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1.
Lancet Oncol ; 17(9): 1261-71, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27498913

RESUMO

BACKGROUND: Sarcomas are rare, phenotypically heterogeneous cancers that disproportionately affect the young. Outside rare syndromes, the nature, extent, and clinical significance of their genetic origins are not known. We aimed to investigate the genetic basis for bone and soft-tissue sarcoma seen in routine clinical practice. METHODS: In this genetic study, we included 1162 patients with sarcoma from four cohorts (the International Sarcoma Kindred Study [ISKS], 966 probands; Project GENESIS, 48 probands; Asan Bio-Resource Center, 138 probands; and kConFab, ten probands), who were older than 15 years at the time of consent and had a histologically confirmed diagnosis of sarcoma, recruited from specialist sarcoma clinics without regard to family history. Detailed clinical, pathological, and pedigree information was collected, and cancer diagnoses in probands and relatives were independently verified. Targeted exon sequencing using blood (n=1114) or saliva (n=48) samples was done on 72 genes (selected due to associations with increased cancer risk) and rare variants were stratified into classes approximating the International Agency for Research on Cancer (IARC) clinical classification for genetic variation. We did a case-control rare variant burden analysis using 6545 Caucasian controls included from three cohorts (ISKS, 235 controls; LifePool, 2010 controls; and National Heart, Lung, and Blood Institute Exome Sequencing Project [ESP], 4300 controls). FINDINGS: The median age at cancer diagnosis in 1162 sarcoma probands was 46 years (IQR 29-58), 170 (15%) of 1162 probands had multiple primary cancers, and 155 (17%) of 911 families with informative pedigrees fitted recognisable cancer syndromes. Using a case-control rare variant burden analysis, 638 (55%) of 1162 sarcoma probands bore an excess of pathogenic germline variants (combined odds ratio [OR] 1·43, 95% CI 1·24-1·64, p<0·0001), with 227 known or expected pathogenic variants occurring in 217 individuals. All classes of pathogenic variants (known, expected, or predicted) were associated with earlier age of cancer onset. In addition to TP53, ATM, ATR, and BRCA2, an unexpected excess of functionally pathogenic variants was seen in ERCC2. Probands were more likely than controls to have multiple pathogenic variants compared with the combined control cohort group and the LifePool control cohort (OR 2·22, 95% CI 1·57-3·14, p=1·2 × 10(-6)) and the cumulative burden of multiple variants correlated with earlier age at cancer diagnosis (Mantel-Cox log-rank test for trend, p=0·0032). 66 of 1162 probands carried notifiable variants following expert clinical review (those recognised to be clinically significant to health and about which patients should be advised), whereas 293 (25%) probands carried variants with potential therapeutic significance. INTERPRETATION: About half of patients with sarcoma have putatively pathogenic monogenic and polygenic variation in known and novel cancer genes, with implications for risk management and treatment. FUNDING: Rainbows for Kate Foundation, Johanna Sewell Research Foundation, Australian National Health and Medical Research Council, Cancer Australia, Sarcoma UK, National Cancer Institute, Liddy Shriver Sarcoma Initiative.


Assuntos
Biomarcadores Tumorais/genética , Exoma/genética , Mutação/genética , Saliva/química , Sarcoma/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Seguimentos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Lactente , Recém-Nascido , Agências Internacionais , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Linhagem , Prognóstico , Fatores de Risco , Sarcoma/sangue , Adulto Jovem
2.
Genet Med ; 15(3): 187-94, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22975758

RESUMO

PURPOSE: The Kathleen Cuningham Foundation Consortium for Research into Familial Aspects of Breast Cancer (kConFab) is a large-scale research study that notifies participants when new, personally relevant, information is discovered. In 2009, the (kConFab) instituted an intensive notification process to ensure at-risk individuals were effectively notified. This study (i) evaluated the impact of intensive notification on genetic testing uptake; (ii) identified those most likely to undergo testing postnotification; and (iii) identified those most likely to acknowledge that they had been notified. METHODS: Clinical/demographic data were retrieved from the (kConFab) database. Logistic regression analyses were conducted to identify potential predictors of testing uptake and notification acknowledgment using IBM SPSS. RESULTS: A total of 155 of 1,812 individuals underwent testing after standard notification (8.6%). In comparison, 23/291 individuals (7.9%) notified using the "intensive" approach underwent testing (χ(2) = 0.14; P = 0.71). After controlling for notification process, females and participants with a previous cancer were most likely to have undergone testing (P < 0.006). Older individuals (50+ years) were most likely to acknowledge they had been notified (P = 0.038). CONCLUSION: Increasing the intensity of participant follow-up did not increase genetic testing uptake. The challenge to effectively notify participants, and increase the proportion whose risk is managed clinically, remains, particularly for males and individuals unaffected by cancer.Genet Med 2013:15(3):187-194.


Assuntos
Neoplasias da Mama/genética , Mutação , Acesso dos Pacientes aos Registros , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Genes BRCA1 , Genes BRCA2 , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Pesquisa , Adulto Jovem
3.
Per Med ; 15(1): 13-24, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29714116

RESUMO

AIM: To compare Australian and French perceptions of genetics and preferences regarding the return of incidental findings. METHODS: Participants from the International Sarcoma Kindred Study received a survey at intake to cancer referral units. A total of 1442 Australian and 479 French individuals affected by sarcoma and their unaffected family members responded to four hypothetical scenarios depicting hereditary conditions of varying treatability and severity. RESULTS: Australians' preference for the return of incidental findings was consistently higher than French for all scenarios. Country group differences were significant for two scenarios when individual characteristics were controlled through multivariable analyses. CONCLUSION: Findings support the need for guidelines that are sensitive to sociocultural context and promote autonomous decision-making.


