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Hereditary SDHB-mutant pheochromocytomas (PC) and paragangliomas (PG) are rare tumours with a high propensity to metastasize although their clinical behaviour is unpredictable. To characterize the genomic landscape of these tumours and identify metastasis biomarkers, we performed multi-omic analysis on 94 tumours from 79 patients using seven molecular methods. Sympathetic (chromaffin cell) and parasympathetic (non-chromaffin cell) PCPG had distinct molecular profiles reflecting their cell-of-origin and biochemical profile. TERT and ATRX-alterations were associated with metastatic PCPG and these tumours had an increased mutation load, and distinct transcriptional and telomeric features. Most PCPG had quiet genomes with some rare co-operative driver events observed, including EPAS1/HIF-2α mutations. Two mechanisms of acquired resistance to DNA alkylating chemotherapies were also detected - MGMT overexpression and mismatch repair-deficiency causing hypermutation. Our comprehensive multi-omic analysis of SDHB-mutant PCPG therefore identified features of metastatic disease and treatment response, expanding our understanding of these rare neuroendocrine tumours.
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BACKGROUND: Many families and individuals do not meet criteria for a known hereditary cancer syndrome but display unusual clusters of cancers. These families may carry pathogenic variants in cancer predisposition genes and be at higher risk for developing cancer. METHODS: This multi-centre prospective study recruited 195 cancer-affected participants suspected to have a hereditary cancer syndrome for whom previous clinical targeted genetic testing was either not informative or not available. To identify pathogenic disease-causing variants explaining participant presentation, germline whole-genome sequencing (WGS) and a comprehensive cancer virtual gene panel analysis were undertaken. RESULTS: Pathogenic variants consistent with the presenting cancer(s) were identified in 5.1% (10/195) of participants and pathogenic variants considered secondary findings with potential risk management implications were identified in another 9.7% (19/195) of participants. Health economic analysis estimated the marginal cost per case with an actionable variant was significantly lower for upfront WGS with virtual panel ($8744AUD) compared to standard testing followed by WGS ($24,894AUD). Financial analysis suggests that national adoption of diagnostic WGS testing would require a ninefold increase in government annual expenditure compared to conventional testing. CONCLUSIONS: These findings make a case for replacing conventional testing with WGS to deliver clinically important benefits for cancer patients and families. The uptake of such an approach will depend on the perspectives of different payers on affordability.
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Síndromes Neoplásicas Hereditárias , Humanos , Estudos Prospectivos , Oncogenes , Testes Genéticos , Células GerminativasRESUMO
INTRODUCTION: Individuals at an inherited high-risk of developing adult-onset disease, such as breast cancer, are rare in the population. These individuals require lifelong clinical, psychological and reproductive assistance. After a positive germline test result, clinical genetic services provide support and care coordination. However, ongoing systematic clinical follow-up programmes are uncommon. Digital health solutions offer efficient and sustainable ways to deliver affordable and equitable care. This paper outlines the codesign and development of a digital health platform to facilitate long-term clinical and psychological care, and foster self-efficacy in individuals with a genetic disease predisposition. METHODS AND ANALYSIS: We adopt a mixed-methods approach for data gathering and analysis. Data collection is in two phases. In phase 1, 300 individuals with a high-risk genetic predisposition to adult disease will undertake an online survey to assess their use of digital health applications (apps). In phase 2, we will conduct focus groups with 40 individuals with a genetic predisposition to cardiac or cancer syndromes, and 30 clinicians from diverse specialities involved in their care. These focus groups will inform the platform's content, functionality and user interface design, as well as identify the barriers and enablers to the adoption and retention of the platform by all endusers. The focus groups will be audiorecorded and transcribed, and thematic and content data analysis will be undertaken by adopting the Unified Theory of Acceptance and Use of Technology. Descriptive statistics will be calculated from the survey data. Phase 3 will identify the core skillsets for a novel digital health coordinator role. Outcomes from phases 1 and 2 will inform development of the digital platform, which will be user-tested and optimised in phase 4. ETHICS AND DISSEMINATION: This study was approved by the Peter MacCallum Human Research Ethics Committee (HREC/88892/PMCC). Results will be disseminated in academic forums, peer-reviewed publications and used to optimise clinical care.
