RESUMEN

BACKGROUND: Pre-test genetic counseling for patients with breast cancer is increasingly being provided by nongenetic healthcare professionals. We evaluated the attitudes, knowledge, and self-efficacy of surgeons, oncologists, and nurses regarding mainstream genetic testing and the feasibility to incorporate pre-test genetic counseling into routine care. METHODS: We offered an online training to healthcare professionals from 13 hospitals and implemented a mainstream genetic testing pathway in 11/13 (85%) hospitals. Questionnaires were sent before (T0) and 6 months after (T1) completing the training. Those who did not complete the training received a questionnaire to assess their motivations. RESULTS: In 11 hospitals, 80 (65%) healthcare professionals completed the training, of whom 70 (88%) completed both questionnaires. The attitudes, (perceived) knowledge and self-efficacy of healthcare professionals were high both at baseline and 6 months after completing the training. After 6 months, their perceived knowledge about the advantages and disadvantages of a genetic test and implications for family members had significantly improved (p = 0.012 and p = 0.021, respectively). For the majority (89%), the time investment for pre-test genetic counseling was less than 15 min per patient and as expected or better. Healthcare professionals considered the total time investment feasible to incorporate mainstream genetic testing into their daily practice. The main barrier to complete the training was lack of time. The online training was considered useful, with a rating of 8/10. CONCLUSION: Surgical oncologists and nurses in breast cancer care feel well-equipped and motivated to provide pre-test genetic counseling after completion of an online training module.

Asunto(s)

Neoplasias de la Mama , Oncólogos , Humanos , Femenino , Asesoramiento Genético , Neoplasias de la Mama/genética , Neoplasias de la Mama/cirugía , Pruebas Genéticas , Personal de Salud , Encuestas y Cuestionarios , Oncólogos/psicología

RESUMEN

OBJECTIVE: To describe clinical characteristics of Lynch syndrome associated ovarian cancer and the efficacy of surveillance in the early detection of these ovarian cancers. METHODS: All Lynch syndrome associated ovarian cancer cases identified in either the Dutch Lynch syndrome registry (DLSR) between 1987 and 2016, and/or the cohort at the University Medical Center Groningen (UMCG) between 1993 and 2016 were included. Clinical data on age at diagnosis, mutation type, histological type, FIGO stage, treatment, follow-up and gynecological surveillance were collected. RESULTS: A total of 46/798 (6%) women in the DLSR and 7/80 (9%) in the UMCG cohort were identified as LS associated ovarian cancer patients. The median age at ovarian cancer diagnosis was 46.0 years (range 20-75 years). The most frequently reported histological type was endometrioid adenocarcinoma (40%; n = 21) and serous carcinoma (36%; n = 19). Most tumors (87%; n = 46) were detected at an early stage (FIGO I/II). Forty-one of 53 (77%) patients were diagnosed with ovarian cancer before LS was diagnosed. In the other 12/53 (23%) women, ovarian cancer developed after starting annual gynecological surveillance for LS; three ovarian cancers were screen-detected in asymptomatic women. Overall survival was 83%. CONCLUSION: Ovarian cancer in women with LS has a wide age-range of onset, is usually diagnosed at an early stage with predominantly endometrioid type histology and a good overall survival. The early stage at diagnosis could not be attributed to annual gynecological surveillance.

Asunto(s)

Neoplasias Colorrectales Hereditarias sin Poliposis/epidemiología , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Neoplasias Ováricas/epidemiología , Neoplasias Ováricas/patología , Adulto , Factores de Edad , Anciano , Estudios de Cohortes , Femenino , Humanos , Persona de Mediana Edad , Países Bajos/epidemiología , Estudios Prospectivos , Sistema de Registros

