RESUMEN
Peutz-Jeghers syndrome (PJS, MIM175200) is an autosomal dominant condition defined by the development of characteristic polyps throughout the gastrointestinal tract and mucocutaneous pigmentation. The majority of patients that meet the clinical diagnostic criteria have a causative mutation in the STK11 gene, which is located at 19p13.3. The cancer risks in this condition are substantial, particularly for breast and gastrointestinal cancer, although ascertainment and publication bias may have led to overestimates in some publications. Current surveillance protocols are controversial and not evidence-based, due to the relative rarity of the condition. Initially, endoscopies are more likely to be done to detect polyps that may be a risk for future intussusception or obstruction rather than cancers, but surveillance for the various cancers for which these patients are susceptible is an important part of their later management. This review assesses the current literature on the clinical features and management of the condition, genotype-phenotype studies, and suggested guidelines for surveillance and management of individuals with PJS. The proposed guidelines contained in this article have been produced as a consensus statement on behalf of a group of European experts who met in Mallorca in 2007 and who have produced guidelines on the clinical management of Lynch syndrome and familial adenomatous polyposis.
Asunto(s)
Síndrome de Peutz-Jeghers/diagnóstico , Adulto , Anciano , Neoplasias de la Mama/diagnóstico , Niño , Preescolar , Endoscopía Gastrointestinal , Medicina Basada en la Evidencia/métodos , Femenino , Neoplasias Gastrointestinales/diagnóstico , Neoplasias de los Genitales Femeninos/diagnóstico , Genotipo , Humanos , Cuidados a Largo Plazo/métodos , Masculino , Tamizaje Masivo/métodos , Persona de Mediana Edad , Síndrome de Peutz-Jeghers/genética , Síndrome de Peutz-Jeghers/terapia , Fenotipo , Vigilancia de la Población/métodos , Adulto JovenRESUMEN
Familial colorectal cancer (CRC) accounts for 10-15% of all CRCs. In about 5% of all cases, CRC is associated with a highly penetrant dominant inherited syndrome. The most common inherited form of non-polyposis CRC is the Lynch syndrome which is responsible for about 2-4% of all cases. Surveillance of individuals at high risk for CRC prevents the development of advanced CRC. About 1 million individuals in Western Europe are at risk for Lynch syndrome. We performed a survey to evaluate the strategies currently used to identify individuals at high risk for CRC in 14 Western European countries. Questionnaires were distributed amongst members of a European collaborative group of experts that aims to improve the prognosis of families with hereditary CRC. The survey showed that in all countries obtaining a family history followed by referral to clinical genetics centres of suspected cases was the main strategy to identify familial and hereditary CRC. In five out of seven countries with a (regional or national) CRC population screening program, attention was paid in the program to the detection of familial CRC. In only one country were special campaigns organized to increase the awareness of familial CRC among the general population. In almost all countries, the family history is assessed when a patient visits a general practitioner or hospital. However, the quality of family history taking was felt to be rather poor. Microsatellite instability testing (MSI) or immunohistochemical analysis (IHC) of CRC are usually recommended as tools to select high-risk patients for genetic testing and are performed in most countries in patients suspected of Lynch syndrome. In one country, IHC was recommended in all new cases of CRC. In most countries there are no specific programs on cancer genetics in the teaching curriculum for medical doctors. In conclusion, the outcome of this survey and the discussions within an European expert group may be used to improve the strategies to identify individuals at high risk of CRC. More attention should be given to increasing the awareness of the general population of hereditary CRC. Immunohistochemical analysis or MSI-analysis of all CRCs may be an effective tool for identifying all Lynch syndrome families. The cost-effectiveness of this approach should be further evaluated. All countries with a CRC population screening program should obtain a full family history as part of patient assessment.
Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/epidemiología , Reparación de la Incompatibilidad de ADN , Europa (Continente)/epidemiología , Asesoramiento Genético , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Directrices para la Planificación en Salud , Humanos , Anamnesis , Proteína 2 Homóloga a MutS/genética , Mutación , Linaje , Factores de RiesgoRESUMEN
We present a patient with an unusual enterocutaneous syndrome. Long-term, low-dose acitretin treatment has stabilized the development of gastrointestinal lesions while synchronously reducing cutaneous morbidity.
Asunto(s)
Acitretina/administración & dosificación , Pólipos Adenomatosos/tratamiento farmacológico , Carcinoma de Células Escamosas/tratamiento farmacológico , Poliposis Intestinal/tratamiento farmacológico , Queratolíticos/administración & dosificación , Neoplasias Cutáneas/tratamiento farmacológico , Pólipos Adenomatosos/diagnóstico , Carcinoma de Células Escamosas/diagnóstico , Femenino , Genes Relacionados con las Neoplasias/genética , Humanos , Poliposis Intestinal/diagnóstico , Hígado/enzimología , Persona de Mediana Edad , Neoplasias Cutáneas/diagnóstico , Síndrome , Resultado del TratamientoRESUMEN
BACKGROUND: Familial adenomatous polyposis (FAP) is a well-described inherited syndrome, which is responsible for <1% of all colorectal cancer (CRC) cases. The syndrome is characterised by the development of hundreds to thousands of adenomas in the colorectum. Almost all patients will develop CRC if they are not identified and treated at an early stage. The syndrome is inherited as an autosomal dominant trait and caused by mutations in the APC gene. Recently, a second gene has been identified that also gives rise to colonic adenomatous polyposis, although the phenotype is less severe than typical FAP. The gene is the MUTYH gene and the inheritance is autosomal recessive. In April 2006 and February 2007, a workshop was organised in Mallorca by European experts on hereditary gastrointestinal cancer aiming to establish guidelines for the clinical management of FAP and to initiate collaborative studies. Thirty-one experts from nine European countries participated in these workshops. Prior to the meeting, various participants examined the most important management issues according to the latest publications. A systematic literature search using Pubmed and reference lists of retrieved articles, and manual searches of relevant articles, was performed. During the workshop, all recommendations were discussed in detail. Because most of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, many of them were based on expert opinion. The guidelines described herein may be helpful in the appropriate management of FAP families. In order to improve the care of these families further, prospective controlled studies should be undertaken.
Asunto(s)
Poliposis Adenomatosa del Colon/terapia , Poliposis Adenomatosa del Colon/diagnóstico , Poliposis Adenomatosa del Colon/genética , Edad de Inicio , Antiinflamatorios no Esteroideos/uso terapéutico , Neoplasias Duodenales/diagnóstico , Neoplasias Duodenales/terapia , Femenino , Fibromatosis Agresiva/diagnóstico , Fibromatosis Agresiva/terapia , Genes APC , Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Humanos , Masculino , Factores de RiesgoRESUMEN
BACKGROUND: Colonoscopic surveillance for hereditary non-polyposis colorectal cancer (HNPCC) reduces death rates, but early interval cancers still occur, probably due to missed small, aggressive adenomas. Narrow band imaging (NBI), a novel endoscopic technology, highlights superficial mucosal capillaries and improves contrast for adenomas. This study examined whether a second pass with NBI in the proximal colon helped detect additional adenomas in patients with HNPCC. METHODS: 62 patients from HNPCC families (Amsterdam II or genetic criteria) attending for colonoscopic surveillance were examined twice from caecum to sigmoid-descending junction, first with high definition white light and then a second pass with NBI in a back-to-back fashion. All polyps detected were removed for histopathological analysis. RESULTS: At least one adenoma in the proximal colon was detected during the initial white light pass in 17/62 (27%). NBI detected additional adenomas in 17/62 (27%). 26/62 (42%) patients had at least one adenoma detected after both white light and NBI; absolute difference 15% (95% CI 4-25%), p = 0.004 versus white light alone. The total number of adenomas increased from 25 before NBI to 46 after NBI examination, p<0.001. The proportion of flat adenomas detected in the NBI pass, 9/21 (45%), was higher than in the white light pass, 3/25 (12%), p = 0.03. Including white light examination of the sigmoid and rectum, overall 28/62 (45%) patients had at least one adenoma detected. CONCLUSIONS: Use of NBI in the proximal colon for patients undergoing HNPCC surveillance appears to improve adenoma detection, particularly those with a flat morphology. NBI could help reduce interval cancer rates.
