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1.
Genet Med ; 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33257847

RESUMO

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

2.
J Clin Med ; 9(7)2020 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-32708519

RESUMO

PURPOSE: To survey risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) practice and advice regarding hormone replacement therapy (HRT) in women with Lynch syndrome. METHODS: We conducted a survey in 31 contributing centers from the Prospective Lynch Syndrome Database (PLSD), which incorporates 18 countries worldwide. The survey covered local policies for risk-reducing hysterectomy and BSO in Lynch syndrome, the timing when these measures are offered, the involvement of stakeholders and advice regarding HRT. RESULTS: Risk-reducing hysterectomy and BSO are offered to path_MLH1 and path_MSH2 carriers in 20/21 (95%) contributing centers, to path_MSH6 carriers in 19/21 (91%) and to path_PMS2 carriers in 14/21 (67%). Regarding the involvement of stakeholders, there is global agreement (~90%) that risk-reducing surgery should be offered to women, and that this discussion may involve gynecologists, genetic counselors and/or medical geneticists. Prescription of estrogen-only HRT is offered by 15/21 (71%) centers to women of variable age range (35-55 years). CONCLUSIONS: Most centers offer risk-reducing gynecological surgery to carriers of path_MLH1, path_MSH2 and path_MSH6 variants but less so for path_PMS2 carriers. There is wide variation in how, when and to whom this is offered. The Manchester International Consensus Group developed recommendations to harmonize clinical practice across centers, but there is a clear need for more research.

4.
Genet Med ; 22(9): 1524-1532, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32398773

RESUMO

PURPOSE: Juvenile polyposis syndrome (JPS) is a rare, autosomal-dominantly inherited cancer predisposition caused in approximately 50% of cases by pathogenic germline variants in SMAD4 and BMPR1A. We aimed to gather detailed clinical and molecular genetic information on JPS disease expression to provide a basis for management guidelines and establish open access variant databases. METHODS: We performed a retrospective, questionnaire-based European multicenter survey on and established a cohort of SMAD4/BMPR1A pathogenic variant carriers from the medical literature. RESULTS: We analyzed questionnaire-based data on 221 JPS patients (126 kindreds) from ten European centers and retrieved literature-based information on 473 patients. Compared with BMPR1A carriers, SMAD4 carriers displayed anemia twice as often (58% vs. 26%), and exclusively showed overlap symptoms with hemorrhagic telangiectasia (32%) and an increased prevalence (39% vs. 13%) of gastric juvenile polyps. Cancer, reported in 15% of JPS patients (median age 41 years), mainly occurred in the colorectum (overall: 62%, SMAD4: 58%, BMPR1A: 88%) and the stomach (overall: 21%; SMAD4: 27%, BMPR1A: 0%). CONCLUSION: This comprehensive retrospective study on genotype-phenotype correlations in 694 JPS patients corroborates previous observations on JPS in general and SMAD4 carriers in particular, facilitates recommendations for clinical management, and provides the basis for open access variant SMAD4 and BMPR1A databases.

5.
J Med Genet ; 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32179705

RESUMO

BACKGROUND: Although considerable effort has been put into decoding of the osteosarcoma genome, very little is known about germline mutations that underlie this primary malignant tumour of bone. METHODS AND RESULTS: We followed here a coincidental finding in a multiple endocrine neoplasia family in which a 32-year-old patient carrying a germline pathogenic RET mutation developed an osteosarcoma 2 years after the resection of a medullary thyroid carcinoma. Sequencing analysis of additional 336 patients with osteosarcoma led to the identification of germline activating mutations in the RET proto-oncogene in three cases and somatic amplifications of the gene locus in five matched tumours (4%, n=5/124 tumours). Functional analysis of the pathogenic variants together with an integrative analysis of osteosarcoma genomes confirmed that the mutant RET proteins couple functional kinase activity to dysfunctional ligand binding. RET mutations further co-operated with alterations in TP53 and RB1, suggesting that osteosarcoma pathogenesis bears reminiscence to the stepwise model of medullary thyroid carcinoma. CONCLUSIONS: After Li-Fraumeni-predisposing mutations in TP53, RET becomes the second most mutated cancer-predisposing gene in the germline of patients with osteosarcoma. Hence, early identification of RET mutation carriers can help to identify at-risk family members and carry out preventive measures.

