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1.
J Transl Med ; 21(1): 282, 2023 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-37101184

RESUMO

Routine screening of tumors for DNA mismatch repair (MMR) deficiency (dMMR) in colorectal (CRC), endometrial (EC) and sebaceous skin (SST) tumors leads to a significant proportion of unresolved cases classified as suspected Lynch syndrome (SLS). SLS cases (n = 135) were recruited from Family Cancer Clinics across Australia and New Zealand. Targeted panel sequencing was performed on tumor (n = 137; 80×CRCs, 33×ECs and 24xSSTs) and matched blood-derived DNA to assess for microsatellite instability status, tumor mutation burden, COSMIC tumor mutational signatures and to identify germline and somatic MMR gene variants. MMR immunohistochemistry (IHC) and MLH1 promoter methylation were repeated. In total, 86.9% of the 137 SLS tumors could be resolved into established subtypes. For 22.6% of these resolved SLS cases, primary MLH1 epimutations (2.2%) as well as previously undetected germline MMR pathogenic variants (1.5%), tumor MLH1 methylation (13.1%) or false positive dMMR IHC (5.8%) results were identified. Double somatic MMR gene mutations were the major cause of dMMR identified across each tumor type (73.9% of resolved cases, 64.2% overall, 70% of CRC, 45.5% of ECs and 70.8% of SSTs). The unresolved SLS tumors (13.1%) comprised tumors with only a single somatic (7.3%) or no somatic (5.8%) MMR gene mutations. A tumor-focused testing approach reclassified 86.9% of SLS into Lynch syndrome, sporadic dMMR or MMR-proficient cases. These findings support the incorporation of tumor sequencing and alternate MLH1 methylation assays into clinical diagnostics to reduce the number of SLS patients and provide more appropriate surveillance and screening recommendations.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais , Síndromes Neoplásicas Hereditárias , Humanos , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Reparo de Erro de Pareamento de DNA/genética , Neoplasias Colorretais/genética , Síndromes Neoplásicas Hereditárias/genética , Proteína 1 Homóloga a MutL/genética , Metilação de DNA/genética , Instabilidade de Microssatélites
2.
medRxiv ; 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36909643

RESUMO

Routine screening of tumors for DNA mismatch repair (MMR) deficiency (dMMR) in colorectal (CRC), endometrial (EC) and sebaceous skin (SST) tumors leads to a significant proportion of unresolved cases classified as suspected Lynch syndrome (SLS). SLS cases (n=135) were recruited from Family Cancer Clinics across Australia and New Zealand. Targeted panel sequencing was performed on tumor (n=137; 80xCRCs, 33xECs and 24xSSTs) and matched blood-derived DNA to assess for microsatellite instability status, tumor mutation burden, COSMIC tumor mutational signatures and to identify germline and somatic MMR gene variants. MMR immunohistochemistry (IHC) and MLH1 promoter methylation were repeated. In total, 86.9% of the 137 SLS tumors could be resolved into established subtypes. For 22.6% of these resolved SLS cases, primary MLH1 epimutations (2.2%) as well as previously undetected germline MMR pathogenic variants (1.5%), tumor MLH1 methylation (13.1%) or false positive dMMR IHC (5.8%) results were identified. Double somatic MMR gene mutations were the major cause of dMMR identified across each tumor type (73.9% of resolved cases, 64.2% overall, 70% of CRC, 45.5% of ECs and 70.8% of SSTs). The unresolved SLS tumors (13.1%) comprised tumors with only a single somatic (7.3%) or no somatic (5.8%) MMR gene mutations. A tumor-focused testing approach reclassified 86.9% of SLS into Lynch syndrome, sporadic dMMR or MMR-proficient cases. These findings support the incorporation of tumor sequencing and alternate MLH1 methylation assays into clinical diagnostics to reduce the number of SLS patients and provide more appropriate surveillance and screening recommendations.

3.
Hered Cancer Clin Pract ; 20(1): 18, 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35509103

RESUMO

BACKGROUND: To inform effective genomic medicine strategies, it is important to examine current approaches and gaps in well-established applications. Lynch syndrome (LS) causes 3-5% of colorectal cancers (CRCs). While guidelines commonly recommend LS tumour testing of all CRC patients, implementation in health systems is known to be highly variable. To provide insights on the heterogeneity in practice and current bottlenecks in a high-income country with universal healthcare, we characterise the approaches and gaps in LS testing and referral in seven Australian hospitals across three states. METHODS: We obtained surgery, pathology, and genetics services data for 1,624 patients who underwent CRC resections from 01/01/2017 to 31/12/2018 in the included hospitals. RESULTS: Tumour testing approaches differed between hospitals, with 0-19% of patients missing mismatch repair deficiency test results (total 211/1,624 patients). Tumour tests to exclude somatic MLH1 loss were incomplete at five hospitals (42/187 patients). Of 74 patients with tumour tests completed appropriately and indicating high risk of LS, 36 (49%) were missing a record of referral to genetics services for diagnostic testing, with higher missingness for older patients (0% of patients aged ≤ 40 years, 76% of patients aged > 70 years). Of 38 patients with high-risk tumour test results and genetics services referral, diagnostic testing was carried out for 25 (89%) and identified a LS pathogenic/likely pathogenic variant for 11 patients (44% of 25; 0.7% of 1,624 patients). CONCLUSIONS: Given the LS testing and referral gaps, further work is needed to identify strategies for successful integration of LS testing into clinical care, and provide a model for hereditary cancers and broader genomic medicine. Standardised reporting may help clinicians interpret tumour test results and initiate further actions.