RESUMEN

Non-invasive prenatal testing (NIPT) of cell-free DNA in maternal plasma, which is a mixture of maternal DNA and a low percentage of fetal DNA, can detect fetal aneuploidies using massively parallel sequencing. Because of the low percentage of fetal DNA, methods with high sensitivity and precision are required. However, sequencing variation lowers sensitivity and hampers detection of trisomy samples. Therefore, we have developed three algorithms to improve sensitivity and specificity: the chi-squared-based variation reduction (χ2VR), the regression-based Z-score (RBZ) and the Match QC score. The χ2VR reduces variability in sequence read counts per chromosome between samples, the RBZ allows for more precise trisomy prediction, and the Match QC score shows if the control group used is representative for a specific sample. We compared the performance of χ2VR to that of existing variation reduction algorithms (peak and GC correction) and that of RBZ to trisomy prediction algorithms (standard Z-score, normalized chromosome value and median-absolute-deviation-based Z-score). χ2VR and the RBZ both reduce variability more than existing methods, and thereby increase the sensitivity of the NIPT analysis. We found the optimal combination of algorithms was to use both GC correction and χ2VR for pre-processing and to use RBZ as the trisomy prediction method.

Asunto(s)

Algoritmos , Pruebas Genéticas , Diagnóstico Prenatal/métodos , Ácidos Nucleicos Libres de Células , Femenino , Pruebas Genéticas/métodos , Pruebas Genéticas/normas , Humanos , Embarazo , Diagnóstico Prenatal/normas , Análisis de Regresión , Reproducibilidad de los Resultados , Sensibilidad y Especificidad

RESUMEN

Familial adenomatous polyposis (FAP) is a dominantly inherited syndrome caused by germline mutations in the APC gene and characterized by the development of multiple colorectal adenomas and a high risk of developing colorectal cancer (CRC). The severity of polyposis is correlated with the site of the APC mutation. However, there is also phenotypic variability within families with the same underlying APC mutation, suggesting that additional factors influence the severity of polyposis. Genome-wide association studies identified several single nucleotide polymorphisms (SNPs) that are associated with CRC. We assessed whether these SNPs are associated with polyp multiplicity in proven APC mutation carriers. Sixteen CRC-associated SNPs were analysed in a cohort of 419 APC germline mutation carriers from 182 families. Clinical data were retrieved from the Dutch Polyposis Registry. Allele frequencies of the SNPs were compared for patients with <100 colorectal adenomas versus patients with ≥100 adenomas, using generalized estimating equations with the APC genotype as a covariate. We found a trend of association of two of the tested SNPs with the ≥100 adenoma phenotype: the C alleles of rs16892766 at 8q23.3 (OR 1.71, 95 % CI 1.05-2.76, p = 0.03, dominant model) and rs3802842 at 11q23.1 (OR 1.51, 95 % CI 1.03-2.22, p = 0.04, dominant model). We identified two risk variants that are associated with a more severe phenotype in APC mutation carriers. These risk variants may partly explain the phenotypic variability in families with the same APC gene defect. Further studies with a larger sample size are recommended to evaluate and confirm the phenotypic effect of these SNPs in FAP.

Asunto(s)

Proteína de la Poliposis Adenomatosa del Colon/genética , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 8 , Neoplasias Colorrectales/genética , Adenoma/genética , Poliposis Adenomatosa del Colon/genética , Adulto , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Mutación , Polimorfismo de Nucleótido Simple

RESUMEN

OBJECTIVE: Endoscopic ultrasonography (EUS) and MRI are promising tests to detect precursors and early-stage pancreatic ductal adenocarcinoma (PDAC) in high-risk individuals (HRIs). It is unclear which screening technique is to be preferred. We aimed to compare the efficacy of EUS and MRI in their ability to detect clinically relevant lesions in HRI. DESIGN: Multicentre prospective study. The results of 139 asymptomatic HRI (>10-fold increased risk) undergoing first-time screening by EUS and MRI are described. Clinically relevant lesions were defined as solid lesions, main duct intraductal papillary mucinous neoplasms and cysts ≥10 mm. Results were compared in a blinded, independent fashion. RESULTS: Two solid lesions (mean size 9 mm) and nine cysts ≥10 mm (mean size 17 mm) were detected in nine HRI (6%). Both solid lesions were detected by EUS only and proved to be a stage I PDAC and a multifocal pancreatic intraepithelial neoplasia 2. Of the nine cysts ≥10 mm, six were detected by both imaging techniques and three were detected by MRI only. The agreement between EUS and MRI for the detection of clinically relevant lesions was 55%. Of these clinically relevant lesions detected by both techniques, there was a good agreement for location and size. CONCLUSIONS: EUS and/or MRI detected clinically relevant pancreatic lesions in 6% of HRI. Both imaging techniques were complementary rather than interchangeable: contrary to EUS, MRI was found to be very sensitive for the detection of cystic lesions of any size; MRI, however, might have some important limitations with regard to the timely detection of solid lesions.

