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1.
J Genet Couns ; 2023 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-37877326

RESUMO

Cascade testing, the site-specific genetic testing of relatives within families with an inherited condition, is underutilized. Long wait times for appointments in specialty genetics clinics are a known barrier to genetic testing access. In our cancer genetics, New Patient Clinic (NPC), the long wait time for an appointment (on average 5 months for routine referrals), was identified by both providers and patients as a barrier to uptake of cascade testing. Timely testing of at-risk relatives is essential to maximize the benefits of cascade testing and reduce cancer morbidity and mortality. Our objective was to improve access via implementation of a different clinical model that designated appointments for patients seeking cascade testing. A secondary goal was to improve use of genetic counselor time. We implemented a dedicated Cascade Testing Clinic (CTC) with an expedited triaging and unique scheduling model to decrease patient wait time to appointment and optimize clinician time. We report on the process and outcomes here. Between October 2016 and February 2020, the average wait time between referral date and first scheduled appointment date was 46 days for the CTC compared to 144 days for the NPC (p < 0.0001). No-show/cancelation/rescheduling rate was 11.7% in the CTC compared to 29.7% in the NPC (p < 0.0001). Genetic counselors saw approximately twice as many patients per half-day clinic in the CTC compared to the NPC (p < 0.00001). Modifications to clinic staffing and appointment times were made based on provider feedback. Implementation of a dedicated clinic specifically for patients seeking cascade testing significantly shortened wait times for this population, reduced patient drop-off, and improved clinician efficiency. The relatively straightforward indications and generally uncomplicated medical histories made this an ideal population for expedited appointments.

2.
J Urol ; 208(5): 1007-1017, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35930793

RESUMO

PURPOSE: Indications for germline testing in prostate cancer patients have expanded substantially over the past decade. With a near-universal shortage of genetic counselors and increasing demand, increased access to genetic counseling is crucial. We sought to prospectively implement and assess a clinician-led approach to genetic counseling and testing. MATERIALS AND METHODS: Patients with metastatic or localized prostate cancer meeting National Comprehensive Cancer Network® criteria for consideration of genetic testing were offered pre-test genetic counseling by their urologist or medical oncologist as part of their routine clinical care and concurrently approached for enrollment in the Germline Genetics in Prostate Cancer Study. Consented patients filled out a post-counseling survey using validated instruments to assess the quality of counseling. For patients who elected to undergo genetic testing, an additional validated questionnaire was completed following disclosure of results. The primary outcome was the proportion of patients undergoing testing, with a target >60% of patients. The secondary outcome was overall satisfaction with counseling, with a target >85% of patients. RESULTS: A total of 275 patients enrolled, and 203 patients elected to undergo genetic testing. Post-counseling surveys were obtained from 265 patients, and post-genetic testing surveys were obtained from 132 patients. Patient satisfaction was high, with 98% of patients reporting being satisfied with the overall quality of pre-test counseling, and 74% of patients elected to undergo genetic testing. CONCLUSIONS: These results support the effectiveness of clinician-led genetic counseling in prostate cancer. With clinician training, this approach can be utilized to expand access to appropriate germline genetic testing.


Assuntos
Aconselhamento Genético , Neoplasias da Próstata , Aconselhamento Genético/métodos , Testes Genéticos , Células Germinativas , Mutação em Linhagem Germinativa , Humanos , Masculino , Satisfação do Paciente , Satisfação Pessoal , Neoplasias da Próstata/genética , Neoplasias da Próstata/terapia
3.
Pediatr Blood Cancer ; 69(9): e29791, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35735208

RESUMO

Next-generation sequencing offers opportunities for targeted cancer therapies and may identify pathogenic germline variants. Adolescents' perception of testing is not well understood. We surveyed 16 adolescents and 59 parents regarding motivations, attitudes, and knowledge related to paired tumor/germline sequencing. Participants generally had a good objective understanding of germline genetics and cancer risk, with parents scoring higher than adolescents. Nearly all participants were motivated by a desire to help other patients and to treat their child/themselves. Most adolescents reported involvement in the decision to enroll in the study. Study findings suggest important similarities and differences between parent and adolescent views.


