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1.
J Med Genet ; 2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33168572

RESUMO

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.

2.
J Community Genet ; 11(3): 291-302, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31879826

RESUMO

Screening programmes for BRCA1/2 Jewish Founder mutations (JFM) in the Jewish community have been advocated internationally. Implementation of these programmes could decrease morbidity and mortality of BRCA1/2 JFM carriers through the uptake of cancer screening strategies and risk-reducing surgery. An online programme offered to the Sydney Jewish community that delivers pre-test information and collects consent for BRCA1/2 JFM testing via a website is currently being evaluated (JeneScreen). Forty-three participants from JeneScreen were invited to participate in a sub-study, of semi-structured pre- and post-result telephone interviews. Eleven participants consented to the sub-study. The interviews explored their experiences regarding the online model of obtaining pre-test genetic information, giving consent and receiving results. Inductive thematic analysis was carried out on the interviews. Overarching themes identified include (1) embracing online testing, (2) the online pre-test experience, (3) the result notification experience, (4) concerns associated with online testing and (5) testing as a responsibility. Overall, participants were highly satisfied with online BRCA1/2 JFM testing, an indication that the a website for pre-test information provision is an acceptable alternative to in-person genetic counselling for BRCA1/2 JFM screening and represents a feasible model for future community screening efforts.

3.
NPJ Breast Cancer ; 5: 38, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31700994

RESUMO

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.

4.
Hum Mutat ; 39(5): 593-620, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29446198

RESUMO

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Internacionalidade , Mutação/genética , Bases de Dados Genéticas , Família , Geografia , Humanos
5.
Artigo em Inglês | MEDLINE | ID: mdl-29344385

RESUMO

Background: Gynaecological cancers may be the sentinel malignancy in women who carry a mutation in BRCA1 or 2, a mis-match repair gene causing Lynch Syndrome or other genes. Despite published guidelines for referral to a genetics service, a substantial number of women do not attend for the recommended genetic assessment. The study aims to determine the outcomes of systematic follow-up of patients diagnosed with ovarian or endometrial cancer from Gynaecologic-oncology multidisciplinary meetings who were deemed appropriate for genetics assessment. Methods: Women newly diagnosed with gynaecological cancer at the Royal Hospital for Women between 2010 and 2014 (cohort1) and 2015-2016 (cohort 2) who were identified as suitable for genetics assessment were checked against the New South Wales/Australian Capital Territory genetic database. The doctors of non-attenders were contacted regarding suitability for re-referral, and patients who were still suitable for genetics assessment were contacted by mail. Attendance was again checked against the genetics database. Results: Among 462 patients in cohort 1, flagged for genetic assessment, 167 had not consulted a genetic service at initial audit conducted in 2014. 86 (18.6%) women whose referral was pending clarification of family history and/or immunohistochemistry did not require further genetic assessment. Letters were sent to 40 women. 7 women (1.5%) attended hereditary cancer clinic in the following 6 months.The audit conducted in 2016 identified 148 patients (cohort 2) appropriate for genetic assessment at diagnosis. 66 (44.6%) had been seen by a genetics service, 51 (34.5%) whose referral was pending additional information did not require further genetic assessment. Letters were sent to 15 women, of whom 9 (6.1%) attended genetics within 6 months. Conclusions: To improve the effectiveness of guidelines for the genetic referral of women newly diagnosed with ovarian cancer, clinicians need to obtain a thorough family history at diagnosis; arrange for reflex MMR IHC according to guidelines; offer BRCA or panel testing to all women with non-mucinous ovarian cancer prior to discharge and systematically follow up all women referred to genetics at the post-op visit.

