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1.
Intern Med J ; 51(2): 268-271, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33631848

RESUMO

The rapid evolution and wide applicability of genomic testing means that medical practitioners outside the field are not appropriately skilled to understand the utility of genomics for their patients. Rotating junior doctors through genomic medicine provides them with the hands-on experience necessary to understand the complexities in this field. In this study, we analysed the training experience of 12 hospital medical officers who rotated through genomic medicine at the Royal Melbourne Hospital. Here, we demonstrate that immersion in clinical genomics aids in mainstreaming genomics knowledge.

2.
Gut ; 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33414168

RESUMO

OBJECTIVE: Germline pathogenic variants (PVs) in the DNA mismatch repair (MMR) genes and in the base excision repair gene MUTYH underlie hereditary colorectal cancer (CRC) and polyposis syndromes. We evaluated the robustness and discriminatory potential of tumour mutational signatures in CRCs for identifying germline PV carriers. DESIGN: Whole-exome sequencing of formalin-fixed paraffin-embedded (FFPE) CRC tissue was performed on 33 MMR germline PV carriers, 12 biallelic MUTYH germline PV carriers, 25 sporadic MLH1 methylated MMR-deficient CRCs (MMRd controls) and 160 sporadic MMR-proficient CRCs (MMRp controls) and included 498 TCGA CRC tumours. COSMIC V3 single base substitution (SBS) and indel (ID) mutational signatures were assessed for their ability to differentiate CRCs that developed in carriers from non-carriers. RESULTS: The combination of mutational signatures SBS18 and SBS36 contributing >30% of a CRC's signature profile was able to discriminate biallelic MUTYH carriers from all other non-carrier control CRCs with 100% accuracy (area under the curve (AUC) 1.0). SBS18 and SBS36 were associated with specific MUTYH variants p.Gly396Asp (p=0.025) and p.Tyr179Cys (p=5×10-5), respectively. The combination of ID2 and ID7 could discriminate the 33 MMR PV carrier CRCs from the MMRp control CRCs (AUC 0.99); however, SBS and ID signatures, alone or in combination, could not provide complete discrimination (AUC 0.79) between CRCs from MMR PV carriers and sporadic MMRd controls. CONCLUSION: Assessment of SBS and ID signatures can discriminate CRCs from biallelic MUTYH carriers and MMR PV carriers from non-carriers with high accuracy, demonstrating utility as a potential diagnostic and variant classification tool.

3.
J Mol Diagn ; 23(3): 358-371, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33383211

RESUMO

Patients in whom mismatch repair (MMR)-deficient cancer develops in the absence of pathogenic variants of germline MMR genes or somatic hypermethylation of the MLH1 gene promoter are classified as having suspected Lynch syndrome (SLS). Germline whole-genome sequencing (WGS) and targeted and genome-wide tumor sequencing were applied to identify the underlying cause of tumor MMR deficiency in SLS. Germline WGS was performed on samples from 14 cancer-affected patients with SLS, including two sets of first-degree relatives. MMR genes were assessed for germline pathogenic variants, including complex structural rearrangements and noncoding variants. Tumor tissue was assessed for somatic MMR gene mutations using targeted, whole-exome sequencing or WGS. Germline WGS identified pathogenic MMR variants in 3 of the 14 cases (21.4%), including a 9.5-megabase inversion disrupting MSH2 in a mother and daughter. Excluding these 3 MMR carriers, tumor sequencing identified at least two somatic MMR gene mutations in 8 of 11 tumors tested (72.7%). In a second mother-daughter pair, a somatic cause of tumor MMR deficiency was supported by the presence of double somatic MSH2 mutations in their respective tumors. More than 70% of SLS cases had double somatic MMR mutations in the absence of germline pathogenic variants in the MMR or other DNA repair-related genes on WGS, and, therefore, were confidently assigned a noninherited cause of tumor MMR deficiency.