Assuntos
Comportamento do Adolescente , Neoplasias , Adolescente , Criança , Genômica , Humanos , Neoplasias/genética , Neoplasias/terapia , Pais , Inquéritos e Questionários
4.
J Genet Couns ; 30(2): 544-552, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33118289

RESUMO

Previous work at St. Paul's Hospital Millennium Medical College (SPHMMC) in Addis Ababa, Ethiopia, demonstrated a need for genetic counseling (GC) services, with 4% of pediatric, neonatal intensive care, and prenatal patients identified as having indications for genetic evaluation (Quinonez et al, 2019). The aim of this study was to investigate SPHMMC patients' familiarity with, knowledge of, and attitudes toward GC services. Surveys were adapted from previous work in North America populations (Riesgraf et al, 2015 and Gemmell et al, 2017) and administered to 102 patients, and results were compared to North American populations using Student's t test. 30% of respondents reported at least some familiarity with GC, primarily via the media or healthcare providers. Patients had generally positive attitudes toward GC, reporting they would trust information provided by a genetic counselor and that GC is in line with their values. Knowledge of GC showed similar trends overall when compared to results from North American populations. Our work indicates limited exposure to GC in this population, but generally positive feelings toward GC. Patients' attitudes toward GC were comparable to rural North American populations surveyed using the same tool on most items; however, cultural differences including views on abortions and directiveness of healthcare providers could account for discrepancies and are important considerations when implementing genetic services globally.


Assuntos
Aconselhamento Genético , Hospitais , Atitude , Criança , Estudos Transversais , Etiópia , Feminino , Humanos , Recém-Nascido , Gravidez
5.
Gastroenterology ; 157(1): 87-96, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30935944

RESUMO

BACKGROUND & AIMS: Pathogenic germline variants in CDH1 are associated with risk for diffuse gastric cancer (DGC) and lobular breast cancer. The reported high incidence of DGC and limited sensitivity of endoscopy in detection have prompted recommendation for total prophylactic gastrectomy for carriers of pathogenic or likely pathogenic (PLP) germline variants of CDH1. Multigene panel tests have identified increasing numbers of carriers of PLP variants in CDH1 who lack a family history of DGC. We evaluated outcomes of endoscopic surveillance for carriers of PLP variants of CDH1 with and without family history of DGC. METHODS: Individuals from 13 families with germline PLP variants of CDH1 were evaluated at the Michigan Medicine Cancer Genetics Clinic from January 1998 through May 2018. Outcomes of esophagogastroduodenoscopy examinations, histopathology analyses, and surgery were compared between individuals with and without a family history of DGC. RESULTS: We identified 20 carriers of germline CDH1 PLP variants; they underwent endoscopic examinations and/or gastrectomy. None had abnormal findings visible during endoscopy. Signet ring cell carcinoma (SRCC) was detected in 12 of 20 subjects. All but 1 of the carcinomas were tiny and confined to the lamina propria, and 1 was transmural. Seven of 12 subjects who had SRCC reported no diagnoses of DGC in first-degree relatives and did not meet established criteria for CDH1 analysis based on a 3-generation family pedigree. CONCLUSIONS: More than half of individuals with germlines variants of CDH1 that are PLP had histopathologic evidence for DGC on endoscopy and/or gastrectomy. Family history of DGC and endoscopic findings therefore do not appear to be reliable determinants of risk of SRCC in individuals with genetic predisposition to DGC.


Assuntos
Carcinoma de Células em Anel de Sinete/diagnóstico , Detecção Precoce de Câncer/métodos , Endoscopia do Sistema Digestório , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Gástricas/diagnóstico , Adulto , Idoso , Antígenos CD/genética , Caderinas/genética , Carcinoma de Células em Anel de Sinete/genética , Carcinoma de Células em Anel de Sinete/patologia , Carcinoma de Células em Anel de Sinete/prevenção & controle , Estudos de Casos e Controles , Feminino , Gastrectomia , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Procedimentos Cirúrgicos Profiláticos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Neoplasias Gástricas/prevenção & controle , Adulto Jovem
6.
Genet Med ; 22(12): 2101-2107, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32741965