Asunto(s)

Carcinoma Ductal Pancreático , Endosonografía , Imagen por Resonancia Magnética , Páncreas/diagnóstico por imagen , Quiste Pancreático , Neoplasias Pancreáticas , Adulto , Enfermedades Asintomáticas , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/patología , Estudios de Cohortes , Investigación sobre la Eficacia Comparativa/métodos , Detección Precoz del Cáncer/métodos , Endosonografía/métodos , Endosonografía/estadística & datos numéricos , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Imagen por Resonancia Magnética/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Países Bajos , Páncreas/patología , Quiste Pancreático/diagnóstico , Quiste Pancreático/patología , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/patología , Estudios Prospectivos

RESUMEN

OBJECTIVE: Based on previous studies, standard gynecological screening consisting of annual transvaginal ultrasonography (TVU) was added with endometrial sampling in women with Lynch syndrome (LS). The aim of this study was to evaluate the additional value of endometrial sampling in detecting (pre)malignancies of the endometrial tissue in women with LS or first-degree relatives. METHODS: All women above 30 years of age with LS or first-degree relatives at 50% risk of LS are offered annual gynecological screening in our family cancer clinic. Endometrial screening results from January 2003-December 2007 (period I: standard screening by transvaginal sonography and serum CA125) were compared with screening results from January 2008-June 2012 (period II: standard screening added with endometrial sampling). RESULTS: Seventy five women (300 patient years) were screened annually. There were 266 screening visits, 117 in period I and 149 in period II. In period I, four premalignant endometrial lesions were detected and one endometrial carcinoma (FIGO stage IB). In period II, two premalignancies were found. None of the lesions would have been missed without standard endometrial sampling. No interval endometrial cancers were detected in this study. CONCLUSION: In this study, annual endometrial screening seems an effective screening tool in the detection of premalignancies and early endometrial cancer in women with LS. Adding standard endometrial sampling to annual TVU has no additional value in the early detection of (pre)malignant endometrial lesions in women with LS in this study.

Asunto(s)

Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Neoplasias Endometriales/diagnóstico , Endometrio/patología , Lesiones Precancerosas/diagnóstico , Adulto , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico por imagen , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Detección Precoz del Cáncer/métodos , Neoplasias Endometriales/diagnóstico por imagen , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Salud de la Familia , Femenino , Humanos , Persona de Mediana Edad , Mutación , Lesiones Precancerosas/diagnóstico por imagen , Lesiones Precancerosas/genética , Lesiones Precancerosas/patología , Ultrasonografía

RESUMEN

This article provides a historical overview of the online database ( www.insight-group.org/mutations ) maintained by the International Society for Gastrointestinal Hereditary Tumours. The focus is on the mismatch repair genes which are mutated in Lynch Syndrome. APC, MUTYH and other genes are also an important part of the database, but are not covered here. Over time, as the understanding of the genetics of Lynch Syndrome increased, databases were created to centralise and share the variants which were being detected in ever greater numbers. These databases were eventually merged into the InSiGHT database, a comprehensive repository of gene variant and disease phenotype information, serving as a starting point for important endeavours including variant interpretation, research, diagnostics and enhanced global collection. Pivotal to its success has been the collaborative spirit in which it has been developed, its association with the Human Variome Project, the appointment of a full time curator and its governance stemming from the well established organizational structure of InSiGHT.

Asunto(s)

Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Bases de Datos Genéticas/historia , Historia del Siglo XX , Historia del Siglo XXI , Humanos