5.
JNCI Cancer Spectr ; 4(5): pkaa062, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33134836

RESUMO

Background: In many countries, population colorectal cancer (CRC) screening is based on age and family history, though more precise risk prediction could better target screening. We examined the impact of a CRC risk prediction model (incorporating age, sex, lifestyle, genomic, and family history factors) to target screening under several feasible screening scenarios. Methods: We estimated the model's predicted CRC risk distribution in the Australian population. Predicted CRC risks were categorized into screening recommendations under 3 proposed scenarios to compare with current recommendations: 1) highly tailored, 2) 3 risk categories, and 3) 4 sex-specific risk categories. Under each scenario, for 35- to 74-year-olds, we calculated the number of CRC screens by immunochemical fecal occult blood testing (iFOBT) and colonoscopy and the proportion of predicted CRCs over 10 years in each screening group. Results: Currently, 1.1% of 35- to 74-year-olds are recommended screening colonoscopy and 56.2% iFOBT, and 5.7% and 83.2% of CRCs over 10 years were predicted to occur in these groups, respectively. For the scenarios, 1) colonoscopy was recommended to 8.1% and iFOBT to 37.5%, with 36.1% and 50.1% of CRCs in each group; 2) colonoscopy was recommended to 2.4% and iFOBT to 56.0%, with 13.2% and 76.9% of cancers in each group; and 3) colonoscopy was recommended to 5.0% and iFOBT to 54.2%, with 24.5% and 66.5% of cancers in each group. Conclusions: A highly tailored CRC screening scenario results in many fewer screens but more cancers in those unscreened. Category-based scenarios may provide a good balance between number of screens and cancers detected and are simpler to implement.

6.
Public Health Genomics ; 23(3-4): 110-121, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32688362

RESUMO

INTRODUCTION: Genomic tests can predict risk and tailor screening recommendations for colorectal cancer (CRC). Primary care could be suitable for their widespread implementation. OBJECTIVE: We aimed to assess the feasibility and acceptability of administering a CRC genomic test in primary care. METHODS: Participants aged 45-74 years recruited from 4 Australian general practices were offered a genomic CRC risk test. Participants received brief verbal information about the test comprising 45 CRC-associated single-nucleotide polymorphisms, before choosing whether to undertake the test. Personalized risks were given to testers. Uptake and knowledge of the genomic test, cancer-specific anxiety (Cancer Worry Scale), psychosocial impact (Multidimensional Impact of Cancer Risk Assessment [MICRA] score), and impact on CRC screening behaviour within 6 months were measured. RESULTS: In 150 participants, test uptake was high (126, 84%), with 125 (83%) having good knowledge of the genomic test. Moderate risk participants were impacted more by the test (MICRA mean: 15.9) than average risk participants (mean: 9.5, difference in means: 6.4, 95% confidence interval (CI): 1.5, 11.2, p = 0.01), but all scores were low. Average risk participants' cancer-specific anxiety decreased (mean differences from baseline: 1 month -0.5, 95% CI: -1.0, -0.1, p = 0.03; 6 months -0.6, 95% CI: -1.0, -0.2, p = 0.01). We found limited evidence for genomic testers being more likely to complete the risk-appropriate CRC screening than non-testers (41 vs. 17%, odds ratio = 3.4, 95% CI: 0.6, 34.8, p = 0.19), but some mediators of screening behaviour were altered in genomic testers. CONCLUSIONS: Genomic testing for CRC risk in primary care is acceptable and likely feasible. Further development of the risk assessment intervention could strengthen the impact on screening behaviour.

