/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Genes Supresores de Tumor , Síndromes Neoplásicos Hereditarios/genética , Adulto , Anciano , Neoplasias Colorrectales Hereditarias sin Poliposis/clasificación , Metilación de ADN , Reparación de la Incompatibilidad de ADN/genética , Femenino , Humanos , Pérdida de Heterocigocidad , Masculino , Persona de Mediana Edad , Síndromes Neoplásicos Hereditarios/clasificación , Proteínas Nucleares/genética , Portugal , Regiones Promotoras Genéticas/genéticaRESUMEN
BACKGROUND: The aim of this study was to identify patient and tumor characteristics that may be useful for clinicians in the identification of possible familial colorectal cancer (CRC). METHODS: Among 562 unselected, consecutively diagnosed colorectal cancer patients, 490 patients were included and divided into familial or sporadic CRC based on family history data collected by standardized patient interviews. Clinical data were collected from the patients' medical records. Patients were classified as familial CRC according to currently accepted family history criteria. Each patient was also classified according to Amsterdam II criteria and the 4th and 5th criteria in the Revised Bethesda Guidelines that address information on family history. Tumors were described by location and histopathology; 316 tumors were examined by molecular analyses. RESULTS: Right-sided colonic tumors and synchronous CRC tumors were associated with familial CRC, and patients with metachronous CRC or Lynch syndrome-related tumors were more likely to be classified as familial CRC. The patients' age at diagnosis did not differ between the groups. Other patient or tumor characteristics were not associated with familial CRC. CONCLUSION: CRC patients with right-sided colonic cancers, synchronous cancers and previous CRC and/or LS-related tumors were more likely to have familial CRC, and young age at diagnosis was not associated with familial CRC in these data. A detailed family history of colorectal cancer is essential in the identification of patients and families with familial CRC.
Asunto(s)
Adenoma/patología , Pólipos del Colon/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Primarias Múltiples/patología , Neoplasias Primarias Secundarias/patología , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/clasificación , Neoplasias Colorrectales Hereditarias sin Poliposis/clasificación , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Primarias Múltiples/clasificación , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Secundarias/clasificación , Neoplasias Primarias Secundarias/genética , Virus NorwalkRESUMEN
Gastroenterologists removing colorectal polyps expect standardized and well-structured pathological reports, providing them with all relevant data for the further clinical management of the patient. Over the last year, a task force of clinicians and pathologists has developed a checklist to improve and harmonize endoscopic and pathological reporting of colorectal polyps. This checklist concentrates more on concrete recommendations from evidence-based guidelines and established international classifications for daily practice rather than detailed molecular pathological pathways of carcinogenesis. These recommendations are based on the current S3 guidelines for colorectal cancer (the chapter entitled "Management of colorectal polyps"), the histomorphological consensus manuscript of the GI working group of the German Society for Pathology, as well as the current WHO classification for tumors of the digestive system.