6.
Eur J Hum Genet ; 28(8): 1010-1019, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32203201

RESUMO

Genetic testing decision-making for cancer predisposition is inherently complex. Understanding the mechanisms and influencing factors of the decision-making process is essential for genetic counselling and has not yet been investigated in Switzerland. This study's aim is thus to provide a theory about the individual's decision-making process regarding genetic testing for cancer predispositions in order to provide medical geneticists and genetic counsellors with insights into the needs and expectations of counsellees. We interviewed at-risk individuals who underwent genetic counselling in a clinical setting in Switzerland, using a grounded theory approach. Based on the interview data, we propose that a control-fate continuum, which is part of the individuals' life philosophy, importantly influences the decision-making process. Those in need for control decide differently compared with those leaving their future to fate. Several psychosocial factors influence the position on the control-fate continuum: "looking for certainty"; "anticipating consequences"; "being socially influenced"; "simplifying risks"; and "deciding intuitively vs reflectively". The control-fate continuum theory gives insights into the possible reasons behind decision-making regarding genetic testing for cancer predispositions. It includes both acceptors and decliners of genetic testing. Our theory helps healthcare professionals offering genetic counselling to anticipate problems within at-risk families and adapting their services to people's needs.

7.
Genet Med ; 22(1): 15-25, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31337882

RESUMO

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


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Proteínas de Ligação a DNA/economia , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Mutação , Adulto , Idoso , Neoplasias Colorretais Hereditárias sem Polipose/mortalidade , Reparo de Erro de Pareamento de DNA , Bases de Dados Genéticas , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Penetrância , Estudos Prospectivos , Medição de Risco , Caracteres Sexuais , Análise de Sobrevida
8.
Genet Med ; 21(12): 2706-2712, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31204389

RESUMO

PURPOSE: Biallelic pathogenic variants in the mismatch repair (MMR) genes cause a recessive childhood cancer predisposition syndrome known as constitutional mismatch repair deficiency (CMMRD). Family members with a heterozygous MMR variant have Lynch syndrome. We aimed at estimating cancer risk in these heterozygous carriers as a novel approach to avoid complicated statistical methods to correct for ascertainment bias. METHODS: Cumulative colorectal cancer incidence was estimated in a cohort of PMS2- and MSH6-associated families, ascertained by the CMMRD phenotype of the index, by using mutation probabilities based on kinship coefficients as analytical weights in a proportional hazard regression on the cause-specific hazards. Confidence intervals (CIs) were obtained by bootstrapping at the family level. RESULTS: The estimated cumulative colorectal cancer risk at age 70 years for heterozygous PMS2 variant carriers was 8.7% (95% CI 4.3-12.7%) for both sexes combined, and 9.9% (95% CI 4.9-15.3%) for men and 5.9% (95% CI 1.6-11.1%) for women separately. For heterozygous MSH6 variant carriers these estimates are 11.8% (95% CI 4.5-22.7%) for both sexes combined, 10.0% (95% CI 1.83-24.5%) for men and 11.7% (95% CI 2.10-26.5%) for women. CONCLUSION: Our findings are consistent with previous reports that used more complex statistical methods to correct for ascertainment bias. These results underline the need for MMR gene-specific surveillance protocols for Lynch syndrome.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias Colorretais/etiologia , Medição de Risco/métodos , Adulto , Idoso , Estudos de Coortes , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo , Reparo de Erro de Pareamento de DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Mutação , Fatores de Risco
9.
Thyroid ; 29(7): 1018-1022, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31030636

RESUMO

Six patients are described with bi-allelic DUOX2 variants and widely variable phenotypes. Patient 1 is an infant with a compressive hypothyroid goiter causing respiratory distress, which was promptly alleviated by levothyroxine (LT4). He was a compound heterozygote for DUOX2 variants, including a novel deletion of 540 base pairs. Patients 2 and 3 are siblings with the same compound heterozygous mutations of DUOX2, yet one had overt hypothyroidism at 14 months and the other lifelong euthyroidism. Patient 4 is a compound heterozygote individual and has mild persistent congenital hypothyroidism; his sister (patient 5) only had a borderline thyrotropin elevation at newborn screening, consistent with homozygous DUOX2 variants with a mild impact on enzyme activity. Their euthyroid mother (patient 6) is a compound heterozygote for the same DUOX2 mutations as her son. Targeted exome sequencing did not reveal any relevant modifiers. It is concluded that (i) prompt LT4 replacement in infants with respiratory distress due to a hypothyroid goiter makes surgery unnecessary; and (ii) the clinical expression of DUOX2 deficiency varies widely between individuals and over time, justifying periodic reevaluation of the need for LT4 replacement.