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Predisposição Genética para Doença , Projetos de Pesquisa , Humanos , Adulto , Autoeficácia , Grupos FocaisRESUMO
Background Research identifying and returning clinically actionable germline variants offer a new avenue of access to genetic information. The psychosocial and clinical outcomes for women who have received this 'genome-first care' delivering hereditary breast and ovarian cancer risk information outside of clinical genetics services are unknown. Methods: An exploratory sequential mixed-methods case-control study compared outcomes between women who did (cases; group 1) and did not (controls; group 2) receive clinically actionable genetic information from a research cohort in Victoria, Australia. Participants completed an online survey examining cancer risk perception and worry, and group 1 also completed distress and adaptation measures. Group 1 participants subsequently completed a semi structured interview. Results: Forty-five participants (group 1) and 96 (group 2) completed the online survey, and 31 group 1 participants were interviewed. There were no demographic differences between groups 1 and 2, although more of group 1 participants had children (p = 0.03). Group 1 reported significantly higher breast cancer risk perception (p < 0.001) compared to group 2, and higher cancer worry than group 2 (p < 0.001). Some group 1 participants described how receiving their genetic information heightened their cancer risk perception and exacerbated their cancer worry while waiting for risk-reducing surgery. Group 1 participants reported a MICRA mean score of 27.4 (SD 11.8, range 9−56; possible range 0−95), and an adaptation score of 2.9 (SD = 1.1). Conclusion: There were no adverse psychological outcomes amongst women who received clinically actionable germline information through a model of 'genome-first' care compared to those who did not. These findings support the return of clinically actionable research results to research participants.
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PURPOSE: Lynch syndrome-related colorectal cancer (CRC) risk substantially varies by mismatch repair (MMR) gene. We evaluated the health impact and cost-effectiveness of MMR gene-tailored colonoscopic surveillance. METHODS: We first estimated sex- and MMR gene-specific cumulative lifetime risk of first CRC without colonoscopic surveillance using an optimization algorithm. Next, we harnessed these risk estimates in a microsimulation model, "Policy1-Lynch," and compared 126 colonoscopic surveillance strategies against no surveillance. RESULTS: The most cost-effective strategy was 3-yearly surveillance from age 25 to 70 years (pathogenic variants [path_] in MLH1 [path_MLH1], path_MSH2) with delayed surveillance for path_MSH6 (age 30-70 years) and path_PMS2 (age 35-70 years) heterozygotes (incremental cost-effectiveness ratio = Australian dollars (A) $8,833/life-year saved). This strategy averted 60 CRC deaths (153 colonoscopies per death averted) over the lifetime of 1000 confirmed patients with Lynch syndrome (vs no surveillance). This also reduced colonoscopies by 5% without substantial change in health outcomes (vs nontailored 3-yearly surveillance from 25-70 years). Generally, starting surveillance at age 25 (vs 20) years was more cost-effective with minimal effect on life-years saved and starting 5 to 10 years later for path_MSH6 and path_PMS2 heterozygotes (vs path_MLH1 and path_MSH2) further improved cost-effectiveness. Surveillance end age (70/75/80 years) had a minor effect. Three-yearly surveillance strategies were more cost-effective (vs 1 or 2-yearly) but prevented 3 fewer CRC deaths. CONCLUSION: MMR gene-specific colonoscopic surveillance would be effective and cost-effective.
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Neoplasias Colorretais Hereditárias sem Polipose , Adulto , Idoso , Austrália , Colonoscopia , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Análise Custo-Benefício , Reparo de Erro de Pareamento de DNA/genética , Humanos , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genéticaRESUMO
PURPOSE: This study aimed to correlate the indications and diagnostic yield of exome sequencing (ES) in adult patients across various clinical settings. The secondary aim was to examine the clinical utility of ES in adult patients. METHODS: Data on demographics, clinical indications, results, management changes, and cascade testing were collected for 250 consecutive patients who underwent ES through an adult genetics department between 2016 and 2021. Data were analyzed using descriptive and inferential statistics. Testing in which traditional gene panels were in standard use, such as in heritable cancers, was excluded. RESULTS: The average age at testing was 43 years (range = 17-80 years). A molecular diagnosis was identified in 29% of patients. Older age at symptom onset did not pre-exclude a substantial diagnostic yield. Patients with syndromic intellectual disability and multiple system disorders had the highest yield. In >50% of patients with an exome diagnosis, the results changed management. Cascade testing occured in at least one family member for 30% of patients with a diagnosis. Diagnostic results had reproductive implications for 26% of patients and 31% of patients' relatives. CONCLUSION: ES has a robust diagnostic yield and clear clinical utility in adult patients across a range of ages and phenotypes.