Asunto(s)
Pólipos Adenomatosos/patología , Lista de Verificación , Neoplasias del Colon/patología , Pólipos del Colon/patología , Pólipos Intestinales/patología , Neoplasias del Recto/patología , Proteínas Adaptadoras Transductoras de Señales/genética , Adenocarcinoma/clasificación , Adenocarcinoma/genética , Adenocarcinoma/patología , Pólipos Adenomatosos/clasificación , Pólipos Adenomatosos/genética , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Inestabilidad Cromosómica/genética , Colon/patología , Neoplasias del Colon/clasificación , Neoplasias del Colon/genética , Pólipos del Colon/clasificación , Pólipos del Colon/genética , Colonoscopía , Neoplasias Colorrectales Hereditarias sin Poliposis/clasificación , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Metilación de ADN , Análisis Mutacional de ADN , Diagnóstico Diferencial , Medicina Basada en la Evidencia , Adhesión a Directriz , Humanos , Pólipos Intestinales/clasificación , Pólipos Intestinales/genética , Inestabilidad de Microsatélites , Homólogo 1 de la Proteína MutL , Proteínas Nucleares/genética , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias del Recto/clasificación , Neoplasias del Recto/genética , Recto/patología , Organización Mundial de la SaludRESUMEN
BACKGROUND AND OBJECTIVES: The objective was to study the clinicopathologic characteristics of patients diagnosed of colorectal cancer (CRC) with clinical criteria for Lynch syndrome, in our region, in order to assess and improve the care of them and their families in the Genetic Counseling Unit of our hospital. PATIENTS AND METHODS: This was an observational, transversal retrospective study. The studied sample was made up of all the patients with clinical criteria for Lynch syndrome, who underwent a molecular analysis test in the Genetic Counseling Unit of Salamanca, during the period 2004-2009. We included patient and tumor related variables and the presence or absence of mutations in MLH1 and MSH2. RESULTS: A total of 76 patients were included in the analysis. Fifteen of them carried a mutation either in MLH1 or in MSH2. The mean age at diagnosis of colorectal cancer was 51.2 and 54.3 years in the group with and without mutation respectively, with a similar gender distribution in both groups. A wide phenotypic heterogeneity was found in the sample. CONCLUSIONS: Lynch syndrome is an entity difficult to categorize from a clinical point of view. Therefore, it is important to be alert for a better management of these patients and their families.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Adenocarcinoma/epidemiología , Neoplasias Colorrectales Hereditarias sin Poliposis/epidemiología , Reparación del ADN/genética , Heterogeneidad Genética , Proteína 2 Homóloga a MutS/genética , Mutación , Proteínas Nucleares/genética , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Edad de Inicio , Anciano , Neoplasias Colorrectales Hereditarias sin Poliposis/clasificación , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Estudios Transversales , Neoplasias Endometriales/epidemiología , Neoplasias Endometriales/genética , Femenino , Asesoramiento Genético , Humanos , Masculino , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL , Fenotipo , Estudios Retrospectivos , España/epidemiologíaRESUMEN
BACKGROUND: Lynch syndrome (LS) is an autosomal dominant inherited cancer syndrome characterized by early onset cancers of the colorectum, endometrium and other tumours. A significant proportion of DNA variants in LS patients are unclassified. Reports on the pathogenicity of the c.1852_1853AA>GC (p.Lys618Ala) variant of the MLH1 gene are conflicting. In this study, we provide new evidence indicating that this variant has no significant implications for LS. METHODS: The following approach was used to assess the clinical significance of the p.Lys618Ala variant: frequency in a control population, case-control comparison, co-occurrence of the p.Lys618Ala variant with a pathogenic mutation, co-segregation with the disease and microsatellite instability in tumours from carriers of the variant. We genotyped p.Lys618Ala in 1034 individuals (373 sporadic colorectal cancer [CRC] patients, 250 index subjects from families suspected of having LS [revised Bethesda guidelines] and 411 controls). Three well-characterized LS families that fulfilled the Amsterdam II Criteria and consisted of members with the p.Lys618Ala variant were included to assess co-occurrence and co-segregation. A subset of colorectal tumour DNA samples from 17 patients carrying the p.Lys618Ala variant was screened for microsatellite instability using five mononucleotide markers. RESULTS: Twenty-seven individuals were heterozygous for the p.Lys618Ala variant; nine had sporadic CRC (2.41%), seven were suspected of having hereditary CRC (2.8%) and 11 were controls (2.68%). There were no significant associations in the case-control and case-case studies. The p.Lys618Ala variant was co-existent with pathogenic mutations in two unrelated LS families. In one family, the allele distribution of the pathogenic and unclassified variant was in trans, in the other family the pathogenic variant was detected in the MSH6 gene and only the deleterious variant co-segregated with the disease in both families. Only two positive cases of microsatellite instability (2/17, 11.8%) were detected in tumours from p.Lys618Ala carriers, indicating that this variant does not play a role in functional inactivation of MLH1 in CRC patients. CONCLUSIONS: The p.Lys618Ala variant should be considered a neutral variant for LS. These findings have implications for the clinical management of CRC probands and their relatives.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Mutación , Proteínas Nucleares/genética , Estudios de Casos y Controles , Neoplasias Colorrectales/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/clasificación , Neoplasias Colorrectales Hereditarias sin Poliposis/epidemiología , Familia , Genotipo , Humanos , Inestabilidad de Microsatélites , Homólogo 1 de la Proteína MutLRESUMEN