7.
Br J Cancer ; 121(10): 869-876, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31551580

RESUMO

BACKGROUND: Type 2 diabetes mellitus and high total cholesterol and triglycerides are known to be associated with increased colorectal cancer risk for the general population. These associations are unknown for people with a germline DNA mismatch repair gene mutation (Lynch syndrome), who are at high risk of colorectal cancer. METHODS: This study included 2023 (56.4% female) carriers with a mismatch repair gene mutation (737 in MLH1, 928 in MSH2, 230 in MSH6, 106 in PMS2, 22 in EPCAM) recruited by the Colon Cancer Family Registry between 1998 and 2012. Weighted Cox regression was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for the associations between self-reported type 2 diabetes, high cholesterol, triglyceride and colorectal cancer risk. RESULTS: Overall, 802 carriers were diagnosed with colorectal cancer at a median age of 42 years. A higher risk of colorectal cancer was observed in those with self-reported type-2 diabetes (HR 1.92; 95% CI, 1.03-3.58) and high cholesterol (HR 1.76; CI 1.23-2.52) compared with those without these conditions. There was no evidence of high triglyceride being associated with colorectal cancer risk. CONCLUSION: For people with Lynch syndrome, self-reported type-2 diabetes mellitus and high cholesterol were associated with increased colorectal cancer risk.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Predisposição Genética para Doença , Adulto , Idoso , Idoso de 80 Anos ou mais , Colesterol/sangue , Neoplasias Colorretais/sangue , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose/sangue , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Molécula de Adesão da Célula Epitelial/genética , Feminino , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Modelos de Riscos Proporcionais , Fatores de Risco , Triglicerídeos/sangue
8.
Alzheimers Dement ; 15(12): 1612-1623, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31506248

RESUMO

INTRODUCTION: Individuals with homozygosity for the apolipoprotein E (APOE) ε4 allele are in the highest risk category for late-onset Alzheimer's disease (LOAD). However, some individuals in this category do not develop LOAD beyond the age of 75 years, despite being at elevated genetic risk. These "resilient" individuals may carry protective genetic factors. METHODS: This study aimed to systematically review any previous studies that involved resilient APOE ε4 homozygotes and to identify possible modifying or protective genetic factors. RESULTS: Fifteen studies met our inclusion criteria and reported genetic factors contributing to reduced risk. We found that only two single nucleotide polymorphisms, CASP7 rs10553596 and SERPINA3 rs4934-A/A, had strong evidence. DISCUSSION: We found a paucity of studies adequately designed to discover protective genetic factors against LOAD. Many studies combined APOE ε4 homozygotes and heterozygotes together because of small sample sizes and used control populations too young to be clearly defined as controls for LOAD.


Assuntos
Doença de Alzheimer , Apolipoproteína E4/genética , Homozigoto , Fatores de Proteção , Alelos , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de Risco
9.
Fam Cancer ; 18(4): 389-397, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31209717

RESUMO

Before SNP-based risk can be incorporated in colorectal cancer (CRC) screening, the ability of these SNPs to estimate CRC risk for persons with and without a family history of CRC, and the screening implications need to be determined. We estimated the association with CRC of a 45 SNP-based risk using 1181 cases and 999 controls, and its correlation with CRC risk predicted from detailed family history. We estimated the predicted change in the distribution across predefined risk categories, and implications for recommended screening commencement age, from adding SNP-based risk to family history. The inter-quintile risk ratio for colorectal cancer risk of the SNP-based risk was 3.28 (95% CI 2.54-4.22). SNP-based and family history-based risks were not correlated (r = 0.02). For persons with no first-degree relatives with CRC, screening could commence 4 years earlier for women (5 years for men) in the highest quintile of SNP-based risk. For persons with two first-degree relatives with CRC, screening could commence 16 years earlier for men and women in the highest quintile, and 7 years earlier for the lowest quintile. This 45 SNP panel in conjunction with family history, can identify people who could benefit from earlier screening. Risk reclassification by 45 SNPs could inform targeted screening for CRC prevention, particularly in clinical genetics settings when mutations in high-risk genes cannot be identified. Yet to be determined is cost-effectiveness, resources requirements, community, patient and clinician acceptance, and feasibility with potentially ethical, legal and insurance implications.