4.
J Clin Oncol ; 40(18): 2036-2047, 2022 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-35263119

RESUMO

PURPOSE: Tubo-ovarian cancer (TOC) is a sentinel cancer for BRCA1 and BRCA2 pathogenic variants (PVs). Identification of a PV in the first member of a family at increased genetic risk (the proband) provides opportunities for cancer prevention in other at-risk family members. Although Australian testing rates are now high, PVs in patients with TOC whose diagnosis predated revised testing guidelines might have been missed. We assessed the feasibility of detecting PVs in this population to enable genetic risk reduction in relatives. PATIENTS AND METHODS: In this pilot study, deceased probands were ascertained from research cohort studies, identification by a relative, and gynecologic oncology clinics. DNA was extracted from archival tissue or stored blood for panel sequencing of 10 risk-associated genes. Testing of deceased probands ascertained through clinic records was performed with a consent waiver. RESULTS: We identified 85 PVs in 84 of 787 (11%) probands. Familial contacts of 39 of 60 (65%) deceased probands with an identified recipient (60 of 84; 71%) have received a written notification of results, with follow-up verbal contact made in 85% (33 of 39). A minority of families (n = 4) were already aware of the PV. For many (29 of 33; 88%), the genetic result provided new information and referral to a genetic service was accepted in most cases (66%; 19 of 29). Those who declined referral (4 of 29) were all male next of kin whose family member had died more than 10 years before. CONCLUSION: We overcame ethical and logistic challenges to demonstrate that retrospective genetic testing to identify PVs in previously untested deceased probands with TOC is feasible. Understanding reasons for a family member's decision to accept or decline a referral will be important for guiding future TRACEBACK projects.


Assuntos
Neoplasias da Mama , Neoplasias Ovarianas , Austrália , Neoplasias da Mama/genética , Carcinoma Epitelial do Ovário/genética , Família , Feminino , Predisposição Genética para Doença , Testes Genéticos/métodos , Humanos , Masculino , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/prevenção & controle , Projetos Piloto , Estudos Retrospectivos
5.
J Genet Couns ; 31(1): 120-129, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34223688

RESUMO

Hereditary breast cancer is associated with known genetic changes: either variants that affect function in a few rare genes or an ever-increasing number of common genomic risk variants, which combine to produce a cumulative effect, known as a polygenic risk (PR) score. While the clinical validity and utility of PR scores are still being determined, the communication of PR is a new challenge for genetic health professionals. This study investigated how PR scores are discussed in the familial cancer clinic compared with a previous study assessing the communication of monogenic risk (MR) for breast cancer. Sixty-five PR consultations between genetic health professionals and women at familial risk of breast cancer were audiotaped, transcribed, and coded using a methodology adapted from the MR study. Analysis of consultations shows that while there were similarities in communicating MR and PR, the complexity and novelty of the polygenic information influenced the style of counseling used by genetic health professionals toward a teaching model of genetic counseling, rather than a patient-centered approach. In particular, compared to MR consultations, in PR consultations significantly fewer counselees (a) were asked about their reasons for attending genetic counseling; or (b) had their information preferences, decision-making style, medical knowledge, understanding, or concerns checked. In conclusion, it is anticipated that PR scores will become part of standard clinical practice. Thus, it will be important for all genetic health professionals to be appropriately educated so that they can tailor their communication to meet patient needs.


Assuntos
Neoplasias da Mama , Neoplasias da Mama/genética , Neoplasias da Mama/psicologia , Comunicação , Feminino , Aconselhamento Genético/psicologia , Predisposição Genética para Doença , Testes Genéticos , Humanos , Fatores de Risco
6.
Med Probl Perform Art ; 36(4): 225-232, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34854457

RESUMO

OBJECTIVE: Clarinetists often report discomfort of the right wrist and thumb and note that it is likely the result of the constant force applied to the area from the instrument's weight and the musician's technique. One preventative measure to reduce this discomfort is the use of a neck strap. The objective of the current study was to document the biomechanical impacts of this intervention. METHODS: Eight experienced clarinetists played a series of three etude pieces while playing both with and without a neck strap. For each condition, the force between the right thumb and clarinet was measured, electromyographic (EMG) data were collected from seven muscle groups, and subjective assessment of perceived effort was obtained. RESULTS: The results showed that when the neck strap was used, there was a significant decrease in the average force between the thumb and clarinet (p<0.05) and a decrease in the average perceived effort required for the right shoulder and thumb of the participants (p<0.05). Importantly, there were no statistically significant increases in the muscle activity of any of the neck and shoulder muscles with the introduction of the neck strap intervention. CONCLUSION: A neck strap intervention had positive effects on the right thumb while not causing any known adverse effects to other areas such as the neck, upper back, and shoulders.