Assuntos
Hipotireoidismo Congênito/genética , Oxidases Duais/genética , Bócio/genética , Hipotireoidismo/genética , Tiroxina/uso terapêutico , Adolescente , Adulto , Obstrução das Vias Respiratórias/diagnóstico por imagem , Obstrução das Vias Respiratórias/etiologia , Criança , Pré-Escolar , Hipotireoidismo Congênito/sangue , Hipotireoidismo Congênito/fisiopatologia , Oxidases Duais/deficiência , Feminino , Bócio/complicações , Bócio/diagnóstico por imagem , Bócio/tratamento farmacológico , Heterozigoto , Homozigoto , Humanos , Hipotireoidismo/sangue , Hipotireoidismo/tratamento farmacológico , Hipotireoidismo/fisiopatologia , Lactente , Recém-Nascido , Masculino , Triagem Neonatal , Linhagem , Fenótipo , Tireotropina/sangue , Tiroxina/sangue
10.
Artigo em Inglês | MEDLINE | ID: mdl-30858900

RESUMO

Background: Recent epidemiological evidence shows that colorectal cancer (CRC) continues to occur in carriers of pathogenic mismatch repair (path_MMR) variants despite frequent colonoscopy surveillance in expert centres. This observation conflicts with the paradigm that removal of all visible polyps should prevent the vast majority of CRC in path_MMR carriers, provided the screening interval is sufficiently short and colonoscopic practice is optimal. Methods: To inform the debate, we examined, in the Prospective Lynch Syndrome Database (PLSD), whether the time since last colonoscopy was associated with the pathological stage at which CRC was diagnosed during prospective surveillance. Path_MMR carriers were recruited for prospective surveillance by colonoscopy. Only variants scored by the InSiGHT Variant Interpretation Committee as class 4 and 5 (clinically actionable) were included. CRCs detected at the first planned colonoscopy, or within one year of this, were excluded as prevalent cancers. Results: Stage at diagnosis and interval between last prospective surveillance colonoscopy and diagnosis were available for 209 patients with 218 CRCs, including 162 path_MLH1, 45 path_MSH2, 10 path_MSH6 and 1 path_PMS2 carriers. The numbers of cancers detected within < 1.5, 1.5-2.5, 2.5-3.5 and at > 3.5 years since last colonoscopy were 36, 93, 56 and 33, respectively. Among these, 16.7, 19.4, 9.9 and 15.1% were stage III-IV, respectively (p = 0.34). The cancers detected more than 2.5 years after the last colonoscopy were not more advanced than those diagnosed earlier (p = 0.14). Conclusions: The CRC stage and interval since last colonoscopy were not correlated, which is in conflict with the accelerated adenoma-carcinoma paradigm. We have previously reported that more frequent colonoscopy is not associated with lower incidence of CRC in path_MMR carriers as was expected. In contrast, point estimates showed a higher incidence with shorter intervals between examinations, a situation that may parallel to over-diagnosis in breast cancer screening. Our findings raise the possibility that some CRCs in path_MMR carriers may spontaneously disappear: the host immune response may not only remove CRC precursor lesions in path_MMR carriers, but may remove infiltrating cancers as well. If confirmed, our suggested interpretation will have a bearing on surveillance policy for path_MMR carriers.

11.
Sci Rep ; 9(1): 4611, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30872650

RESUMO

In the recent years, new molecular methods have been proposed to discriminate multicentric hepatocellular carcinomas (HCC) from intrahepatic metastases. Some of these methods utilize sequencing data to assess similarities between cancer genomes, whilst other achieved the same results with transcriptome and methylome data. Here, we attempt to classify two HCC patients with multi-centric disease using the recall-rates of somatic mutations but find that difficult because their tumors share some chromosome-scale copy-number alterations (CNAs) but little-to-no single-nucleotide variants. To resolve the apparent conundrum, we apply a phasing strategy to test if those shared CNAs are identical by descent. Our findings suggest that the conflicting alterations occur on different homologous chromosomes, which argues for multi-centric origin of respective HCCs.