RESUMEN

In the absence of a polyposis phenotype, colorectal cancer (CRC) patients referred for genetic testing because of early-onset disease and/or a positive family history, typically undergo testing for molecular signs of Lynch syndrome in their tumors. In the absence of these signs, DNA testing for germline mutations associated with other known tumor syndromes is usually not performed. However, a few studies in large series of CRC patients suggest that in a small percentage of CRC cases, bi-allelic MUTYH germline mutations can be found in the absence of the MUTYH-associated polyposis phenotype. This has not been studied in the Dutch population. Therefore, we analyzed the MUTYH gene for mutations in 89 patients with microsatellite-low or stable CRC cancer diagnosed before the age of 40 years or otherwise meeting the Bethesda criteria, all of them without a polyposis phenotype. In addition, we studied a series of 693 non-CRC patients with 1-13 adenomatous colorectal polyps for the MUTYH hotspot mutations Y179C, G396D and P405L. No bi-allelic MUTYH mutations were observed. Our data suggest that the contribution of bi-allelic MUTYH mutations to the development of CRC in Dutch non-polyposis patients that meet clinical genetic referral criteria, and to the development of low number of colorectal adenomas in non-CRC patients, is likely to be low.

Asunto(s)

Pólipos Adenomatosos/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales/genética , ADN Glicosilasas/genética , Predisposición Genética a la Enfermedad , Adulto , Anciano , Femenino , Mutación de Línea Germinal , Humanos , Masculino , Persona de Mediana Edad , Mutación , Países Bajos , Adulto Joven

RESUMEN

In predictive DNA testing for hereditary cancer, test results should traditionally be disclosed face-to-face. Increasingly, however, counselees ask to receive their test result at home by letter. To compare the quality of genetic counselling in the traditional way to a procedure in which counselees are offered a choice on how to get their test result. Counselees from families with a known BRCA1/2 or Lynch syndrome mutation were randomised into two groups. The control group was given the DNA test result in a face-to-face consultation. In the intervention group people could choose to learn their test result face-to-face or by letter. The quality of genetic counselling was assessed through questionnaires at three different moments. Data of 198 counselees were analysed. The quality of genetic counselling and psychological functioning were equally good in both groups. The majority of cases chose for disclosure by letter. The counselees with a good test result in the intervention group were the most satisfied. Our results indicate that in predictive DNA testing for BRCA1/2 and Lynch syndrome, a choice protocol is equally safe and more satisfying. Moreover, it is more efficient for both counsellor and counselee.

Asunto(s)

Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/psicología , Revelación , Genes BRCA1 , Genes BRCA2 , Asesoramiento Genético , Adulto , Conducta de Elección , Femenino , Pruebas Genéticas , Humanos , Masculino , Persona de Mediana Edad , Acceso de los Pacientes a los Registros , Satisfacción del Paciente , Investigación Cualitativa , Encuestas y Cuestionarios

RESUMEN

Genetic testing is traditionally preceded by counselling to discuss its advantages and disadvantages with individuals so they can make informed decisions. The new technique of whole genome or exome sequencing, which is currently only used in research settings, can identify many gene mutations, including substantial numbers of mutations with unknown pathological effect; it may, therefore, threaten this balanced approach if it is used in a clinical setting. We discuss the ethical challenges of several approaches to pre- and postnatal DNA testing, individual privacy versus the interests of families and of scientists, and the clinician's duty to re-contact if new information or options become available.

Asunto(s)

Asesoramiento Genético/ética , Enfermedades Genéticas Congénitas/diagnóstico , Predisposición Genética a la Enfermedad , Pruebas Genéticas/ética , Tamizaje Neonatal/ética , Femenino , Asesoramiento Genético/métodos , Enfermedades Genéticas Congénitas/prevención & control , Privacidad Genética/ética , Privacidad Genética/legislación & jurisprudencia , Pruebas Genéticas/métodos , Humanos , Recién Nacido , Masculino , Tamizaje Neonatal/métodos , Países Bajos , Embarazo , Diagnóstico Prenatal/ética , Diagnóstico Prenatal/métodos , Control de Calidad