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Exoma , Deficiência Intelectual , Adulto , Exoma/genética , Testes Genéticos/métodos , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Fenótipo , Sequenciamento do Exoma/métodosRESUMO
PURPOSE: Risk-stratified screening has potential to improve the cost effectiveness of national breast cancer screening programs. This study aimed to inform a socially acceptable and equitable implementation framework by determining what influences a woman's decision to accept a personalized breast cancer risk assessment and what the relative impact of these key determinants is. METHODS: Multicriteria decision analysis was used to elicit the relative weights for 8 criteria that women reported influenced their decision. Preference heterogeneity was explored through cluster analysis. RESULTS: The 2 criteria valued most by the 347 participants related to program access, "Mode of invitation" and "Testing process". Both criteria significantly influenced participation (P < .001). A total of 73% preferred communication by letter/online. Almost all women preferred a multidisease risk assessment with potential for a familial high-risk result. Four preference-based subgroups were identified. Membership to the largest subgroup was predicted by lower educational attainment, and women in this subgroup were concerned with program access. Higher relative perceived breast cancer risk predicted membership to the smallest subgroup that was focused on test parameters, namely "Scope of test" and "Test specificity". CONCLUSION: Overall, Australian women would accept a personalized multidisease risk assessment, but when aligning with their preferences, it will necessitate a focus on program access and the development of online communication frameworks.
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Neoplasias da Mama , Programas de Rastreamento , Austrália/epidemiologia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Neoplasias da Mama/prevenção & controle , Detecção Precoce de Câncer , Feminino , Humanos , Medição de RiscoRESUMO
Personal Breast Cancer (BC) Risk Assessments (PBCRA) have potential to stratify women into clinically-actionable BC risk categories. As this could involve population-wide genomic testing, women's attitudes to PBCRA and views on acceptable implementation platforms must be considered to ensure optimal population participation. We explored these issues with 31 women with different BC risk profiles through semi-structured focus group discussions or interviews. Inductive thematic coding of transcripts was performed. Subsequently, women listed factors that would impact on their decision to participate. Participants' attitudes to PBCRA were positive. Identified themes included that PBCRA acceptance hinges on result actionability. Women value the ability to inform decision-making. Participants reported anxiety, stress, and genetic discrimination as potential barriers. The age at which PBCRA was offered, ease of access, and how results are returned held importance. Most women value the opportunity for PBCRA to inform increased surveillance, while highlighting hesitance to accept reduced surveillance as they find reassurance in regular screening. Women with BRCA pathogenic variants value the potential for PBCRA to identify a lower cancer risk and potentially inform delayed prophylactic surgery. This study highlights complexities in adopting advances in BC early detection, especially for current users who value existing processes as a social good.