Assuntos
Carcinoma Hepatocelular/genética , Variações do Número de Cópias de DNA/genética , Neoplasias Hepáticas/genética , Biomarcadores Tumorais/genética , Humanos , Pessoa de Meia-Idade , Transcriptoma/genética
12.
Eur J Hum Genet ; 27(5): 730-737, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30679815

RESUMO

The monogenic etiology of most severe fetal anomaly syndromes is poorly understood. Our objective was to use exome sequencing (ES) to increase our knowledge on causal variants and novel candidate genes associated with specific fetal phenotypes. We employed ES in a cohort of 19 families with one or more fetuses presenting with a distinctive anomaly pattern and/or phenotype recurrence at increased risk for lethal outcomes. Candidate variants were identified in 12 families (63%); in 6 of them a definite diagnosis was achieved including known or novel variants in recognized disease genes (MKS1, OTX2, FGFR2, and RYR1) and variants in novel disease genes describing new fetal phenotypes (CENPF, KIF14). We identified variants likely causal after clinical and functional review (SMAD3, KIF4A, and PIGW) and propose novel candidate genes (PTK7, DNHD1, and TTC28) for early human developmental disease supported by functional and cross-species phenotyping evidence. We describe rare and novel fetal anomaly syndromes and highlight the diagnostic utility of ES, but also its contribution to discovery. The diagnostic yield of the future application of prenatal ES will depend on our ability to increase our knowledge on the specific phenotype-genotype correlations during fetal development.


Assuntos
Anormalidades Múltiplas/genética , Exoma/genética , Feto/anormalidades , Estudos de Associação Genética , Sequenciamento Completo do Exoma , Criança , Humanos , Mutação/genética , Fenótipo , Síndrome
13.
Nat Ecol Evol ; 2(10): 1661-1672, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30177804

RESUMO

The evolutionary events that cause colorectal adenomas (benign) to progress to carcinomas (malignant) remain largely undetermined. Using multi-region genome and exome sequencing of 24 benign and malignant colorectal tumours, we investigate the evolutionary fitness landscape occupied by these neoplasms. Unlike carcinomas, advanced adenomas frequently harbour sub-clonal driver mutations-considered to be functionally important in the carcinogenic process-that have not swept to fixation, and have relatively high genetic heterogeneity. Carcinomas are distinguished from adenomas by widespread aneusomies that are usually clonal and often accrue in a 'punctuated' fashion. We conclude that adenomas evolve across an undulating fitness landscape, whereas carcinomas occupy a sharper fitness peak, probably owing to stabilizing selection.


Assuntos
Adenoma/genética , Carcinogênese/genética , Carcinoma/genética , Neoplasias Colorretais/genética , Evolução Molecular , Mutação , Adenoma/patologia , Carcinoma/patologia , Neoplasias Colorretais/patologia , Humanos , Modelos Biológicos
14.
Ther Umsch ; 75(10): 601-606, 2018.
Artigo em Alemão | MEDLINE | ID: mdl-31232663

RESUMO

Hereditary Colorectal Cancer: Clinics, Diagnostics and Management Abstract. About five percent of all colorectal cancers are caused by highly penetrant, autosomal dominantly or recessively inherited tumour predispositions. Current molecular genetic diagnostics, making use of high-throughput sequencing technologies, allow a cost-efficient, prompt and comprehensive investigation. In contrast to sporadic colorectal cancer hereditary forms are often associated with an elevated lifetime risk for additional, extracolonic tumours which necessitate specific long-term interdisciplinary prevention measures and surveillance. Moreover, the genetic confirmation of an underlying cancer predisposition allows family members at risk, following genetic counselling, the possibility of predictive carrier testing. This article aims at providing a concise overview of clinics, diagnostics and management for some of the best researched colorectal cancer predispositions.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Neoplasias Colorretais/terapia , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/terapia , Aconselhamento Genético , Predisposição Genética para Doença , Testes Genéticos , Humanos
15.
Public Health Genomics ; 21(3-4): 121-132, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30695780