7.
Artigo em Inglês | MEDLINE | ID: mdl-28936272

RESUMO

BACKGROUND: Endometrial, ovarian and breast cancers are paradigms for global health disparity. Women living in the developing world continue to present in later stages of disease and have fewer options for treatment than those in developed countries. Risk reducing surgery is of proven benefit for women at high risk of gynaecological cancer. There is no specific model for identification and management of such women in the developing world. METHODS: We have integrated data from our published audit of a major gynaecological oncology centre at Royal Hospital for Women in Australia, with data from our survey and a focus group discussion of Nepalese gynaecological health care professionals regarding genetic testing, and findings from the literature. These data have been used to identify current barriers to multidisciplinary gynaecological oncology care in developing nations, and to develop a model to integrate hereditary cancer services into cancer care in Nepal, as a paradigm for other developing nations. RESULTS: The ability to identify women with hereditary gynaecological cancer in developing nations is influenced by their late presentation (if active management is declined or not appropriate), limited access to specialised services and cultural and financial barriers. In order to include genetic assessment in multidisciplinary gynaecological cancer care, education needs to be provided to all levels of health care providers to enable reporting of family history, and appropriate ordering of investigations. Training of genetic counsellors is needed to assist in the interpretation of results and extending care to unaffected at-risk relatives. Novel approaches will be required to overcome geographic and financial barriers, including mainstreaming of genetic testing, telephone counselling, use of mouth swabs and utilisation of international laboratories. CONCLUSION: Women in Nepal have yet to receive benefits from the advances in early cancer diagnosis and management. There is a potential of extending the benefits of hereditary cancer diagnosis in Nepal due to the rapid fall in the cost of genetic testing and the ability to collect DNA from a buccal swab through appropriate training of the gynaecological carers.

9.
Genome Med ; 9(1): 41, 2017 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-28454591

RESUMO

BACKGROUND: The return of research results (RoR) remains a complex and well-debated issue. Despite the debate, actual data related to the experience of giving individual results back, and the impact these results may have on clinical care and health outcomes, is sorely lacking. Through the work of the Australian Pancreatic Cancer Genome Initiative (APGI) we: (1) delineate the pathway back to the patient where actionable research data were identified; and (2) report the clinical utilisation of individual results returned. Using this experience, we discuss barriers and opportunities associated with a comprehensive process of RoR in large-scale genomic research that may be useful for others developing their own policies. METHODS: We performed whole-genome (n = 184) and exome (n = 208) sequencing of matched tumour-normal DNA pairs from 392 patients with sporadic pancreatic cancer (PC) as part of the APGI. We identified pathogenic germline mutations in candidate genes (n = 130) with established predisposition to PC or medium-high penetrance genes with well-defined cancer associated syndromes or phenotypes. Variants from candidate genes were annotated and classified according to international guidelines. Variants were considered actionable if clinical utility was established, with regard to prevention, diagnosis, prognostication and/or therapy. RESULTS: A total of 48,904 germline variants were identified, with 2356 unique variants undergoing annotation and in silico classification. Twenty cases were deemed actionable and were returned via previously described RoR framework, representing an actionable finding rate of 5.1%. Overall, 1.78% of our cohort experienced clinical benefit from RoR. CONCLUSION: Returning research results within the context of large-scale genomics research is a labour-intensive, highly variable, complex operation. Results that warrant action are not infrequent, but the prevalence of those who experience a clinical difference as a result of returning individual results is currently low.


Assuntos
Predisposição Genética para Doença , Genoma Humano , Mutação em Linhagem Germinativa , Neoplasias Pancreáticas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Austrália , Simulação por Computador , Análise Mutacional de DNA , Genômica , Humanos , Pessoa de Meia-Idade
10.
Artigo em Inglês | MEDLINE | ID: mdl-28254144

RESUMO

Mutations in BRCA1 and BRCA2 account for hereditary breast and ovarian cancer syndrome in a majority of families and 14% of epithelial ovarian cancer cases. Despite next-generation sequencing, other identified genes (Lynch Syndrome, RAD51C, RAD51D, and BRIP1) account for only a small proportion of cases. The risk of ovarian cancer by age 70 is approximately 40% for BRCA1 and 18% for BRCA2. Most of these cancers are high-grade serous cancers that predominantly arise in the fimbriae of the fallopian tube. Ovarian screening does not improve outcomes, so women at high risk are recommended to undergo risk-reducing salpingo-oophorectomy around the age of 40, followed by hormone replacement therapy (HRT). Specimens should be carefully examined for occult malignancy. Mutation carriers may benefit from newly developed poly ADP ribose polymerase inhibitors. Genetic testing should only be performed after careful counseling, particularly if testing involves the testing of panels of genes that may identify unsuspected disease predisposition or confusing variants of uncertain significance.