Asunto(s)
Adenoma/diagnóstico , Colonoscopía/métodos , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias del Colon/diagnóstico , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Retratamiento , Sensibilidad y EspecificidadRESUMEN
We have examined chromosomal-scale mutations in 34 large colorectal adenomas (CRAs). A small number of changes (median = 2, IQR = 0-4) were found by array-comparative genomic hybridization (aCGH) in most tumours. The most common changes were deletions of chromosomes 1p, 9q, 17, 19, and 22, and gains of chromosomes 13 and 21. SNP-LOH analysis and pseudo-digital SNP-PCR analysis detected occasional copy-neutral LOH. Some aCGH changes found frequently in colorectal carcinomas, such as deletions of chromosomes 4q and 18q, were very infrequent in the adenomas. Almost all copy number changes were of small magnitude, far below the predicted levels even for single copy gain/loss; investigation suggested that these changes were either artefactual or occurred in sub-clones within the tumours. In some cases, these sub-clones may have represented progression towards carcinoma, but comparison with aCGH data from carcinomas showed this to be unlikely in most cases. In two adenomas, there was evidence of a large, outlying number of copy number changes, mostly resulting from part-chromosome deletions. Overall, moreover, there was evidence of a tendency towards part-chromosome deletions-consistent with chromosomal instability (CIN)--in about one-sixth of all tumours. However, there was no evidence of CIN in the form of whole-chromosome copy number changes. Our data did not support previous contentions that CRAs tend to show chromosome breakage at fragile sites owing to CIN associated with an elevated DNA damage response. Chromosomal-scale mutations occur in some CRAs; although CIN is not the norm in these lesions, it probably affects a minority of cases.
Asunto(s)
Adenoma/genética , Inestabilidad Cromosómica , Cromosomas Humanos , Neoplasias Colorrectales/genética , Poliposis Adenomatosa del Colon/genética , Carcinoma/genética , Deleción Cromosómica , ADN de Neoplasias/genética , Duplicación de Gen , Perfilación de la Expresión Génica , Humanos , Pérdida de Heterocigocidad , Repeticiones de Microsatélite , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido SimpleRESUMEN
Hyperplastic Polyposis (HPPS) is a poorly characterized syndrome that increases colorectal cancer (CRC) risk. We aimed to provide a molecular classification of HPPS. We obtained 282 tumours from 32 putative HPPS patients with >or= 10 hyperplastic polyps (HPs); some patients also had adenomas and CRCs. We found no good evidence of microsatellite instability (MSI) in our samples. The epithelium of HPs was monoclonal. Somatic BRAF mutations occurred in two-thirds of our patients' HPs, and KRAS2 mutations in 10%; both mutations were more common in younger cases. The respective mutation frequencies in a set of 'sporadic' HPs were 18% and 10%. Importantly, the putative HPPS patients generally fell into two readily defined groups, one set whose polyps had BRAF mutations, and another set whose polyps had KRAS2 mutations. The most plausible explanation for this observation is that there exist different forms of inherited predisposition to HPPS, and that these determine whether polyps follow a BRAF or KRAS2 pathway. Most adenomas and CRCs from our putative HPPS patients had 'classical' morphology and few of these lesions had BRAF or KRAS2 mutations. These findings suggest that tumourigenesis in HPPS does not necessarily follow the 'serrated' pathway. Although current definitions of HPPS are sub-optimal, we suggest that diagnosis could benefit from molecular analysis. Specifically, testing BRAF and KRAS2 mutations, and perhaps MSI, in multiple polyps could help to distinguish HPPS from sporadic HPs. We propose a specific model which would have diagnosed five more of our cases as HPPS compared with the WHO clinical criteria.