RESUMEN

OBJECTIVE: Li Fraumeni syndrome (LFS) and Von Hippel-Lindau disease (VHL) are two rare hereditary tumor syndromes, characterized by a high risk of developing multiple tumors at various sites and ages for which preventive and treatment options are limited. For partners, it may be difficult to deal with the on-going threat of tumors in both their spouse and children. Therefore, this study aims to evaluate the prevalence of and factors associated with psychological distress among partners of individuals with or at high risk of LFS or VHL. METHODS: As part of a nationwide, cross-sectional study, partners of individuals diagnosed with or at high risk of LFS or VHL were invited to complete a self-report questionnaire assessing distress, worries, and health-related quality of life. RESULTS: Fifty-five (58%) of those high-risk individuals with a partner consented to having their partner approached for the study. In total, 50 partners (91%) completed the questionnaire, of whom 28% reported clinically relevant levels of syndrome-related distress. Levels of distress and worries of the partners and their high-risk spouse were significantly correlated. Younger age and a lack of social support were also associated significantly with heightened levels of distress and worries. The majority of partners (76%) believed that professional psychosocial support should be routinely offered to them. CONCLUSIONS: Approximately one-quarter of the partners exhibit clinically relevant levels of distress that warrant psychological support. The distress levels of the 'patient' could potentially be used to identify partners at risk of developing clinically relevant levels of distress.

Asunto(s)

Adaptación Psicológica , Trastornos de Adaptación/psicología , Trastornos de Ansiedad/psicología , Trastorno Depresivo/diagnóstico , Predisposición Genética a la Enfermedad/psicología , Síndrome de Li-Fraumeni/diagnóstico , Síndrome de Li-Fraumeni/psicología , Esposos/psicología , Enfermedad de von Hippel-Lindau/diagnóstico , Enfermedad de von Hippel-Lindau/psicología , Trastornos de Adaptación/diagnóstico , Trastornos de Adaptación/epidemiología , Adulto , Anciano , Trastornos de Ansiedad/diagnóstico , Trastornos de Ansiedad/epidemiología , Estudios Transversales , Trastorno Depresivo/epidemiología , Trastorno Depresivo/psicología , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Síndrome de Li-Fraumeni/genética , Masculino , Persona de Mediana Edad , Encuestas y Cuestionarios , Adulto Joven , Enfermedad de von Hippel-Lindau/genética

RESUMEN

Li Fraumeni Syndrome (LFS) is a hereditary cancer syndrome characterized by a high risk of developing various types of cancer from birth through late adulthood. Clinical benefits of surveillance for LFS are limited. The aim of this study is to investigate which advice for regular surveillance, if any, is given to high risk LFS individuals, adherence to that advice, and any psychological gain or burden derived from surveillance. Fifty-five high risk individuals (proven carriers and those at 50% risk) from families with a p53 germline mutation were invited to participate, of whom 82% completed a self-report questionnaire assessing advice for regular surveillance, compliance, perceived benefits and barriers of screening and LFS-related distress (IES) and worries (CWS). In total, 71% of the high risk family members received advice to undergo regular surveillance for LFS. The majority (78%) reported adherence with the recommended advice. All high risk women aged 25 or older reported having been advised to undergo annual breast cancer surveillance (n = 11), of whom 64% (n = 7) in specific received advice to undergo a mammography. Seventy-eight percent of respondents indicated having received tailored surveillance advice based on family cancer history. The large majority of respondents believed in the value of surveillance to detect tumors at an early stage (90%) and reported that it gave them a sense of control (84%) and security (70%). Despite its limited clinical benefits, the majority of high risk LFS family are advised to undergo, and are adherent to, and report psychological benefit from, regular surveillance programs.

Asunto(s)

Detección Precoz del Cáncer , Genes p53 , Mutación de Línea Germinal/genética , Síndrome de Li-Fraumeni/genética , Síndrome de Li-Fraumeni/psicología , Cooperación del Paciente , Adulto , Estudios Transversales , Femenino , Humanos , Síndrome de Li-Fraumeni/diagnóstico , Persona de Mediana Edad , Estrés Psicológico , Encuestas y Cuestionarios

RESUMEN

Von Hippel-Lindau disease (VHL) is a hereditary tumor susceptibility syndrome, characterized by an increased risk of developing multiple benign and malignant tumors at various sites and ages with limited preventive options. This study evaluates the prevalence of distress among VHL family members and factors associated significantly with such distress. Forty-eight families with a VHL mutation were identified via the nine family cancer clinics in the Netherlands. In total, 171 family members (carriers, 50% at-risk, non-carriers) were approached, of whom 123 (72%) completed a self-report questionnaire. Approximately 40% of the VHL family members reported clinically relevant levels of distress, approaching 50% among the carriers and, possibly even more striking, 36% among the non-carriers. Having lost a first degree relative due to VHL during adolescence (OR 11.2; 95% CI 1.4-86.9) was related significantly to heightened levels of distress. Approximately, only one-third of those who reported heightened levels of distress had received professional psychosocial support. A substantial percentage of family members experience clinically relevant levels of distress. We would recommend the introduction of a procedure for screening for distress in this vulnerable population. Special attention should be paid to those individuals who have lost a close relative due to VHL during adolescence.