PURPOSE: Lynch syndrome is a genetic disease that predisposes to colorectal tumors, caused by mutation in mismatch repair genes. The use of genetic tests to identify mutation carriers does not always give perfectly clear results, as happens when an unclassified variant is found. This study aimed to define the pathogenic role of 35 variants present in MSH2, MLH1, MSH6, and PMS2 genes identified in our 15-year case study. METHODS: We collected clinical and molecular data of all carriers, and then we analyzed the variants pathogenic role with web tools and molecular analyses. Using a Bayesian approach, we derived a posterior probability of pathogenicity and classified each variant according to a standardized five-class system. RESULTS: The MSH2 p.Pro349Arg, p.Met688Arg, the MLH1 p.Gly67Arg, p.Thr82Ala, p.Lys618Ala, the MSH6 p.Ala1236Pro, and the PMS2 p.Arg20Gln were classified as pathogenic, and the MSH2 p.Cys697Arg and the PMS2 p.Ser46Ile were classified as likely pathogenic. Seven variants were likely nonpathogenic, 3 were nonpathogenic, and 16 remained uncertain. CONCLUSION: Quantitative assessment of several parameters and their integration in a multifactorial likelihood model is the method of choice for classifying the variants. As such classifications can be associated with surveillance and testing recommendations, the results and the method developed in our study can be useful for helping laboratory geneticists in evaluation of genetic tests and clinicians in the management of carriers.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Adenosina Trifosfatasas/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/clasificación , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Reparación de la Incompatibilidad de ADN/genética , Enzimas Reparadoras del ADN/genética , Proteínas de Unión al ADN/genética , Proteína 2 Homóloga a MutS/genética , Proteínas Nucleares/genética , Cromatografía Líquida de Alta Presión/métodos , Interpretación Estadística de Datos , Predisposición Genética a la Enfermedad , Variación Genética , Heterocigoto , Humanos , Pérdida de Heterocigocidad/genética , Inestabilidad de Microsatélites , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto , Homólogo 1 de la Proteína MutL , MutaciónRESUMEN
At its core, quality improvement in gastrointestinal (GI) practice relies on continuous training, education, and information among all health care providers, whether gastroenterologists, GI trainees, endoscopy nurses, or GI pathologists. Over the past few years, it became clear that objective criteria are needed to assess the quality of colonoscopy, such as cecum intubation rate, quality of bowel preparation, withdrawal time, and adenoma detection rate. In this context, development of competence among practicing endoscopists to adequately detect and treat non-polypoid colorectal neoplasms (NP-CRNs) deserves special attention. We describe a summary of the path to develop expertise in detection and management of NP-CRNs, based on experience at our academic GI unit.
Asunto(s)
Colonoscopía/métodos , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Centros Médicos Académicos/estadística & datos numéricos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Catárticos/administración & dosificación , Catárticos/efectos adversos , Pólipos del Colon/clasificación , Pólipos del Colon/diagnóstico , Pólipos del Colon/patología , Neoplasias Colorrectales Hereditarias sin Poliposis/clasificación , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Enema/métodos , Femenino , Humanos , Laxativos/administración & dosificación , Masculino , Persona de Mediana Edad , Países Bajos , Calidad de la Atención de Salud , Servicio de Cirugía en Hospital/estadística & datos numéricos , Adulto JovenRESUMEN
The importance and prevalence of the superficial lesions in the colon and rectum caught worldwide public attention in 2008 when Soetikno and colleagues reported the prevalence of non-polypoid (flat and depressed) colorectal neoplasms in asymptomatic and symptomatic adults in North America and the public media disseminated their findings. The publication put to rest the question of whether or not the flat and depressed colorectal neoplasms exist in Western countries; flat and depressed colorectal neoplasms can be found throughout the world. In this article, the author highlights the importance of the macroscopic classification of the colorectal neoplasm and emphasizes the distinction between so-called flat lesions (IIa and IIb) and 0-IIc (superficial depressed) neoplastic colorectal lesions.