Assuntos
Fenômenos Fisiológicos Musculoesqueléticos , Polegar , Fenômenos Biomecânicos , Eletromiografia , Humanos , Músculo Esquelético , Pescoço , Ombro
7.
Genet Med ; 23(12): 2316-2323, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34341522

RESUMO

PURPOSE: To prospectively assess patient reported outcomes and risk management behavior of women choosing to receive (receivers) or decline (decliners) their breast cancer polygenic risk score (PRS). METHODS: Women either unaffected or affected by breast cancer and from families with no identified pathogenic variant in a breast cancer risk gene were invited to receive their PRS. All participants completed a questionnaire at study enrollment. Receivers completed questionnaires at two weeks and 12 months after receiving their PRS, and decliners a second questionnaire at 12 months post study enrollment. RESULTS: Of the 208 participants, 165 (79%) received their PRS. Among receivers, there were no changes in anxiety or distress following testing. However, compared to women with a low PRS, those with a high PRS reported greater genetic testing-specific distress, perceived risk, decisional regret, and less genetic testing-positive response. At 12 months, breast screening and uptake of risk-reducing strategies were consistent with current Australian guidelines of breast cancer risk management. Reasons for declining PRS included being unable to attend the appointment in person and concerns over potential emotional response. CONCLUSION: The outcomes of the study provide insight into women's responses to receiving PRS and highlight the issues that need to be addressed in the associated model of genetic counseling.


Assuntos
Neoplasias da Mama , Austrália , Neoplasias da Mama/genética , Neoplasias da Mama/psicologia , Feminino , Predisposição Genética para Doença , Humanos , Medidas de Resultados Relatados pelo Paciente , Estudos Prospectivos , Fatores de Risco , Gestão de Riscos
8.
Patient Educ Couns ; 104(10): 2512-2521, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33706980

RESUMO

OBJECTIVE: To describe the communication of polygenic risk scores (PRS) in the familial breast cancer setting. METHODS: Consultations between genetic healthcare providers (GHP) and female patients who received their PRS for breast cancer risk were recorded (n = 65). GHPs included genetic counselors (n = 8) and medical practitioners (n = 5) (i.e. clinical geneticists and oncologists). A content analysis was conducted and logistic regression was used to assess differences in communication behaviors between genetic counselors (n = 8) and medical practitioners (n = 5). RESULTS: Of the 65 patients, 31 (47.7 %) had a personal history of breast cancer, 18 of whom received an increased PRS (relative risk >1.2). 25/34 unaffected patients received an increased PRS. Consultations were primarily clinician-driven and focused on biomedical information. There was little difference between the biomedical information provided by genetic counselors and medical practitioners. However, genetic counselors were significantly more likely to utilize strategies to build patient rapport and counseling techniques. CONCLUSIONS: Our findings provide one of the earliest reports on how breast cancer PRSs are communicated to women. PRACTICE IMPLICATIONS: Key messages for communicating PRSs were identified, namely: discussing differences between polygenic and monogenic testing, the multifactorial nature of breast cancer risk, polygenic inheritance and current limitation of PRSs.


Assuntos
Neoplasias da Mama , Neoplasias da Mama/genética , Feminino , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Herança Multifatorial , Fatores de Risco
9.
Clin Genet ; 97(3): 492-501, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31833054

RESUMO

Polygenic risk scores (PRSs) are increasingly being implemented to assess breast cancer risk. This study aimed to assess and determine factors associated with uptake of PRS among women at increased risk of breast cancer for whom genetic testing to date had been uninformative. Participants were recruited from the Variants in Practice study from which breast cancer PRS had been calculated. Four hundred women were notified by letter of the availability of their PRS and invited to complete a self-administered survey comprising several validated scales. Considering non-participants, uptake of PRS was between 61.8% and 42.1%. Multivariate logistic regression identified that women were more likely to receive their PRS if they reported greater benefits (odds ratio [OR] = 1.17, P = .011) and fewer barriers to receiving their PRS (OR = 0.80, P = .007), had completed higher level education (OR = 3.32, P = .004), and did not have daughters (0.29, P = .006). Uptake of breast cancer PRS varied according to several testing- and patient-related factors. Knowledge of these factors will facilitate the implementation of polygenic testing in clinical practice and support informed decision making by patients.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Testes Genéticos , Herança Multifatorial/genética , Adolescente , Adulto , Idoso , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Análise Multivariada , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Adulto Jovem
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