Assuntos
Neoplasias Colorretais/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Estudos de Casos e Controles , Neoplasias Colorretais/prevenção & controle , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Programas de Rastreamento , Anamnese , Pessoa de Meia-Idade , Razão de Chances
10.
Mol Genet Genomic Med ; 7(7): e00781, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31162827

RESUMO

BACKGROUND: Muir-Torre syndrome is defined by the development of sebaceous skin lesions in individuals who carry a germline mismatch repair (MMR) gene mutation. Loss of expression of MMR proteins is frequently observed in sebaceous skin lesions, but MMR-deficiency alone is not diagnostic for carrying a germline MMR gene mutation. METHODS: Whole exome sequencing was performed on three MMR-deficient sebaceous lesions from individuals with MSH2 gene mutations (Lynch syndrome) and three MMR-proficient sebaceous lesions from individuals without Lynch syndrome with the aim of characterizing the tumor mutational signatures, somatic mutation burden, and microsatellite instability status. Thirty predefined somatic mutational signatures were calculated for each lesion. RESULTS: Signature 1 was ubiquitous across the six lesions tested. Signatures 6 and 15, associated with defective DNA MMR, were significantly more prevalent in the MMR-deficient lesions from the MSH2 carriers compared with the MMR-proficient non-Lynch sebaceous lesions (mean ± SD=41.0 ± 8.2% vs. 2.3 ± 4.0%, p = 0.0018). Tumor mutation burden was, on average, significantly higher in the MMR-deficient lesions compared with the MMR-proficient lesions (23.3 ± 11.4 vs. 1.8 ± 0.8 mutations/Mb, p = 0.03). All four sebaceous lesions observed in sun exposed areas of the body demonstrated signature 7 related to ultraviolet light exposure. CONCLUSION: Tumor mutational signatures 6 and 15 and somatic mutation burden were effective in differentiating Lynch-related from non-Lynch sebaceous lesions.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Síndrome de Muir-Torre/genética , Proteína 2 Homóloga a MutS/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Idoso , Biomarcadores Tumorais , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo , Reparo de Erro de Pareamento de DNA/genética , Proteínas de Ligação a DNA/genética , Feminino , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 2 Homóloga a MutS/metabolismo , Mutação , Proteínas Nucleares/genética , Transcriptoma/genética , Sequenciamento Completo do Exoma/métodos
11.
Front Immunol ; 10: 904, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31118932

RESUMO

We characterized the NK cell phenotype and function in three family members with Hereditary Hemorrhagic Telangiectasia (HHT) due to heterozygous SMAD4 mutations. Loss-of-function mutation in this gene did not induce developmental effects to alter CD56bright or CD56dim NK cell subset proportions in peripheral blood; and did not result in major differences in either their IL-15-induced proliferation, or their cytokine secretion response to TGF-ß1. These data suggest that SMAD4 plays a redundant role in downstream TGF-ß signaling in NK cells.


Assuntos
Células Matadoras Naturais/imunologia , Proteína Smad4/imunologia , Telangiectasia Hemorrágica Hereditária/imunologia , Fator de Crescimento Transformador beta/imunologia , Idoso , Feminino , Humanos , Mutação com Perda de Função , Masculino , Pessoa de Meia-Idade , Proteína Smad4/genética , Telangiectasia Hemorrágica Hereditária/genética
12.
Fam Cancer ; 18(3): 311-315, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30671715

RESUMO

The AXIN2 gene, like APC, plays a role in the Wnt signalling pathway involved in colorectal tumour formation. Heterozygous mutations in AXIN2 have been shown to cause ectodermal dysplasia (including tooth agenesis, or more specifically, oligodontia), and, in some carriers, colorectal cancer and/or adenomatous polyposis develops. There is a paucity of published AXIN2 families making genotype-phenotype (polyposis, colorectal cancer and oligodontia) correlations challenging. In this case report we describe a family with c.1972delA, p.Ser658Alafs*31 nonsense variant in AXIN2 where the three confirmed carriers presented with both oligodontia and colorectal adenomatous polyposis; mean number of teeth missing in carriers was 16.5 (range 11-22) and mean number of polyps in carriers was 49 (range 5->100, polyps were predominantly adenomatous). This highlights the importance of confirming phenotypic information in familial polyposis, to guide appropriate genetic investigations, as well as providing additional phenotypic and penetrance data to aid in clinical risk management recommendations. Our experience supports the inclusion of AXIN2 on panels for testing of patients with polyposis.