Asunto(s)
Neoplasias Colorrectales/genética , Poliposis Intestinal/genética , Adolescente , Adulto , Anciano , Transformación Celular Neoplásica/genética , Niño , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/patología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Hiperplasia/genética , Mucosa Intestinal/metabolismo , Poliposis Intestinal/diagnóstico , Poliposis Intestinal/patología , Pérdida de Heterocigocidad , Masculino , Persona de Mediana Edad , Mutación , Proteínas de Neoplasias/genética , Fenotipo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras) , Proteínas ras/genéticaRESUMEN
Patients with multiple (5-100) colorectal adenomas (MCRAs) often have no germline mutation in known predisposition genes, but probably have a genetic origin. We collected a set of 25 MCRA patients with no detectable germline mutation in APC, MYH/MUTYH or the mismatch repair genes. Extracolonic tumours were absent in these cases. No vertical transmission of the MCRA phenotype was found. Based on the precedent of MYH-associated polyposis (MAP), we searched for a mutational signature in 241 adenomatous polyps from our MCRA cases. Somatic mutation frequencies and spectra at APC, K-ras and BRAF were, however, similar to those in sporadic colorectal adenomas. Our data suggest that the genetic pathway of tumorigenesis in the MCRA patients' tumours is very similar to the classical pathway in sporadic adenomas. In sharp contrast to MAP tumours, we did not find evidence of a specific mutational signature in any individual patient or in the overall set of MCRA cases. These results suggest that hypermutation of APC does not cause our patients' disease and strongly suggests that MAP is not a paradigm for the remaining MCRA patients. Our MCRA patients' colons showed no evidence of microadenomas, unlike in MAP and familial adenomatous polyposis (FAP). However, nuclear beta-catenin expression was significantly greater in MCRA patients' tumours than in sporadic adenomas. We suggest that, at least in some cases, the MCRA phenotype results from germline variation that acts subsequent to tumour initiation, perhaps by causing more rapid or more likely progression from microadenoma to macroadenoma.
Asunto(s)
Adenoma/genética , Neoplasias Colorrectales/genética , ADN Glicosilasas/genética , Genes APC , Mutación de Línea Germinal , Poliposis Adenomatosa del Colon/genética , Adulto , Anciano , Regulación Neoplásica de la Expresión Génica , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Pérdida de Heterocigocidad , Persona de Mediana Edad , beta Catenina/genéticaRESUMEN
OBJECTIVE: To analyse somatic molecular changes, clinicopathological features, family history, and germline mutations in families with colorectal cancer (CRC). METHODS: Molecular changes (K-ras and beta-catenin mutations, chromosome 18q allele loss (LOH), APC LOH, microsatellite instability (MSI), and expression of beta-catenin and p53) were examined in four series of CRC patients with proven or probable hereditary disease: hereditary non-polyposis colon cancer (HNPCC); MYH associated polyposis (MAP); multiple (>5) colorectal adenomas without familial adenomatous polyposis (FAP); and other families/cases referred to family cancer clinics (FCC series). HNPCC was diagnosed using a combination of germline mutation screening and tumour studies. A series of unselected CRC patients was also studied. RESULTS: There was overlap between genetic pathways followed by each type of CRC, but significant differences included: increased frequency of K-ras mutation and reduced frequency of APC LOH in cancers from MAP, but not from multiple adenoma patients; reduced frequency of LOH in HNPCC CRCs; and increased MSI in CRCs from HNPCC, but not from FCC or multiple adenoma patients. HNPCC was apparently detected efficiently by combined germline and somatic analysis. Cancers from the FCC, unselected, and multiple adenoma series shared similar molecular characteristics. In the FCC and multiple adenoma series, hierarchical cluster analysis using the molecular features of the cancers consistently identified two distinct groups, distinguished by presence or absence of K-ras mutation. CONCLUSIONS: While K-ras mutation status is known to differentiate hereditary bowel cancer syndromes such as MAP and FAP, it may also distinguish groups of non-HNPCC, FCC patients whose disease has different, as yet unknown, genetic origins.
Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales/genética , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Adulto , Alelos , Análisis por Conglomerados , Análisis Mutacional de ADN , Genes ras , Humanos , Pérdida de Heterocigocidad , Repeticiones de Microsatélite , Persona de Mediana Edad , Modelos Genéticos , MutaciónRESUMEN
PURPOSE: Hereditary nonpolyposis colon cancer (HNPCC) is a Mendelian dominant syndrome of bowel, endometrial, and other cancers and results from germline mutations in mismatch repair (MMR) genes. HNPCC is now best diagnosed on molecular grounds using MMR mutation screening, aided by microsatellite instability (MSI) and immunohistochemistry in tumors. Selection of families for molecular investigation of HNPCC is usually based on suboptimal methods (Amsterdam Criteria or Bethesda Guidelines), but these can be improved using additional clinical data (mean ages of affected persons and presence of endometrial cancer) in a quantitative model. METHODS: We have verified the performance of the Wijnen model and have shown that it remains valid when HNPCC is diagnosed using mutation screening, MSI, and immunohistochemistry. We have also set up and verified our own models (Amsterdam-plus and Alternative), which perform at least as well as the Wijnen model. RESULTS: The Amsterdam-plus model improves on the Amsterdam Criteria by using five extra variables (numbers of colorectal and endometrial cancers in the family, number of patients with five or more adenomas, number with more than one primary cancer of the colorectum or endometrium, and mean age of presentation) and performs better than the Wijnen model. The Alternative model avoids the need to evaluate the Amsterdam Criteria and performs nearly as well as the other models. CONCLUSION: We believe that a quantitative model, such as the Amsterdam-plus model, should be the first choice for selecting families or patients for evaluation of HNPCC using molecular tests. We present an algorithm for this process.
Asunto(s)
Algoritmos , Neoplasias Colorrectales Hereditarias sin Poliposis/complicaciones , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales/genética , Análisis Mutacional de ADN , Reparación del ADN/genética , Neoplasias Endometriales/genética , Predisposición Genética a la Enfermedad , Modelos Teóricos , Guías de Práctica Clínica como Asunto , Adulto , Disparidad de Par Base , Femenino , Mutación de Línea Germinal , Humanos , Inmunohistoquímica , Masculino , Repeticiones de Microsatélite , Persona de Mediana Edad , Linaje , Factores de RiesgoRESUMEN
Genetic testing for cancer susceptibility (e.g. hereditary non-polyposis colorectal cancer) is available for some families with a history of colon cancer. Our aim was to investigate participants' anticipated emotional and behavioral reactions to genetic testing for colon cancer and whether gender or clinical risk influences these reactions. 437 asymptomatic participants with a colorectal cancer family history completed a questionnaire about anticipated emotions and actions, under different genetic testing scenarios. More women than men anticipated feeling worried, regretful, and angry if tested positive. People at lower-risk anticipated more surprise and disbelief than those at higher-risk. People anticipated feeling more guilt, regret and less relief if they were not tested than if they were. High-risk results were anticipated to increase depression and worry. Most people still wanted screening if at low risk, anticipated leading healthier lifestyles whatever the result, but would make more plans for the future if they were at high risk. Clinical implications are that as anticipated emotional effects of not being tested may be more severe than having a test, people choosing to forgo testing should feel able to reconsider their decision anytime. Most people did not anticipate strong emotional reactions but thought it would change their lifestyle and would like continued clinical surveillance whatever the result.