Asunto(s)

Enfermedad de von Hippel-Lindau/psicología , Adulto , Femenino , Humanos , Modelos Logísticos , Masculino , Calidad de Vida , Apoyo Social , Encuestas y Cuestionarios

RESUMEN

The current clinical diagnosis of Von Hippel-Lindau (VHL) disease demands at least one specific [corrected] VHL manifestation in a patient with familial VHL disease, or, in a [corrected] sporadic patient, at least two or more hemangioblastomas or a single hemangioblastoma in combination with a typical visceral lesion. To evaluate this definition, we studied the frequency of germline VHL mutation in three patients groups: (i) multi-organ involvement (classic VHL), (ii) limited VHL manifestations meeting criteria (non-classic VHL) and (iii) patients with VHL-associated tumors not meeting current diagnostic VHL criteria. In addition, we validated multiplex ligation-dependent probe amplification (MLPA) as a rapid and reliable quantitative method for the identification of germline VHL deletions. The frequency of germline VHL mutations was very high in classic VHL cases with multi-organ involvement (95%), lower in non-classic cases that meet current diagnostic criteria but have limited VHL manifestations or single-organ involvement (24%) and low (3.3%), but tangible in cases not meeting current diagnostic VHL criteria. The detection of germline VHL mutations in patients or families with limited VHL manifestations, or single-organ involvement is relevant for follow-up of probands and early identification of at-risk relatives.

Asunto(s)

Frecuencia de los Genes , Mutación de Línea Germinal , Enfermedad de von Hippel-Lindau/diagnóstico , Enfermedad de von Hippel-Lindau/genética , Southern Blotting , Análisis Mutacional de ADN , Humanos , Técnicas de Amplificación de Ácido Nucleico , Linaje , Prevalencia , Análisis de Secuencia de ADN

RESUMEN

This study examined prospectively the contribution of family functioning, differentiation to parents, family communication and support from relatives to psychological distress in individuals undergoing genetic susceptibility testing for a known familial pathogenic BRCA1/2 or Hereditary nonpolyposis colorectal cancer-related mutation. Family functioning, differentiation to parents, hereditary cancer-related family communication and perceived support from relatives were assessed in 271 participants for genetic testing before test result disclosure. Hereditary cancer distress (assessed by the Impact of Event Scale) and cancer worry (assessed by the Cancer Worry Scale) were assessed before, 1 week after, and 6 months after test result disclosure. Participants reporting more cancer-related distress over the study period more frequently perceived the communication about hereditary cancer with relatives as inhibited, the nuclear family functioning as disengaged-rigid or enmeshed-chaotic, the support from partner as less than adequate and the relationship to mother as less differentiated. Especially, open communication regarding hereditary cancer and partner support may be important buffers against hereditary cancer distress. Identifying individuals with insufficient sources of support and addressing the family communication concerning hereditary cancer in genetic counseling may help the counselee to adjust better to genetic testing.

Asunto(s)

Neoplasias de la Mama/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Familia/psicología , Genes BRCA1 , Genes BRCA2 , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas/psicología , Estrés Psicológico/psicología , Adulto , Neoplasias de la Mama/psicología , Neoplasias Colorrectales Hereditarias sin Poliposis/psicología , Comunicación , Femenino , Asesoramiento Genético/métodos , Humanos , Masculino , Persona de Mediana Edad , Países Bajos , Estudios Prospectivos , Apoyo Social , Encuestas y Cuestionarios

RESUMEN

BACKGROUND: A testicular germ cell tumour (TGCT) predisposing gene has been mapped to the Xq27 region on the X chromosome. These linkage findings remain to be confirmed by other studies. METHODS: In 276 patients and 169 unaffected first-degree male relatives, 12 microsatellite markers covering the candidate region were genotyped and used to study possible association of TGCT with Xq27. RESULTS: In contrast to previously reported linkage of familial TGCT and cryptorchidism with Xq27, we observed an association between the subset of TGCT cases without a family history of TGCT or cryptorchism and marker DXS1193 (p=0.014). Carriers of minor alleles were at increased risk (odds ratio (OR) 4.7, confidence interval (CI) 1.1-19.6) CONCLUSION: We found an association on Xq27 in a subset of TGCT cases, which suggests the presence of an X-linked gene that slightly or moderately increases risk to develop sporadic TGCT but not cryptorchidism.