RESUMO

BACKGROUND: An international workshop on cancer predisposition cascade genetic screening for hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS) took place in Switzerland, with leading researchers and clinicians in cascade screening and hereditary cancer from different disciplines. The purpose of the workshop was to enhance the implementation of cascade genetic screening in Switzerland. Participants discussed the challenges and opportunities associated with cascade screening for HBOC and LS in Switzerland (CASCADE study); family implications and the need for family-based interventions; the need to evaluate the cost-effectiveness of cascade genetic screening; and interprofessional collaboration needed to lead this initiative. METHODS: The workshop aims were achieved through exchange of data and experiences from successful cascade screening programs in the Netherlands, Australia, and the state of Ohio, USA; Swiss-based studies and scientific experience that support cancer cascade screening in Switzerland; programs of research in psychosocial oncology and family-based studies; data from previous cost-effectiveness analyses of cascade genetic screening in the Netherlands and in Australia; and organizational experience from a large interprofessional collaborative. Scientific presentations were recorded and discussions were synthesized to present the workshop findings. RESULTS: The key elements of successful implementation of cascade genetic screening are a supportive network of stakeholders and connection to complementary initiatives; sample size and recruitment of relatives; centralized organization of services; data-based cost-effectiveness analyses; transparent organization of the initiative; and continuous funding. CONCLUSIONS: This paper describes the processes and key findings of an international workshop on cancer predisposition cascade screening, which will guide the CASCADE study in Switzerland.


Assuntos
Neoplasias da Mama/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Predisposição Genética para Doença , Testes Genéticos , Internacionalidade , Neoplasias Ovarianas/genética , Carcinoma Epitelial do Ovário , Análise Custo-Benefício , Detecção Precoce de Câncer , Feminino , Testes Genéticos/economia , Humanos , Apoio Social , Suíça
16.
JMIR Res Protoc ; 6(9): e184, 2017 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-28931501

RESUMO

BACKGROUND: Breast, colorectal, ovarian, and endometrial cancers constitute approximately 30% of newly diagnosed cancer cases in Switzerland, affecting more than 12,000 individuals annually. Hundreds of these patients are likely to carry germline pathogenic variants associated with hereditary breast ovarian cancer (HBOC) or Lynch syndrome (LS). Genetic services (counseling and testing) for hereditary susceptibility to cancer can prevent many cancer diagnoses and deaths through early identification and risk management. OBJECTIVE: Cascade screening is the systematic identification and testing of relatives of a known mutation carrier. It determines whether asymptomatic relatives also carry the known variant, needing management options to reduce future harmful outcomes. Specific aims of the CASCADE study are to (1) survey index cases with HBOC or LS from clinic-based genetic testing records and determine their current cancer status and surveillance practices, needs for coordination of medical care, psychosocial needs, patient-provider and patient-family communication, quality of life, and willingness to serve as advocates for cancer genetic services to blood relatives, (2) survey first- and second-degree relatives and first-cousins identified from pedigrees or family history records of HBOC and LS index cases and determine their current cancer and mutation status, cancer surveillance practices, needs for coordination of medical care, barriers and facilitators to using cancer genetic services, psychosocial needs, patient-provider and patient-family communication, quality of life, and willingness to participate in a study designed to increase use of cancer genetic services, and (3) explore the influence of patient-provider communication about genetic cancer risk on patient-family communication and the acceptability of a family-based communication, coping, and decision support intervention with focus group(s) of mutation carriers and relatives. METHODS: CASCADE is a longitudinal study using surveys (online or paper/pencil) and focus groups, designed to elicit factors that enhance cascade genetic testing for HBOC and LS in Switzerland. Repeated observations are the optimal way for assessing these outcomes. Focus groups will examine barriers in patient-provider and patient-family communication, and the acceptability of a family-based communication, coping, and decision-support intervention. The survey will be developed in English, translated into three languages (German, French, and Italian), and back-translated into English, except for scales with validated versions in these languages. RESULTS: Descriptive analyses will include calculating means, standard deviations, frequencies, and percentages of variables and participant descriptors. Bivariate analyses (Pearson correlations, chi-square test for differences in proportions, and t test for differences in means) will assess associations between demographics and clinical characteristics. Regression analyses will incorporate generalized estimating equations for pairing index cases with their relatives and explore whether predictors are in direct, mediating, or moderating relationship to an outcome. Focus group data will be transcribed verbatim and analyzed for common themes. CONCLUSIONS: Robust evidence from basic science and descriptive population-based studies in Switzerland support the necessity of cascade screening for genetic predisposition to HBOC and LS. CASCADE is designed to address translation of this knowledge into public health interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT03124212; https://clinicaltrials.gov/ct2/show/NCT03124212 (Archived by WebCite at http://www.webcitation.org/6tKZnNDBt).