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Neoplasias Colorretais Hereditárias sem Polipose , Ginecologia , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/terapia , Testes Genéticos , Humanos , Gestão de RiscosRESUMO
BACKGROUND: This nationwide study assessed the impact of nationally agreed cancer genetics guidelines on use of BRCA1/2 germline testing, risk management advice given by health professionals to women with pathogenic BRCA1/2 variants and uptake of such advice by patients. METHODS: Clinic files of 883 women who had initial proband screens for BRCA1/2 pathogenic variants at 12 familial cancer clinics between July 2008-July 2009 (i.e. before guideline release), July 2010-July 2011 and July 2012-July 2013 (both after guideline release) were audited to determine reason given for genetic testing. Separately, the clinic files of 599 female carriers without a personal history of breast/ovarian cancer who underwent BRCA1/2 predictive genetic testing and received their results pre- and post-guideline were audited to ascertain the risk management advice given by health professionals. Carriers included in this audit were invited to participate in a telephone interview to assess uptake of advice, and 329 agreed to participate. RESULTS: There were no significant changes in the percentages of tested patients meeting at least one published indication for genetic testing - 79, 77 and 78% of files met criteria before guideline, and two-, and four-years post-guideline, respectively (χ = 0.25, p = 0.88). Rates of documentation of post-test risk management advice as per guidelines increased significantly from pre- to post-guideline for 6/9 risk management strategies. The strategies with the highest compliance amongst carriers or awareness post-release of guidelines were annual magnetic resonance imaging plus mammography in women 30-50 years (97%) and annual mammography in women > 50 years (92%). Of women aged over 40 years, 41% had a risk-reducing bilateral mastectomy. Amongst women aged > 40 years, 75% had a risk-reducing salpingo-oophorectomy. Amongst women who had not had a risk-reducing bilateral mastectomy, only 6% took risk-reducing medication. Fear of side-effects was cited as the main reasons for not taking these medicines by 73% of women. CONCLUSIONS: Guidelines did not change the percentages of tested patients meeting genetic testing criteria but improved documentation of risk management advice by health professionals. Effective approaches to enhance compliance with guidelines are needed to improve risk management and quality of care.
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BACKGROUND: The strength of evidence supporting the validity of gene-disease relationships is variable. Hereditary cancer has the additional complexity of low or moderate penetrance for some confirmed disease-associated alleles. METHODS: To promote national consistency in interpretation of hereditary cancer/tumour gene test results, we requested opinions of representatives from Australian Family Cancer Clinics regarding the clinical utility of 157 genes initially collated for a national research project. Viewpoints were sought by initial survey, face-to-face workshop and follow-up survey. Subsequent review was undertaken by the eviQ Cancer Genetics Reference Committee, a national resource providing evidence-based and consensus-driven cancer treatment protocols. RESULTS: Genes were categorised by clinical actionability as: relevant for testing on presentation of common cancer/tumour types (n=45); relevant for testing in the context of specific rare phenotypes (n=74); insufficient clinical utility (n=34) or contentious clinical utility (n=3). Opinions for several genes altered during the study time frame, due to new information. CONCLUSION: Through an iterative process, consensus was achieved on genes with clinical utility for hereditary cancer/tumour conditions in the Australian setting. This study highlighted need for regular review of gene-disease lists, a role assumed in Australia for hereditary cancer/tumour predisposition genes by the eviQ Cancer Genetics Reference Committee.
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Aconselhamento Genético/métodos , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Anotação de Sequência Molecular/métodos , Neoplasias/genética , Austrália , Consenso , Saúde da Família , Feminino , Estudos de Associação Genética/métodos , Mutação em Linhagem Germinativa , Humanos , Masculino , Oncologia/métodos , Neoplasias/diagnóstico , Linhagem , Proteínas Supressoras de Tumor/genéticaRESUMO
BACKGROUND: Familial cases of appendiceal mucinous tumours (AMTs) are extremely rare and the underlying genetic aetiology uncertain. We identified potential predisposing germline genetic variants in a father and daughter with AMTs presenting with pseudomyxoma peritonei (PMP) and correlated these with regions of loss of heterozygosity (LOH) in the tumours. METHODS: Through germline whole exome sequencing, we identified novel heterozygous loss-of-function (LoF) (i.e. nonsense, frameshift and essential splice site mutations) and missense variants shared between father and daughter, and validated all LoF variants, and missense variants with a Combined Annotation Dependent Depletion (CADD) scaled score of ≥10. Genome-wide copy number analysis was performed on tumour tissue from both individuals to identify regions of LOH. RESULTS: Fifteen novel variants in 15 genes were shared by the father and daughter, including a nonsense mutation in REEP5. None of these germline variants were located in tumour regions of LOH shared by the father and daughter. Four genes (EXOG, RANBP2, RANBP6 and TNFRSF1B) harboured missense variants that fell in a region of LOH in the tumour from the father only, but none showed somatic loss of the wild type allele in the tumour. The REEP5 gene was sequenced in 23 individuals with presumed sporadic AMTs or PMP; no LoF or rare missense germline variants were identified. CONCLUSION: Germline exome sequencing of a father and daughter with AMTs identified novel candidate predisposing genes. Further studies are required to clarify the role of these genes in familial AMTs.