Assuntos
Polipose Adenomatosa do Colo/genética , Anodontia/genética , Proteína Axina/genética , Códon sem Sentido , Éxons , Polipose Adenomatosa do Colo/patologia , Adulto , Idoso , Anodontia/diagnóstico por imagem , Anodontia/patologia , Feminino , Testes Genéticos , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Penetrância , Fenótipo
13.
Eur Heart J ; 40(10): 831-838, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30380018

RESUMO

AIMS: Unexplained sudden cardiac death (SCD) may be attributable to cardiogenetic disease. Presence or absence of autopsy anomalies detected following premature sudden death direct appropriate clinical evaluation of at-risk relatives towards inherited cardiomyopathies or primary arrhythmia syndromes, respectively. We investigated the relevance of non-diagnostic pathological abnormalities of indeterminate causality (uncertain) such as myocardial hypertrophy, fibrosis, or inflammatory infiltrates to SCD. METHODS AND RESULTS: At-risk relatives of unexplained SCD cases aged 1-64 years without prior cardiac disease (n = 98) with either normal and negative (40%, true sudden arrhythmic death syndrome; SADS) or isolated non-diagnostic (60%, uncertain sudden unexplained death; SUD) cardiac histological autopsy findings at a central forensic pathology unit were referred to the regional unexplained SCD clinic for clinical cardiac phenotyping. Uncertain SUD were older than true SADS cases (31.8 years vs. 21.1 years, P < 0.001). A cardiogenetic diagnosis was established in 24 families (24.5%) following investigation of 346 referred relatives. The proportions of uncertain SUD and true SADS explained by familial cardiogenetic diagnoses were similar (20% vs. 31%, P = 0.34, respectively), with primary arrhythmia syndromes predominating. Unexplained SCD cases were more likely than matched non-cardiac premature death controls to demonstrate at least one uncertain autopsy finding (P < 0.001). CONCLUSION: Primary arrhythmia syndromes predominate as familial cardiogenetic diagnoses amongst both uncertain SUD and true SADS cases. Non-diagnostic or uncertain histological findings associate with SUD, though cannot be attributed a causative status. At-risk relatives of uncertain SUD cases should be evaluated for phenotypic evidence of both ion channel disorders and cardiomyopathies.


Assuntos
Morte Súbita Cardíaca , Adolescente , Adulto , Arritmias Cardíacas , Autopsia , Criança , Pré-Escolar , Estudos de Coortes , Morte Súbita Cardíaca/epidemiologia , Morte Súbita Cardíaca/etiologia , Morte Súbita Cardíaca/patologia , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Vitória , Adulto Jovem
14.
Australas J Dermatol ; 60(2): 126-133, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30506759

RESUMO

BACKGROUND/OBJECTIVES: Loss of expression of mismatch repair (MMR) proteins is frequently observed in sebaceous skin lesions and can be a herald for Lynch syndrome. The aim of this study was to identify clinico-pathological predictors of MMR deficiency in sebaceous neoplasia that could aid dermatologists and pathologists in determining which sebaceous lesions should undergo MMR immunohistochemistry (IHC). METHODS: An audit of sebaceous skin lesions (excluding hyperplasia) where pathologist-initiated MMR IHC was performed between January 2009 to December 2016 was undertaken from a single pathology practice identifying 928 lesions from 882 individuals. Lesions were further analysed for differences in gender, age at diagnosis, lesion type and anatomic location, stratified by MMR status. RESULTS: The 882 individuals (67.7% male) had a mean (SD) age of diagnosis of 68.4 ± 13.3 years. Nearly two-thirds of the lesions were sebaceous adenomas, with 82.6% of all lesions occurring on the head and neck. MMR deficiency, observed in 282 of the 919 lesions (30.7%), was most common in sebaceous adenomas (210/282; 74.5%). MMR-deficient lesions occurred predominantly on the trunk or limbs (64.7%), compared with 23.2% in head or neck (P < 0.001). Loss of MSH2 and MSH6 protein expression was most frequent pattern of loss (187/281; 66.5%). The highest AUC for discriminating MMR-deficient sebaceous lesions from MMR-proficient lesions was observed for the ROC curve based on subgroups defined by type and anatomic location of the sebaceous lesion (AUC = 0.68). CONCLUSION: The best combination of measured clinico-pathological features achieved only modest positive predictive values, sensitivity and specificity for identifying MMR-deficient sebaceous skin lesions.