RESUMO

PURPOSE: Minimal data exist regarding the efficacy of screening protocols for individuals with SDHx germline pathogenic variants with hereditary paraganglioma-pheochromocytoma syndrome. This study aimed to evaluate the SDHx-related tumor detection rate in individuals undergoing clinical screening protocols. METHODS: A multicenter retrospective longitudinal observational study was conducted. Individuals with germline SDHx pathogenic variants underwent clinical whole-body imaging and biochemical testing. RESULTS: Two hundred sixty-three individuals with SDHx germline pathogenic variants completed 491 imaging screens. Individuals with SDHB germline pathogenic variants were most common (n = 188/263, 72%), followed by SDHD (n = 35/263, 13%) and SDHC (n = 28/263, 11%). SDHx-related tumors were found in 17% (n = 45/263) of the cohort. Most SDHx-related tumors were identified on baseline imaging screen (n = 39/46, 85%). Individuals with SDHD pathogenic variants had the highest tumor detection rate (n = 14/35, 40%). Of imaging screens identifying SDHx-related paraganglioma/pheochromocytoma, 29% (n = 12/41) had negative biochemical testing. Secondary actionable findings were identified in 15% (n = 75/491) of imaging screens. CONCLUSION: Current SDHx screening protocols are effective at identifying SDHx-related tumors. Tumor detection rates vary by SDHx gene and screening has the potential to uncover actionable secondary findings. Imaging is an essential part of the screening process as biochemical testing alone does not detect all disease.


Assuntos
Neoplasias das Glândulas Suprarrenais , Paraganglioma , Feocromocitoma , Neoplasias das Glândulas Suprarrenais/diagnóstico por imagem , Neoplasias das Glândulas Suprarrenais/genética , Mutação em Linhagem Germinativa , Humanos , Paraganglioma/diagnóstico por imagem , Paraganglioma/genética , Feocromocitoma/diagnóstico por imagem , Feocromocitoma/genética , Estudos Retrospectivos , Succinato Desidrogenase/genética
7.
J Pediatr Hematol Oncol ; 42(6): e463-e465, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-31259827

RESUMO

Ataxia-telangiectasia is a rare autosomal recessive neurodegenerative disease characterized by ataxia, radiosensitivity, telangiectases, and increased risk for hematologic malignancies. We present a case of a female individual diagnosed with T-cell acute lymphocytic leukemia at 13 years and subsequently with αß subtype of hepatosplenic T-cell lymphoma (HSTCL) at 20 years. During her diagnostic work up for HSTCL, paired tumor-germline sequencing identified a diagnosis of ataxia-telangiectasia. We also describe a very refractory clinical course of her αß HSTCL, including only a brief response to multiagent chemotherapy and an allogenic bone marrow transplant.


Assuntos
Ataxia Telangiectasia/complicações , Neoplasias Hepáticas/patologia , Linfoma de Células T/patologia , Segunda Neoplasia Primária/patologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Neoplasias Esplênicas/patologia , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/etiologia , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/etiologia , Segunda Neoplasia Primária/tratamento farmacológico , Segunda Neoplasia Primária/etiologia , Prognóstico , Neoplasias Esplênicas/tratamento farmacológico , Neoplasias Esplênicas/etiologia , Adulto Jovem
8.
J Urol ; 202(2): 223-230, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30730411

RESUMO

PURPOSE: Until recently the role of germline genetics in prostate cancer care was not well defined. While important questions remain, we reviewed the current understanding of germline genetic alterations related to prostate cancer. We discuss the clinical implications for genetic counseling, genetic testing, early detection and treatment in men with these mutations. MATERIALS AND METHODS: We searched PubMed® for English language articles published since 2001 with the key words "germline mutations," "BRCA," "family history" or "prostate cancer genetics." We also used relevant data from websites, including the Centers for Medicare and Medicaid Services, National Comprehensive Cancer Network®, Bureau of Labor Statistics and National Society of Genetic Counselors websites. RESULTS: A number of germline mutations in DNA damage repair genes ( BRCA1, BRCA2, CHEK2, ATM and PALB2) and in DNA mismatch repair genes ( MLH1, MSH2, MSH6 and PMS2) can drive the development of prostate cancer. Careful genetic counseling coupled with multipanel gene testing can help identify men with these mutations and provide enhanced understanding of the disease risk. Cascade testing of family members can then have an impact extending well beyond the index patient. In men with a pathogenic germline mutation the optimal early detection paradigm is not well defined. Data from the IMPACT study ( ClinicalTrials.gov NCT00261456) that the cancer detection rate is substantially elevated in BRCA1 and BRCA2 carriers at prostate specific antigen greater than 3 ng/ml has helped establish the importance of close prostate specific antigen screening in these men. Additionally, BRCA2 and likely other DNA damage repair mutations are associated with aggressive disease, although it is not yet clear how this impacts localized disease management. However, there is strong evidence that patients with metastatic, castration resistant prostate cancer who have DNA damage repair defects respond positively to targeting PARP enzymes. In many cancers there is also evidence that patients with an increased tumor mutational burden, such as in Lynch syndrome, are particularly sensitive to immune checkpoint inhibitors. CONCLUSIONS: Emerging evidence supports the implementation of germline genetic counseling and testing as a key component of prostate cancer management. Further research is needed to elucidate the clinical significance of lesser known germline mutations and develop optimal screening, early detection and treatment paradigms in this patient population.