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Adenocarcinoma Mucinoso/genética , Neoplasias do Apêndice/genética , Exoma , Mutação em Linhagem Germinativa , Pseudomixoma Peritoneal/genética , Adenocarcinoma Mucinoso/patologia , Adulto , Idoso , Neoplasias do Apêndice/patologia , Biomarcadores Tumorais/genética , Feminino , Seguimentos , Humanos , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Linhagem , Prognóstico , Pseudomixoma Peritoneal/patologia , Sequenciamento do ExomaAssuntos
Leucemia Linfoide , Linfoma não Hodgkin , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Criança , DNA Helicases , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genéticaRESUMO
PURPOSE: Women who inherit a BRCA1 or BRCA2 pathogenic variant are at high risk of developing breast and ovarian cancer. Evidence for the effectiveness and cost-effectiveness of long-term management in clinical practice is lacking. The purpose of this study was to evaluate the real-world cost-effectiveness of BRCA carrier management within a structured clinical program. METHODS: Lifetime health outcomes and costs of clinical management for female unaffected BRCA carriers aged 20 were measured using a microsimulation model. For the intervention, women could attend a high-risk clinic, undergo risk-reducing surgery, and receive annual breast screening. Input data for the model was from a clinical database of 983 BRCA carriers. The comparator was no risk management. Outcomes were discounted at 5%. RESULTS: The incremental cost-effectiveness ratio for the program was $32,359 to $48,263 per quality-adjusted life-year (QALY). Limiting uptake of risk-reducing salpingo-oophorectomy to <50% of carriers decreased cost-effectiveness by $7000-8000 per QALY. Achieving perfect adherence to guidelines was less cost-effective for BRCA2 due to increased risk-reducing mastectomy costs with smaller incremental health benefit. CONCLUSION: Long-term management of BRCA carriers within a structured clinical program is cost-effective. Suboptimal adherence to risk management guidelines can substantially affect outcomes and is an important consideration for future studies.
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Neoplasias da Mama , Neoplasias Ovarianas , Adulto , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Análise Custo-Benefício , Feminino , Humanos , Mastectomia , Mutação , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/prevenção & controle , Ovariectomia , Anos de Vida Ajustados por Qualidade de Vida , Adulto JovemRESUMO
OBJECTIVES: To evaluate the health impact and cost-effectiveness of systematic testing for Lynch syndrome (LS) in people with incident colorectal cancer (CRC) in Australia. DESIGN, SETTING, PARTICIPANTS: We investigated the impact of LS testing strategies in a micro-simulation model (Policy1-Lynch), explicitly modelling the cost of testing all patients diagnosed with incident CRC during 2017, with detailed modelling of outcomes for patients identified as LS carriers (probands) and their at-risk relatives throughout their lifetimes. For people with confirmed LS, we modelled ongoing colonoscopic surveillance. MAIN OUTCOME MEASURES: Cost-effectiveness of six universal tumour testing strategies (testing for DNA mismatch repair deficiencies) and of universal germline gene panel testing of patients with incident CRC; impact on cost-effectiveness of restricting testing by age at CRC diagnosis (all ages, under 50/60/70 years) and of colonoscopic surveillance interval (one, two years). RESULTS: The cost-effectiveness ratio of universal tumour testing strategies (annual colonoscopic surveillance, no testing age limit) compared with no testing ranged from $28 915 to $31 904/life-year saved (LYS) (indicative willingness-to-pay threshold: $30 000-$50 000/LYS). These strategies could avert 184-189 CRC deaths with an additional 30 597-31 084 colonoscopies over the lifetimes of 1000 patients with incident CRC with LS and 1420 confirmed LS carrier relatives (164-166 additional colonoscopies/death averted). The most cost-effective strategy was immunohistochemistry and BRAF V600E testing (incremental cost-effectiveness ratio [ICER], $28 915/LYS). Universal germline gene panel testing was not cost-effective compared with universal tumour testing strategies (ICER, $2.4 million/LYS). Immunohistochemistry and BRAF V600E testing was cost-effective at all age limits when paired with 2-yearly colonoscopic surveillance (ICER, $11 525-$32 153/LYS), and required 4778-15 860 additional colonoscopies to avert 46-181 CRC deaths (88-103 additional colonoscopies/death averted). CONCLUSIONS: Universal tumour testing strategies for guiding germline genetic testing of people with incident CRC for LS in Australia are likely to be cost-effective compared with no testing. Universal germline gene panel testing would not currently be cost-effective.