Assuntos
Reparo de Erro de Pareamento de DNA , Neoplasias das Glândulas Sebáceas/metabolismo , Adenoma/genética , Adenoma/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Austrália , Biomarcadores Tumorais/metabolismo , Carcinoma/genética , Carcinoma/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Neoplasias das Glândulas Sebáceas/genética , Adulto Jovem
15.
Fam Cancer ; 18(1): 91-95, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29619618

RESUMO

Hemangioblastomas are rare vascularized central nervous system tumors, which can occur sporadically or be associated with von Hippel Lindau Syndrome. The pathogenesis of hemangioblastomas in von Hippel Lindau Syndrome is proposed to involve a pseudohypoxic intracellular state induced by dysregulation of hypoxia inducible factor alpha due to the absence of von Hippel Lindau protein complex mediated destruction. Dysregulation of fumarate hydratase, a tricarboxylic acid cycle enzyme, occurs in Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome due to germline fumarate hydratase gene mutations, and also results in oncogenesis via hypoxia inducible factor alpha dysregulation. We present a case study of hemangioblastoma occurrence in a Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome patient and propose it as possible evidence of a phenotypic overlap between von Hippel Lindau and Hereditary Leiomyomatosis and Renal Cell Cancer Syndromes due to their overlapping role in the biochemical regulation of hypoxia inducible factor alpha.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Hemangioblastoma/genética , Leiomiomatose/genética , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Cutâneas/genética , Neoplasias Uterinas/genética , Doença de von Hippel-Lindau/genética , Transtorno do Espectro Autista/genética , Triagem de Portadores Genéticos , Hemangioblastoma/diagnóstico , Hemangioblastoma/patologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Leiomiomatose/diagnóstico , Leiomiomatose/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/patologia , Linhagem , Fenótipo , Pele/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/patologia , Doença de von Hippel-Lindau/diagnóstico , Doença de von Hippel-Lindau/patologia
17.
PLoS Med ; 15(8): e1002630, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30114221

RESUMO

BACKGROUND: The Australian National Bowel Cancer Screening Programme (NBCSP) was introduced in 2006. When fully implemented, the programme will invite people aged 50 to 74 to complete an immunochemical faecal occult blood test (iFOBT) every 2 years. METHODS AND FINDINGS: To investigate colorectal cancer (CRC) screening occurring outside of the NBCSP, we classified participants (n = 2,480) in the Australasian Colorectal Cancer Family Registry (ACCFR) into 3 risk categories (average, moderately increased, and potentially high) based on CRC family history and assessed their screening practices according to national guidelines. We developed a microsimulation to compare hypothetical screening scenarios (70% and 100% uptake) to current participation levels (baseline) and evaluated clinical outcomes and cost for each risk category. The 2 main limitations of this study are as follows: first, the fact that our cost-effectiveness analysis was performed from a third-party payer perspective, which does not include indirect costs and results in overestimated cost-effectiveness ratios, and second, that our natural history model of CRC does not include polyp sojourn time, which determines the rate of cancerous transformation. Screening uptake was low across all family history risk categories (64%-56% reported no screening). For participants at average risk, 18% reported overscreening, while 37% of those in the highest risk categories screened according to guidelines. Higher screening levels would substantially reduce CRC mortality across all risk categories (95 to 305 fewer deaths per 100,000 persons in the 70% scenario versus baseline). For those at average risk, a fully implemented NBCSP represented the most cost-effective approach to prevent CRC deaths (AUS$13,000-16,000 per quality-adjusted life year [QALY]). For those at moderately increased risk, higher adherence to recommended screening was also highly cost-effective (AUS$19,000-24,000 per QALY). CONCLUSION: Investing in public health strategies to increase adherence to appropriate CRC screening will save lives and deliver high value for money.