Assuntos
Genes BRCA2 , Predisposição Genética para Doença , Neoplasias Ovarianas/genética , Medição de Risco , Neoplasias da Mama , Feminino , Testes Genéticos , Humanos , Mutação , Neoplasias Ovarianas/prevenção & controle , Neoplasias Ovarianas/cirurgia , Ovariectomia
11.
Fam Cancer ; 16(1): 17-28, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27480161

RESUMO

About 2.5 % of the Ashkenazi-Jewish population carry one of three "founder" mutations in BRCA1 and BRCA2 (BRCA1/2). Currently, testing is offered to Jewish people with a personal and/or family history of breast and/or ovarian cancer; however less than half of BRCA1/2 carriers within the Jewish population are aware of their family history. Population-based testing in other countries has shown to greatly increase the number of mutation carriers identified, compared to targeted testing of people with a family history. We aimed to assess the Australian Jewish community's attitudes towards such a program, including acceptability and interest in having education and testing offered online. Members of Sydney-based Jewish organisations who self-identified as being Jewish were invited by e-mail to participate in an online survey. Of 370 individuals who completed the survey, 96.8 % supported a Jewish community-based BRCA1/2 testing program, and 65.6 % reported being personally interested in undergoing the test. Younger adults aged below 50 years were more interested in undergoing the test than those aged 50 years and above. Almost half (42.9 %) were aware of a family member with breast and/or ovarian cancer; however, of these, 77.1 % had not yet undergone testing. Sixty-five (65.1 %) percent were satisfied with providing consent online, while only 39.6 % of participants' first preference for method of information provision was online. Given the high level of support, and interest in a community testing program, the development and evaluation of a cost-effective and interactive, online BRCA1/2 community testing program appears warranted.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Testes Genéticos , Conhecimentos, Atitudes e Prática em Saúde , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Austrália , Neoplasias da Mama/genética , Feminino , Predisposição Genética para Doença , Humanos , Judeus/genética , Masculino , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Linhagem , Características de Residência , Adulto Jovem
12.
Artigo em Inglês | MEDLINE | ID: mdl-27980798

RESUMO

BACKGROUND: Genetic testing for an inherited susceptibility to cancer is an emerging technology in medical practice. Little information is currently available about physicians' attitudes towards these tests in developing countries. METHODS: We conducted an email survey of Nepalese physicians practicing in academic and non-academic settings in Nepal, regarding knowledge, attitudes and perception towards genetic testing for gynaecologic cancer. RESULTS: Responses were received from 251 of 387 practitioners (65%). Only 46% of all respondents felt prepared to answer patients' questions about genetic testing for gynaecologic cancer, despite 80% reporting that patients had asked questions about genetic testing, and 55% being asked more than 5 times in the past year. 42% reported more than 10 of their patients having had genetic testing for cancer, the majority for BRCA1/2. Access (40%), cost (37%) and lack of physicians' information (24%) were cited as the main barriers to testing. The most commonly identified concerns regarding genetic testing were the potential for increased patient anxiety, misinterpretation of results by patients, and maintaining confidentiality of results (64%, 47% and 38% of respondents respectively). CONCLUSION: This study shows the gap among the health care providers in developing countries and the available modern scientific tools and skills in regard to the benefits of genetic testing for gynaecological cancers in a developing nation. These findings indicate the need for the introduction of further genetic counselling education and support into gynaecological care in Nepal.