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Colonoscopia/estatística & dados numéricos , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Análise Custo-Benefício/estatística & dados numéricos , Testes Genéticos/economia , Idoso , Austrália/epidemiologia , Colonoscopia/economia , Neoplasias Colorretais Hereditárias sem Polipose/economia , Neoplasias Colorretais Hereditárias sem Polipose/mortalidade , Feminino , Humanos , Imuno-Histoquímica/economia , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVES: To develop a validated model for evaluating the real-world effectiveness of long-term clinical management strategies for women with germline BRCA1 or BRCA2 pathogenic variants. METHODS: A microsimulation model was developed that included a BRCA-specific natural history for breast and ovarian cancer, a clinical framework for carrier follow-up, and cancer risk management strategies (breast screening, risk-reducing mastectomy, and bilateral salpingo-oophorectomy). Adherence rates and outcomes for breast screening and risk-reducing surgery were obtained from BRCA carriers seen through a familial cancer service in Melbourne, Australia. The model was assessed for internal and external validity. The model was used to compare women perfectly adhering to screening recommendations versus actual adherence of the clinical cohort. RESULTS: The model accurately predicted cancer incidence, pathology, and mortality. Using actual adherence for breast screening resulted in additional breast cancer deaths (per 1000 women: BRCA1, 2.7; BRCA2, 1.6) compared with perfect screening adherence. This decreased average life expectancy by 0.30 life-years for BRCA1 and 0.07 life-years for BRCA2. When carriers had access to risk-reducing mastectomy, the benefit from improved screening adherence was not significant. CONCLUSIONS: The developed model is a good descriptor of BRCA carriers' lifetime trajectory and its modification by use of risk management strategies alone or in combination. Evaluations of breast screening in BRCA carriers may overestimate the benefits of screening programs unless adherence is considered. By incorporating real-world clinical practice and patient behavior, this model can assist in developing clinical services and improving clinical outcomes for carriers.
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Proteína BRCA1/biossíntese , Proteína BRCA2/biossíntese , Neoplasias da Mama/epidemiologia , Técnicas de Apoio para a Decisão , Neoplasias Ovarianas/epidemiologia , Adulto , Fatores Etários , Austrália , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Detecção Precoce de Câncer/estatística & dados numéricos , Feminino , Humanos , Mastectomia/estatística & dados numéricos , Pessoa de Meia-Idade , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Gestão de Riscos , Salpingo-Ooforectomia/estatística & dados numéricosRESUMO
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.
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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 RiscoRESUMO
PURPOSE: To assess the relative cost-effectiveness of cascade genetic testing in asymptomatic relatives of patients with dilated cardiomyopathy (DCM) compared with periodical clinical surveillance. METHODS: A decision-analytic model, combining a decision tree and a Markov model, was used to determine the lifetime costs and quality-adjusted life years (QALYs) for the two strategies. Deterministic and probabilistic sensitivity analyses were undertaken to assess the robustness of findings and to explore decision uncertainty. RESULTS: The incremental cost per additional QALY of cascade genetic testing prior to periodical clinical surveillance of first-degree relatives compared with periodical clinical surveillance alone was estimated at approximately AUD $6100. At established thresholds of cost-effectiveness, there is a 90% probability that cascade genetic testing is cost-effective. Extensive sensitivity analyses, including the addition of second-degree relatives, did not alter the conclusions drawn from the main analysis. CONCLUSION: Using cascade genetic testing to guide clinical surveillance of asymptomatic relatives of patients with DCM is very likely to be cost-effective. As the DCM pathogenic variant detection rate rises and new evidence for personalized treatment of at-risk individuals becomes available, the cost-effectiveness of cascade testing will further increase.