Asunto(s)
Colonoscopía/métodos , Neoplasias Colorrectales/clasificación , Detección Precoz del Cáncer/métodos , Colon/patología , Pólipos del Colon/diagnóstico , Pólipos del Colon/patología , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/cirugía , Neoplasias Colorrectales Hereditarias sin Poliposis/clasificación , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Neoplasias Colorrectales Hereditarias sin Poliposis/cirugía , Detección Precoz del Cáncer/instrumentación , Diseño de Equipo , Humanos , Microscopía , Estadificación de Neoplasias/métodos , Prevalencia , Recto/patología , Grabación en Video/instrumentación , Grabación en Video/métodosRESUMEN
UNLABELLED: Tumour microsatellite instability (MSI) is useful in identifying patients with hereditary non-polyposis colorectal cancer (HNPCC) with defective DNA mismatch repair (MMR) genes. A reference Bethesda panel has limitations resulting from the inclusion of dinucleotide markers, which are less sensitive and specific for detection of tumours with MMR deficiencies. We developed a multiplex PCR assay with additional four mononucleotide markers and one dinucleotide marker (NR-21, NR-24, BAT-40, TGF-BetaR and D18S58) for a rapid and proper classification of MSI-H, MSI-L and MSS colorectal cancers. Two tetranucleotide markers were added to identify sample mix-ups and/or contamination. RESULTS: all the 44 cases test cases were in agreement with previous classification except for three cases: one case MSI-H-Bethesda unstable only for dinucleotides markers shifted to MSI-L category and two cases MSI-L-Bethesda unstable for mononucleotide markers shifted to MSI-H category. Immunohistochemistry analysis revealed that these two MSI-H cases did not expressed hMLH1 and they were found to be methylated at the MLH1 promoter, while the first one that shifted to MSI-L showed MMR protein expression. CONCLUSION: a complete panel of ten markers including four dinucleotide and six mononucleotide microsatellites allows accurate evaluation of tumor MSI status.
Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/clasificación , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Reparación de la Incompatibilidad de ADN/genética , Inestabilidad de Microsatélites , Reacción en Cadena de la Polimerasa/métodos , Proteínas Adaptadoras Transductoras de Señales/genética , Metilación de ADN , Análisis Mutacional de ADN , Proteínas de Unión al ADN/genética , Humanos , Inmunohistoquímica , Homólogo 1 de la Proteína MutL , Proteína 2 Homóloga a MutS/genética , Proteínas Nucleares/genéticaRESUMEN
Establishing the Amsterdam criteria, based on pedigrees, was essential for defining hereditary nonpolyposis colorectal cancer (HNPCC) syndrome in such a way that the underlying genetic cause could be identified. It is now known that about half of families that fulfill the original Amsterdam criteria have a hereditary DNA mismatch repair (MMR) gene mutation. These families may be said to have Lynch syndrome. The other half of families with HNPCC has no evidence of DNA MMR deficiency, and studies show that these families are different from families with Lynch syndrome. Familial colorectal cancer type X is the name used to refer to the "other half of HNPCC".
Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Reparación de la Incompatibilidad de ADN/genética , Proteínas de Neoplasias/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/clasificación , Humanos , SíndromeRESUMEN
Immunohistochemistry of tumour samples is increasingly used in the triage of families where hereditary non-polyposis colorectal cancer (HNPCC) due to mismatch repair defects is suspected. Usually, this is undertaken in tumours that are a recognised part of the spectrum of HNPCC-related cancers e.g. colon or endometrial cancers. Although breast cancers are not classed as part of this spectrum, this study examined the extent to which some breast tumours do arise by the mismatch repair pathway in these families. This may have clinical utility in families where an individual with a 'classic HNPPC-related' tumour is not available for evaluation. Immunohistochemistry of a breast tumour may identify an individual in whom germline mutation testing is worthwhile.
Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales/genética , Mutación de Línea Germinal , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales Hereditarias sin Poliposis/clasificación , Neoplasias Colorrectales Hereditarias sin Poliposis/inmunología , Análisis Mutacional de ADN , Femenino , Pruebas Genéticas , Humanos , Inmunohistoquímica , Masculino , LinajeRESUMEN
Germline mutations in the mismatch repair (MMR) genes MLH1, MSH2, MSH6, or PMS2 can cause Lynch syndrome. This syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal dominantly-inherited disorder predominantly characterized by colorectal and endometrial cancer. Truncating MMR gene mutations generally offer a clear handle for genetic counseling and allow for presymptomatic testing. In contrast, the clinical implications of most missense mutations and small in-frame deletions detected in patients suspected of having Lynch syndrome are unclear. We have constructed an online database, the Mismatch Repair Gene Unclassified Variants Database (www.mmruv.info), for information on the results of functional assays and other findings that may help in classifying these MMR gene variants. Ideally, such mutations should be clinically classified by a broad expert panel rather than by the individual database curators. In addition, the different MMR gene mutation databases could be interlinked or combined to increase user-friendliness and avoid unnecessary overlap between them. Both activities are presently being organized by the International Society for Gastrointestinal Hereditary Tumours (InSiGHT; www.insight-group.org).
Asunto(s)
Disparidad de Par Base/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/clasificación , Bases de Datos Genéticas , Variación Genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Proteínas de Unión al ADN/genética , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Humanos , Proteína 2 Homóloga a MutS/genéticaRESUMEN
It is important to identify a germline mutation in a patient with an inherited cancer syndrome to allow mutation carriers to be included in cancer surveillance programs, which have been proven to save lives. Many of the mutations identified result in premature termination of translation, and thus in loss-of-function of the encoded mutated protein. However, the significance of a large proportion of the sequence changes reported is unknown. Some of these variants will be associated with a high risk of cancer and have direct clinical consequence. Many criteria can be used to classify variants with unknown significance; most criteria are based on the characteristics of the amino acid change, on segregation data and appearance of the variant, on the presence of the variant in controls, or on functional assays. In inherited cancers, tumor characteristics can also be used to classify variants. It is worthwhile to examine the clinical, morphological and molecular features of a patient, and his or her family, when assessing whether the role of a variant is likely to be neutral or pathogenic. Here we describe the advantages and disadvantages of using the tumor characteristics of patients carrying germline variants of uncertain significance (VUS) in BRCA1, BRCA2, or in one of the mismatch repair (MMR) genes, MLH1, MSH2, or MSH6, to infer pathogenicity.
Asunto(s)
Neoplasias de la Mama/clasificación , Neoplasias Colorrectales Hereditarias sin Poliposis/clasificación , Genes BRCA1 , Genes BRCA2 , Variación Genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Pruebas Genéticas , Mutación de Línea Germinal , Humanos , Factores de Riesgo , IncertidumbreRESUMEN
BACKGROUND: Sebaceous gland tumors are a rare type of neoplasm. In some cases they have been associated with visceral tumors in patients with Muir-Torre syndrome, a hereditary form of nonpolyposis colorectal cancer. The aim of this study was to review the diagnosis and follow-up of a series of patients with sebaceous gland tumors to assess how many met the criteria for Muir-Torre syndrome. PATIENTS AND METHODS: A search was performed of records from 1990 to 2005 in the database of the Department of Dermatology of the Consorcio Hospital General Universitario de Valencia in Valencia, Spain, to identify patients with sebaceous gland tumors. The biopsy material was reviewed to confirm the diagnosis. We also searched the patient histories for information suggestive of a diagnosis of Muir-Torre syndrome; when the histories were incomplete, we contacted the patients by telephone. RESULTS: We identified 20 patients diagnosed with sebaceous gland tumors, but after reviewing the biopsy material diagnosis was only confirmed in 12. Two patients belonged to a family with a history of visceral tumors that met the clinical criteria for hereditary nonpolyposis colorectal cancer syndrome. Follow-up was not uniform in all patients and not all underwent the same tests. CONCLUSIONS: It is essential to rule out the presence of Muir-Torre syndrome in patients with sebaceous gland tumors. The use of new techniques such as immunohistochemistry or detection of microsatellite instability may help to identify families at increased risk of Muir-Torre syndrome.