15.
Aust N Z J Obstet Gynaecol ; 56(6): 633-638, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27530527

RESUMO

BACKGROUND: Genetic participation in gynaecological oncology multidisciplinary team meetings (MDT) may identify the sentinel cancer in women with hereditary breast-ovarian cancer syndrome or Lynch syndrome. AIMS: To identify the changing patterns of genetic referral from 2010 to 2014 and the outcomes of referrals through clinical MDT case review. MATERIALS AND METHODS: Medical records of cases of gynaecological cancer presented at the MDT meetings and genetics databases were reviewed to determine the frequency and outcomes of recommendations for genetic referral between 2010 and 2014. RESULTS: Four hundred and sixty-two women of 2523 cases reviewed were recommended for referral, increasing from 8% in 2010 to 25% in 2014. However, 167 of 462 patients (36%) had not registered with a Hereditary Cancer Clinic in NSW/ACT, including 11 women with high-grade serous ovarian cancer and seven women with abnormal MMR immunohistochemistry. Mutations were identified in 40 of 165 women (24%) undergoing breast cancer BRCA1/2 testing and in ten of 25 women (40%) who underwent MMR genetic testing. Eighty-one first- or second-degree relatives of these women have undergone predictive testing, identifying 48 mutation carriers and 33 non-carriers. CONCLUSION: Changing indications and increased participation by a genetic consultant in the weekly MDT meeting has led to increasing genetic referrals over the last five years. Follow up of referrals needs to be addressed. With decreasing costs of genetic testing and use of readily transportable DNA collected through saliva or mouth swabs, we propose that distance should not be a barrier to this model being extended to all centres providing care to gynaecological cancer patients.


Assuntos
Neoplasias do Endométrio/genética , Testes Genéticos/tendências , Neoplasias Císticas, Mucinosas e Serosas/genética , Neoplasias Ovarianas/genética , Encaminhamento e Consulta/tendências , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas de Ligação a DNA/análise , Proteínas de Ligação a DNA/genética , Bases de Dados Genéticas/estatística & dados numéricos , Neoplasias do Endométrio/química , Feminino , Genes BRCA1 , Genes BRCA2 , Testes Genéticos/estatística & dados numéricos , Humanos , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/análise , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/análise , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/análise , Proteína 2 Homóloga a MutS/genética , Mutação , Neoplasias Císticas, Mucinosas e Serosas/química , Neoplasias Ovarianas/química , Equipe de Assistência ao Paciente , Linhagem , Encaminhamento e Consulta/estatística & dados numéricos , Adulto Jovem
20.
J Genet Couns ; 25(2): 218-27, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26259529

RESUMO

Next generation sequencing (NGS) for patients at risk of hereditary cancer syndromes can also identify non-cancer related mutations, as well as variants of unknown significance. This study aimed to determine what benefits and shortcomings patients perceive in relation to NGS, as well as their interest and information preferences in regards to such testing. Eligible patients had previously received inconclusive results from clinical mutation testing for cancer susceptibility. Semi-structured telephone interviews were subjected to qualitative analysis guided by the approach developed by Miles and Huberman. The majority of the 19 participants reported they would be interested in panel/genomic testing. Advantages identified included that it would enable better preparation and allow implementation of individualized preventative strategies, with few disadvantages mentioned. Almost all participants said they would want all results, not just those related to their previous diagnosis. Participants felt that a face-to-face discussion supplemented by an information booklet would be the best way to convey information and achieve informed consent. All participants wanted their information stored and reviewed in accordance with new developments. Although the findings indicate strong interest among these individuals, it seems that the consent process, and the interpretation and communication of results will be areas that will require revision to meet the needs of patients.


Assuntos
Aconselhamento Genético/métodos , Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Síndromes Neoplásicas Hereditárias/genética , Aceitação pelo Paciente de Cuidados de Saúde , Adulto , Idoso , Análise Mutacional de DNA , Predisposição Genética para Doença/genética , Humanos , Consentimento Livre e Esclarecido , Masculino , Pessoa de Meia-Idade , Síndromes Neoplásicas Hereditárias/diagnóstico , Satisfação do Paciente , Pesquisa Qualitativa , Medição de Risco
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