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Análise Custo-Benefício/métodos , Testes Genéticos/economia , Cardiomiopatia Dilatada/genética , Análise Custo-Benefício/economia , Humanos , Cadeias de Markov , Programas de Rastreamento/economia , Modelos Econômicos , Anos de Vida Ajustados por Qualidade de VidaRESUMO
PURPOSE: The identification of carriers of hereditary breast and ovarian cancer (HBOC) gene variants through family cancer history alone is suboptimal, and most population-based genetic testing studies have been limited to founder mutations in high-risk populations. Here, we determine the clinical utility of identifying actionable variants in a healthy cohort of women. METHODS: Germline DNA from a subset of healthy Australian women participating in the lifepool project was screened using an 11-gene custom sequencing panel. Women with clinically actionable results were invited to attend a familial cancer clinic (FCC) for post-test genetic counseling and confirmatory testing. Outcomes measured included the prevalence of pathogenic variants, and the uptake rate of genetic counseling, risk reduction surgery, and cascade testing. RESULTS: Thirty-eight of 5908 women (0.64%) carried a clinically actionable pathogenic variant. Forty-two percent of pathogenic variant carriers did not have a first-degree relative with breast or ovarian cancer and 89% pursued referral to an FCC. Forty-six percent (6/13) of eligible women pursued risk reduction surgery, and the uptake rate of cascade testing averaged 3.3 family members per index case. CONCLUSION: Within our cohort, HBOC genetic testing was well accepted, and the majority of high-risk gene carriers identified would not meet eligibility criteria for genetic testing based on their existing family history.
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Neoplasias da Mama/genética , Predisposição Genética para Doença , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Neoplasias Ovarianas/genética , Idoso , Austrália , Neoplasias da Mama/patologia , Feminino , Aconselhamento Genético , Genética Populacional , Mutação em Linhagem Germinativa/genética , Síndrome Hereditária de Câncer de Mama e Ovário/patologia , Heterozigoto , Humanos , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/patologiaRESUMO
BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a potentially life-threatening genetic cardiomyopathy with a spectrum of clinical presentations including sudden cardiac death (SCD). METHODS: Clinical and genetic data of 44 probands referred to a cardiac genetics clinic (2007-2017) who met 2010 Task Force Criteria (TFC) for ARVC diagnosis were included. RESULTS: Thirty-three (33) (75%) male, 20 (45%) were referred by the Victorian Institute of Forensic Medicine. Presentation that lead to diagnosis included ARVC-related SCD (n=19), SCD due to alternate cause of death (n=1), aborted cardiac arrest (n=6), stable symptomatic ventricular tachycardia (n=14), palpitations (n=3) and presyncope (n=1). Left ventricular involvement (50%) was more common in the SCD subgroup (84% vs 21%, p<0.001). Genetic testing (n=39) revealed a pathogenic mutation in 16 (commonest: plakophillin-2 (n=9)), a variant of uncertain significance (VUS) in 15, with no abnormality in eight. In the SCD subgroup, median age at death was 44.7 years and 74% were male. Genetic testing (n=16) in this subgroup revealed a pathogenic mutation in six patients (commonest: desmoplakin (n=4)). Comparison of the two commonest mutations (PKP2 and desmoplakin [DSP]) showed DSP mutation was more frequently associated with SCD (p<0.01) and LV involvement (p<0.001). Screening of 117 relatives has lead to ARVC diagnosis in 29 patients. CONCLUSIONS: Arrhythmogenic right ventricular cardiomyopathy has a heterogeneous and often severe clinical presentation. Sudden cardiac death and aborted cardiac arrest (ACA) are common, demonstrating electrical abnormalities appear early in the ARVC phenotype. Left ventricular involvement was common and may reflect a worse prognosis. Genetic testing is essential in family screening and may be helpful in risk assessment. Desmoplakin mutation is associated with LV involvement and may be indicative of worse prognosis and increased risk of SCD. Genetic screening of proband family members in a specialised multidisciplinary clinic is essential in early diagnosis of affected family members.