Assuntos
Testes Genéticos/ética , Conhecimentos, Atitudes e Prática em Saúde/etnologia , Achados Incidentais , Adulto , Atitude Frente a Saúde/etnologia , Austrália/etnologia , Confidencialidade , Tomada de Decisões/ética , Família , Feminino , França/etnologia , Genética/educação , Humanos , Masculino , Pessoa de Meia-Idade , Percepção/ética , Sarcoma/psicologia , Inquéritos e Questionários
4.
Breast Cancer Res ; 8(1): R12, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16507150

RESUMO

INTRODUCTION: The Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) is a multidisciplinary, collaborative framework for the investigation of familial breast cancer. Based in Australia, the primary aim of kConFab is to facilitate high-quality research by amassing a large and comprehensive resource of epidemiological and clinical data with biospecimens from individuals at high risk of breast and/or ovarian cancer, and from their close relatives. METHODS: Epidemiological, family history and lifestyle data, as well as biospecimens, are collected from multiple-case breast cancer families ascertained through family cancer clinics in Australia and New Zealand. We used the Tyrer-Cuzick algorithms to assess the prospective risk of breast cancer in women in the kConFab cohort who were unaffected with breast cancer at the time of enrolment in the study. RESULTS: Of kConFab's first 822 families, 518 families had multiple cases of female breast cancer alone, 239 had cases of female breast and ovarian cancer, 37 had cases of female and male breast cancer, and 14 had both ovarian cancer as well as male and female breast cancer. Data are currently held for 11,422 people and germline DNAs for 7,389. Among the 812 families with at least one germline sample collected, the mean number of germline DNA samples collected per family is nine. Of the 747 families that have undergone some form of mutation screening, 229 (31%) carry a pathogenic or splice-site mutation in BRCA1 or BRCA2. Germline DNAs and data are stored from 773 proven carriers of BRCA1 or BRCA1 mutations. kConFab's fresh tissue bank includes 253 specimens of breast or ovarian tissue--both normal and malignant--including 126 from carriers of BRCA1 or BRCA2 mutations. CONCLUSION: These kConFab resources are available to researchers anywhere in the world, who may apply to kConFab for biospecimens and data for use in ethically approved, peer-reviewed projects. A high calculated risk from the Tyrer-Cuzick algorithms correlated closely with the subsequent occurrence of breast cancer in BRCA1 and BRCA2 mutation positive families, but this was less evident in families in which no pathogenic BRCA1 or BRCA2 mutation has been detected.


Assuntos
Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Neoplasias Ovarianas/genética , Bancos de Tecidos , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Austrália , Estudos de Coortes , Análise Mutacional de DNA , Coleta de Dados , Estudos Epidemiológicos , Feminino , Mutação em Linhagem Germinativa , Humanos , Estilo de Vida , Pessoa de Meia-Idade , Nova Zelândia , Linhagem , Pesquisa/organização & administração , Fatores de Risco , Manejo de Espécimes
5.
Cancer Prev Res (Phila) ; 4(7): 1002-10, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21733824

RESUMO

The role of a germ-line BRCA2 mutation in the development of prostate cancer is established, but the clinical presentation linked to outcome for this group of men has not been well described. A total of 148 men from 1,423 families were ascertained from the kConFab consortium. Each participant met the following criteria: (i) a verified case of prostate cancer; (ii) confirmed as either a carrier or noncarrier of a family-specific BRCA pathogenic mutation; (iii) comprehensive clinical and treatment data were available. Clinical data were linked to treatment received and overall survival was analyzed by Kaplan-Meier. Prostate cancer in men from breast cancer-prone families has a high risk of disease progression, irrespective of mutation status. BRCA2 mutation carriers have an increased risk of death and prostate cancer-related death [HR (95% CI) 4.5 (2.12-9.52), P = 8.9 × 10(-5)] by comparison with noncarriers. Serum PSA readings taken prior to diagnosis in 90% of all men, age adjusted, were above clinical significance. Following D'Amico risk stratification, 77.5% of BRCA2 mutation carriers and 58.7% of noncarriers had high-risk disease. BRCA2 mutation status was also an independent prognostic indicator of overall survival. Furthermore, there was a poor overall survival outcome for both the BRCA2 mutation carriers and noncarriers given curative-intent treatment. All men in breast cancer-prone families are at risk of developing aggressive prostate cancer. This information is significant and should be included in discussions with genetic counselors and medical professionals when discussing prostate cancer treatment options for men in these families, irrespective of mutation status.


Assuntos
Proteína BRCA2/genética , Neoplasias da Mama/complicações , Neoplasias da Mama/genética , Mutação/genética , Neoplasias da Próstata/etiologia , Neoplasias da Próstata/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Masculino , Prontuários Médicos , Pessoa de Meia-Idade , Neoplasias da Próstata/terapia , Fatores de Risco , Taxa de Sobrevida , Resultado do Tratamento
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