Assuntos
Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer/métodos , Idoso , Austrália , Neoplasias Colorretais/economia , Análise Custo-Benefício , Detecção Precoce de Câncer/economia , Feminino , Fidelidade a Diretrizes , Humanos , Imunoquímica , Masculino , Anamnese , Pessoa de Meia-Idade , Modelos Econômicos , Sangue Oculto , Dano ao Paciente , Seleção de Pacientes , Guias de Prática Clínica como Assunto , Anos de Vida Ajustados por Qualidade de Vida
18.
Intern Med J ; 48(11): 1325-1330, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29717530

RESUMO

BACKGROUND: Immunohistochemistry for loss of expression of one or more of the mismatch repair proteins is performed on colorectal cancer tissue as a screening test for Lynch syndrome; however, its role in pre-malignant polyps remains controversial. AIM: To determine the effectiveness of mismatch repair immunohistochemistry performed on pre-malignant colorectal polyps in identifying Lynch syndrome, focusing on clinical utility and value. METHODS: A retrospective audit was conducted of mismatch repair immunohistochemistry performed on non-malignant polyps in patients who attended the Family Cancer Clinic at the Royal Melbourne Hospital. Two hundred and six patient records over a 10-year period (2006-2016) were reviewed. Personal and family history data were collected, including genetic testing results. RESULTS: Of the 57 patients who underwent polyp testing, the family histories comprised Amsterdam II Criteria (12.3%), Lynch syndrome-associated malignancies (42.1%), Lynch syndrome-associated malignancies and polyps (35.1%) and polyps only (8.8%); 10.5% of patients had no significant family history. Normal expression of the mismatch repair proteins was observed in 94.7% of patients; loss of expression was observed in three individuals with concordant germline variants in two patients (one PMS2 variant of unknown significance and one MSH6 mutation). Additional genetic testing in 21 patients with normal immunohistochemistry did not identify any additional Lynch syndrome cases. CONCLUSION: The clinical utility of mismatch repair immunohistochemistry on polyp tissue was low. No additional cases of Lynch syndrome were identified, and a large proportion of patients proceeded to germline testing despite normal polyp immunohistochemistry. We suggest there is no value in this approach.


Assuntos
Pólipos do Colo/genética , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Reparo de Erro de Pareamento de DNA , Testes Genéticos/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Pólipos do Colo/metabolismo , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
19.
Genet Med ; 20(10): 1299, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29388942

RESUMO

The abstract to this article contained errors in the Results and Conclusions section. The corrected sections are shown below.

20.
Clin Colorectal Cancer ; 17(2): e293-e305, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29454559

RESUMO

Colorectal cancer (CRC), one of the most common cancers, is a major public health issue globally, especially in Westernized countries. Up to 35% of CRCs are thought to be due to heritable factors, but currently only 5% to 10% of CRCs are attributable to high-risk mutations in known CRC susceptibility genes, predominantly the mismatch repair genes (Lynch syndrome) and adenomatous polyposis coli gene (APC; familial adenomatous polyposis). In this era of precision medicine, high-risk mutation carriers, when identified, can be offered various risk management options that prevent cancers and improve survival, including risk-reducing medication, screening for early detection, and surgery. The practice of clinical genetics is currently transitioning from phenotype-directed single gene testing to multigene panels, now offered by numerous providers. For CRC, the genes included across these panels vary, ranging from well established, clinically actionable susceptibility genes with quantified magnitude of risk, to genes that lack extensive validation or have less evidence of association with CRC and, therefore, have minimal clinical utility. The current lack of consensus regarding inclusion of genes in CRC panels presents challenges in patient counseling and management, particularly when a variant in a less validated gene is identified. Furthermore, there remain considerable challenges regarding variant interpretation even for the well established CRC susceptibility genes. Ironically though, only through more widespread testing and the accumulation of large international data sets will sufficient information be generated to (i) enable well powered studies to determine if a gene is associated with CRC susceptibility, (ii) to develop better models for variant interpretation and (iii) to facilitate clinical translation.


Assuntos
Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Polipose Adenomatosa do Colo/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Humanos
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