Assuntos
Mutação em Linhagem Germinativa , Neoplasias da Próstata/genética , Detecção Precoce de Câncer , Aconselhamento Genético , Testes Genéticos , Humanos , Masculino , Neoplasias da Próstata/terapia
9.
Curr Opin Urol ; 29(4): 371-377, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31033576

RESUMO

PURPOSE OF REVIEW: With the increasing use of precision medicine in oncology, genetic counseling and germline genetic testing are becoming increasingly important in urologic malignancies. In this review, we summarize the most relevant recent literature regarding genetic counseling in prostate and kidney cancers. RECENT FINDINGS: Genetic counseling and testing is considered as an important component of workup for many patients with urologic malignancies but is likely underutilized. Genetic counseling in prostate cancer is a timely topic, especially as the demand for genetic counselors in oncology continues to increase with expanding guidelines for consideration of genetic testing. Genetic testing has historically been limited to only those with the most suspicious histories, but emerging data from larger studies indicates that the clinical presentation of inherited cancer syndromes are broader than previously appreciated. New models need to be developed for pretest counseling to meet increased demand. SUMMARY: Genetic counseling and testing will become increasingly important for patients with urologic malignancies. There is limited literature on this topic, especially related to kidney cancers. Further studies are needed to determine the best way to incorporate genetic counseling and testing into the care of these patients.


Assuntos
Aconselhamento Genético/métodos , Neoplasias Renais/genética , Neoplasias da Próstata/genética , Predisposição Genética para Doença , Testes Genéticos , Humanos , Masculino , Medicina de Precisão , Sobrevivência
11.
Fam Cancer ; 23(3): 221-232, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38573398

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at an advanced stage, resulting in poor prognosis and low 5-year survival rates. While early evidence suggests increased long-term survival in those with screen-detected resectable cancers, surveillance imaging is currently only recommended for individuals with a lifetime risk of PDAC ≥ 5%. Identification of risk factors for PDAC provides opportunities for early detection, risk reducing interventions, and targeted therapies, thus potentially improving patient outcomes. Here, we summarize modifiable and non-modifiable risk factors for PDAC. We review hereditary cancer syndromes associated with risk for PDAC and their implications for patients and their relatives. In addition, other biologically relevant pathways and environmental and lifestyle risk factors are discussed. Future work may focus on elucidating additional genetic, environmental, and lifestyle risk factors that may modify PDAC risk to continue to identify individuals at increased risk for PDAC who may benefit from surveillance and risk reducing interventions.


Assuntos
Carcinoma Ductal Pancreático , Predisposição Genética para Doença , Neoplasias Pancreáticas , Humanos , Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas/genética , Fatores de Risco , Síndromes Neoplásicas Hereditárias/genética , Estilo de Vida
12.
J Community Genet ; 2024 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-39249721

RESUMO

The first genetic counseling (GC) graduate training program was established in the United States (U.S.) in 1969 and GC is an emerging field of healthcare in many countries. Each year, at least 7% of applicants to U.S.-based GC graduate programs come from countries outside the U.S. ("international GC applicants''). To address the unique needs of international GC applicants, volunteers from the International Special Interest Group (ISIG) of the National Society of Genetic Counselors (NSGC) launched a semi-structured mentorship program (the "International Genetic Counseling Mentorship Program'' (IGCMP)) in 2021, which provides individualized mentorship and optional group activities for networking and learning. Fifty-two people from 19 countries signed up for the IGCMP across three application cycles. Of these, 47 were eligible to participate as mentees, and most were interested in one-on-one virtual meetings with international GCs in the U.S. (n = 41/47, 87.2%). An assessment form was sent to 17 mentees who applied to GC graduate school after participating in the first or second cycle of the IGCMP. Of the 12 responses received, 10 (83.3%) reported being extremely satisfied with their individual mentor(s), and the one-on-one meeting with a mentor was considered helpful to both the application and interview process by nine (75.0%) respondents. Importantly, feedback about program improvement revealed an interest in connecting with additional international applicants and mentors and all respondents expressed interest in receiving mentorship throughout graduate school. Future directions include collaborating with other mentorship and graduate programs to further enhance support for international applicants.