Asunto(s)

Cromosomas Humanos X/genética , Genes Ligados a X/genética , Neoplasias de Células Germinales y Embrionarias/genética , Neoplasias Testiculares/genética , Genotipo , Humanos , Masculino , Repeticiones de Microsatélite , Linaje

RESUMEN

BACKGROUND: Patients with early-onset colorectal cancer (CRC) or those with multiple tumours associated with hereditary non-polyposis colorectal cancer (HNPCC) raise suspicion of the presence of germline DNA mismatch repair (MMR) gene mutations. AIM: To analyse the value of family history, microsatellite instability (MSI) analysis and MMR protein staining in the tumour to predict the presence of an MMR gene mutation in such patients. METHODS: In 281 patients diagnosed with CRC before the age of 50 years or with CRC and at least one additional HNPCC-associated cancer, germline mutation analysis in MLH1, MSH2 and MSH6 was carried out with denaturing gradient gel electrophoresis and multiplex ligation-dependent probe amplification. MSI analysis with five consensus markers and MMR protein staining for MLH1, MSH2 and MSH6 were carried out in the tumours. RESULTS: 25 pathogenic mutations (8 in MLH1, 9 in MSH2 and 8 in MSH6) were found. MSI analysis missed three and immunohistochemistry (IHC) missed two mutation carriers. Sensitivities of family history, MSI analysis and IHC for the presence of a mutation were 76%, 82% and 88%, specificities were 64%, 70% and 84%, and positive predictive values were 19%, 23% and 38%, respectively. Multivariate analysis showed the highest odds ratio for IHC (38.3, 95% confidence interval 9.0 to 184). Prevalence of pathogenic germline MMR gene mutations in patients with CRC before the age of 50 years was 6% and in those with > or =2 HNPCC-associated tumours was 22%. In the second group, no mutation carriers were found among the 29 patients who were diagnosed with their first tumour after the age of 60 years. CONCLUSION: Family history, MSI analysis and IHC are indicative parameters to select patients with CRC for MMR gene mutation analysis. The data show that IHC is the best single selection criterion.

Asunto(s)

Neoplasias Colorrectales/genética , Reparación de la Incompatibilidad de ADN , Mutación de Línea Germinal/genética , Neoplasias Primarias Múltiples/genética , Proteínas Adaptadoras Transductoras de Señales , Adolescente , Adulto , Anciano , Disparidad de Par Base/genética , Proteínas Portadoras/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Análisis Mutacional de ADN/métodos , ADN de Neoplasias/genética , Proteínas de Unión al ADN/genética , Salud de la Familia , Femenino , Heterocigoto , Humanos , Inmunohistoquímica/métodos , Masculino , Inestabilidad de Microsatélites , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL , Proteína 2 Homóloga a MutS/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Valor Predictivo de las Pruebas

RESUMEN

BACKGROUND: This study explores the effect of age at the time of parental cancer diagnosis or death on psychological distress and cancer risk perception in individuals undergoing genetic testing for a specific cancer susceptibility. PATIENTS AND METHODS: Cancer-related distress, worry and risk perception were assessed in 271 applicants for genetic testing of an identified mutation in BRCA1/2 (BReast CAncer) or a HNPCC (Hereditary Nonpolyposis Colorectal Cancer) related gene before, one week after, and six months after genetic test disclosure. The course of distress and risk perception were compared between individuals having witnessed parental cancer or loss due to cancer in childhood, adolescence, adulthood and having unaffected parents. RESULTS: Individuals with parental cancer in childhood (under age 13) reported the highest level of cancer related distress, worry and risk perception. Women having their mother affected by breast cancer in puberty (aged 10-13 years) perceived higher breast cancer risks than women with an affected mother in adulthood or without an affected mother. Individuals with an affected parent perceived cancer risks as higher than individuals without an affected parent, but were not more distressed. CONCLUSIONS: Experience of parental cancer in childhood is a risk factor for psychological distress during the genetic testing process.