17.
ESMO Open ; 2(2): e000172, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28761745

RESUMO

When in a patient more than one tumour in the same or a different organ is diagnosed, multiple primary tumours may be present. For epidemiological studies, different definitions of multiple primaries are used with the two main definitions coming from the project Surveillance Epidemiology and End Results and the International Association of Cancer Registries and International Agency for Research on Cancer. The differences in the two definitions have to be taken into consideration when reports on multiple primaries are analysed. In this review, the literature on multiple primaries is reviewed and summarised. Overall, the frequency of multiple primaries is reported in the range of 2-17%. Aetiological factors that may predispose patients to multiple primaries can be grouped into host related, lifestyle factors and environmental influences. Some of the most common cancer predisposition syndromes based on a clinical presentation are discussed and the relevant genetic evaluation and testing are characterised. Importantly, from a clinical standpoint, clinical situations when multiple primaries should be suspected and ruled out in a patient are discussed. Furthermore, general principles and possible treatment strategies for patients with synchronous and metachronous multiple primary tumours are highlighted.

18.
J Neurooncol ; 134(1): 133-138, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28528424

RESUMO

Subependymoma is a rare primary brain tumor, constituting 0.07-0.51% of brain tumors. Genetic alterations in subependymoma are largely unknown, but familial occurrences have been reported. Trichorhinophalangeal syndrome type 1 (TRPS1) is a rare hereditary malformation complex caused by mutations in a gene identified in the year 2000 on 8q24.12. We report two patients with TRPS I and surgically treated subependymomas, one of whom has a first degree relative, now deceased, who was affected and also had a subependymoma. We therefore sought a role for the TRPS1 gene in the molecular oncogenesis of subependymoma. Formalin fixed tumor specimens and saliva samples were obtained from the two index patients as well as tumor samples from six sporadic subependymoma surgical specimens. A heterozygous TRPS1 germ line mutation predicted to cause a frame shift leading to a premature stop codon was found in the first index patient and also present in the associated tumor. No germline mutation was found in the second index patient, but his tumor displayed copy number neutral loss of heterozygosity in TRPS1. TRPS1 mutation analysis of the sporadic subependymomas revealed genetic, mostly loss of function alterations in one-third (two of six) of samples. Genetic alterations in TRPS1 likely play a role in at least a subgroup of subependymomas. Confirmation and further (epi)genetic investigations, ideally in newly acquired, fresh-frozen tumor samples, are warranted.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/fisiopatologia , Proteínas de Ligação a DNA/genética , Glioma Subependimal/genética , Glioma Subependimal/fisiopatologia , Mutação/genética , Fatores de Transcrição/genética , Adulto , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Proteínas Repressoras
19.
20.
Mol Genet Genomic Med ; 4(3): 359-66, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27247962

RESUMO

BACKGROUND: Poikiloderma is defined as a chronic skin condition presenting with a combination of punctate atrophy, areas of depigmentation, hyperpigmentation and telangiectasia. In a variety of hereditary syndromes such as Rothmund-Thomson syndrome (RTS), Clericuzio-type poikiloderma with neutropenia (PN) and Dyskeratosis Congenita (DC), poikiloderma occurs as one of the main symptoms. Here, we report on genotype and phenotype data of a cohort of 44 index patients with RTS or related genodermatoses. METHODS: DNA samples from 43 patients were screened for variants in the 21 exons of the RECQL4 gene using PCR, SSCP-PAGE analysis and/or Sanger sequencing. Patients with only one or no detectable mutation in the RECQL4 gene were additionally tested for variants in the 8 exons of the USB1 (C16orf57) gene by Sanger sequencing. The effect of novel variants was evaluated by phylogenic studies, single-nucleotide polymorphism (SNP) databases and in silico analyses. RESULTS: We identified 23 different RECQL4 mutations including 10 novel and one homozygous novel USB1 (C16orf57) mutation in a patient with PN. Moreover, we describe 31 RECQL4 and 8 USB1 sequence variants, four of them being novel intronic RECQL4 sequence changes that may have some deleterious effects on splicing mechanisms and need further evaluation by transcript analyses. CONCLUSION: The current study contributes to the improvement of genetic diagnostic strategies and interpretation in RTS and PN that is relevant in order to assess the patients' cancer risk, to avoid continuous and inconclusive clinical evaluations and to clarify the recurrence risk in the families. Additionally, it shows that the phenotype of more than 50% of the patients with suspected Rothmund-Thomson disease may be due to mutations in other genes raising the need for further extended genetic analyses.

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