Asunto(s)
Actitud Frente a la Salud , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Pruebas Genéticas/psicología , Femenino , Humanos , MasculinoRESUMEN
The putative locus for hereditary mixed polyposis syndrome (HMPS) in a large family of Ashkenazi descent (SM96) was previously reported to map to chromosome sub-bands 6q16-q21. However, new clinical data, together with molecular data from additional family members, have shown 6q linkage to be incorrect. A high-density genomewide screen for the HMPS gene was therefore performed on SM96, using stringent criteria for assignment of affection status to minimize phenocopy rates. Significant evidence of linkage was found only on a region on chromosome 15q13-q14. Since this region encompassed CRAC1, a locus involved in inherited susceptibility to colorectal adenomas and carcinomas in another Ashkenazi family (SM1311), we determined whether HMPS and CRAC1 might be the same. We found that affected individuals from both families shared a haplotype between D15S1031 and D15S118; the haplotype was rare in the general Ashkenazi population. A third informative family, SM2952, showed linkage of disease to HMPS/CRAC1 and shared the putative ancestral haplotype, as did a further two families, SMU and RF. Although there are probably multiple causes of the multiple colorectal adenoma and cancer phenotype in Ashkenazim, an important one is the HMPS/CRAC1 locus on 15q13-q14.
Asunto(s)
Poliposis Adenomatosa del Colon/genética , Cromosomas Humanos Par 15/genética , Ligamiento Genético , Haplotipos/genética , Judíos/genética , Mapeo Cromosómico , Cromosomas Humanos Par 6/genética , Femenino , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Humanos , Escala de Lod , Masculino , LinajeAsunto(s)
Adenoma/genética , Neoplasias Colorrectales/genética , ADN Glicosilasas , Mutación de Línea Germinal , Neoplasias Primarias Múltiples/genética , Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas/genética , Receptores de Factores de Crecimiento , Factor de Crecimiento Transformador beta/genética , Proteínas de Pez Cebra , Receptores de Activinas Tipo I/genética , Adolescente , Adulto , Anciano , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1 , Análisis Mutacional de ADN , ADN de Neoplasias/química , ADN de Neoplasias/genética , Proteínas de Unión al ADN/genética , Femenino , Humanos , Pérdida de Heterocigocidad , Masculino , Persona de Mediana Edad , N-Glicosil Hidrolasas/genética , Polimorfismo Conformacional Retorcido-Simple , Proteínas Proto-Oncogénicas/fisiología , Transducción de Señal , Proteína Smad4 , Transactivadores/genética , Proteínas WntRESUMEN
Familial adenomatous polyposis (FAP) is a dominantly inherited colorectal tumor predisposition that results from germ-line mutations in the APC gene (chromosome 5q21). FAP shows substantial phenotypic variability: classical polyposis patients develop more than 100 colorectal adenomas, whereas those with attenuated polyposis (AAPC) have fewer than 100 adenomas. A further group of individuals, so-called "multiple" adenoma patients, have a phenotype like AAPC, with 3-99 polyps throughout the colorectum, but mostly have no demonstrable germ-line APC mutation. Routine mutation detection techniques fail to detect a pathogenic APC germ-line mutation in approximately 30% of patients with classical polyposis and 90% of those with AAPC/multiple adenomas. We have developed a real-time quantitative multiplex PCR assay to detect APC exon 14 deletions. When this technique was applied to a set of 60 classical polyposis and 143 AAPC/multiple adenoma patients with no apparent APC germ-line mutation, deletions were found exclusively in individuals with classical polyposis (7 of 60, 12%). Fine-mapping of the region suggested that the majority (6 of 7) of these deletions encompassed the entire APC locus, confirming that haploinsufficiency can result in a classical polyposis phenotype. Screening for germ-line deletions in APC mutation-negative individuals with classical polyposis seems warranted.