Asunto(s)

Neoplasias de la Mama/psicología , Neoplasias Colorrectales Hereditarias sin Poliposis/psicología , Pruebas Genéticas/psicología , Adolescente , Adulto , Factores de Edad , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Niño , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Análisis Mutacional de ADN/psicología , Femenino , Humanos , Masculino , Padres , Pubertad , Medición de Riesgo

RESUMEN

OBJECTIVE: To investigate the contribution of MYH associated polyposis coli (MAP) among polyposis families in the Netherlands, and the prevalence of colonic and extracolonic manifestations in MAP patients. METHODS: 170 patients with polyposis coli, who previously tested negative for APC mutations, were screened by denaturing gradient gel electrophoresis and direct sequencing to identify MYH germline mutations. RESULTS: Homozygous and compound heterozygous MYH mutations were identified in 40 patients (24%). No difference was found in the percentage of biallelic mutation carriers between patients with 10-99 polyps or 100-1000 polyps (29% in both groups). Colorectal cancer was found in 26 of the 40 patients with MAP (65%) within the age range 21 to 67 years (median 45). Complete endoscopic reports were available for 16 MAP patients and revealed five cases with gastro-duodenal polyps (31%), one of whom also presented with a duodenal carcinoma. Breast cancer occurred in 18% of female MAP patients, significantly more than expected from national statistics (standardised morbidity ratio = 3.75). CONCLUSIONS: Polyp numbers in MAP patients were equally associated with the attenuated and classical polyposis coli phenotypes. Two thirds of the MAP patients had colorectal cancer, 95% of whom were older than 35 years, and one third of a subset of patients had upper gastrointestinal lesions. Endoscopic screening of the whole intestine should be carried out every two years for all MAP patients, starting from age 25-30 years. The frequent occurrence of additional extraintestinal manifestations, such as breast cancer among female MAP patients, should be thoroughly investigated.

Asunto(s)

Poliposis Adenomatosa del Colon/genética , ADN Glicosilasas/genética , Adolescente , Adulto , Anciano , Niño , Neoplasias Colorrectales/genética , Análisis Mutacional de ADN , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Mutación de Línea Germinal , Humanos , Patrón de Herencia/genética , Masculino , Persona de Mediana Edad , Países Bajos , Fenotipo , Riesgo

RESUMEN

OBJECTIVE: To determine whether an investigation of microsatellite instability (MSI) in patients with colorectal carcinoma that have been selected by the pathologist could increase the number of detected families with hereditary non-polyposis colorectal carcinoma (HNPCC). DESIGN: Prospective inventory. METHOD: Pathologists selected patients with a newly diagnosed colorectal carcinoma for MSI analysis of their tumour tissue if they met one of the following four criteria: (a) colorectal carcinoma diagnosed below 50 years of age; (b) a second colorectal carcinoma; (c) a combination of colorectal carcinoma and another HNPCC-related cancer; (d) colorectal adenoma with high-grade dysplasia diagnosed below 40 years of age. Patients with a positive MSI-test were referred to a clinical geneticist. The new strategy was introduced and explored in 5 hospitals for a period of to months. RESULTS: The new strategy was adopted and implemented successfully by pathologists and surgeons and accepted with satisfaction by the patients. Of the 55 patients included, 10 had a positive MSI-test. In 8/10 patients, DNA-mutation analysis was started by the clinical geneticist and 3 germline mutations in the MSH2-gene were detected. In 2 of 3 families with a pathogenic mutation, the family history alone did not fulfil the clinical criteria for HNPCC. CONCLUSION: Selection by the pathologist for MSI investigation was feasible in daily practice and identified more HNPCC patients than selection based on family history alone.

Asunto(s)

Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Mutación de Línea Germinal , Repeticiones de Microsatélite , Adulto , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Diagnóstico Diferencial , Femenino , Pruebas Genéticas , Inestabilidad Genómica , Humanos , Masculino , Persona de Mediana Edad , Países Bajos , Linaje , Valor Predictivo de las Pruebas , Estudios Prospectivos