13.
JCO Precis Oncol ; 8: e2300539, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38484211

RESUMO

PURPOSE: Paired tumor-germline sequencing can identify somatic variants for targeted therapy and germline pathogenic variants (GPVs) causative of hereditary cancer/tumor predisposition syndromes. It is unknown how patients/families in pediatric oncology use information about an identified GPV. We assessed recall of germline results and actions taken on the basis of findings. METHODS: We completed phone surveys with patients (and/or their parent) with GPVs identified via a single academic medical center's paired tumor-germline sequencing study. Seven hundred forty pediatric (aged 0-25 years) oncology patients were enrolled in this sequencing study between May 2012 and August 2021. Ninety-six participants (13.0%) had at least one GPV identified and were therefore eligible for this survey. The parent/guardian (for patients younger than 18 years or deceased patients) or patients themselves (if 18 years or older) were contacted. Survey topics included germline result recall, experience with genetic counseling, changes to patient's cancer treatment/screening, sharing of results with family members, and lifestyle changes. RESULTS: Fifty-three surveys (response rate, 55.2%) were completed between October 2021 and June 2022. Thirty-seven (69.8%) respondents correctly recalled the identified GPV. Discussing results with a genetic counselor (P = .0001), having a GPV related to the cancer/tumor diagnosis (P = .002), and non-Hispanic White race/ethnicity (P = .02) were associated with accurate recall. Twenty-five respondents (47.2%) reported a change in the child's cancer treatment and/or screening recommendations, 17 respondents (32.1%) made a lifestyle change on the basis of the results, and 44 respondents (83.0%) shared results with at least one family member. CONCLUSION: While most respondents remembered that a GPV was identified in the patient, some did not recall having a GPV found, and others recalled germline findings incorrectly. Future work may determine patient/family preferences for timing/method of result return to optimize patient recall and use of germline results.


Assuntos
Predisposição Genética para Doença , Síndromes Neoplásicas Hereditárias , Humanos , Criança , Predisposição Genética para Doença/genética , Oncologia , Mutação em Linhagem Germinativa/genética , Células Germinativas
14.
Urol Pract ; : 101097UPJ0000000000000727, 2024 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-39383006

RESUMO

PURPOSE: There is increasing awareness that patients with prostate cancer frequently harbor germline variants that may carry important implications for them and their family members. Given the variable clinical guidelines, there remains a need to better understand which patients with prostate cancer are likely to harbor pathogenic or likely pathogenic (P/LP) germline variants. We sought to understand factors associated with P/LP germline variants in patients with metastatic or localized prostate cancer qualifying for National Comprehensive Cancer Network genetic testing criteria. MATERIALS AND METHODS: Patients diagnosed with prostate cancer were offered genetic testing in accordance with National Comprehensive Cancer Network guidelines. Patient-level factors, including demographic, clinical, and pathologic data, were tracked in a prospectively collected registry. The association of the presence of a P/LP variant in germline testing results with patient-level factors was assessed using univariate and multivariate logistic regression. Variables were tested for overall significance with chi-squared tests. RESULTS: Five hundred five patients underwent germline testing and had clinical data available. Rates of P/LP germline variants were 7.6% (20/264) in patients with metastatic disease and 11.2% (27/241) in patients with localized disease. The most prevalent P/LP variants were CHEK2 (34%), BRCA2 (22%), ATM (10%), and HOXB13 (10%). CONCLUSIONS: In this cohort of patients undergoing guideline-informed germline testing, P/LP germline variants were found in similar proportions across all age ranges and clinical characteristics. Only age at genetic testing for patients with metastatic disease was demonstrated to be predictive of the presence of a P/LP germline variant, highlighting the challenges associated with refining current clinical testing guidelines.

15.
Fam Cancer ; 22(3): 295-301, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36437392

RESUMO

Immunohistochemistry (IHC) of cutaneous sebaceous lesions (SL) can be used to screen patients for Lynch syndrome (LS). There is little data on rates of genetic referral and outcomes of genetic testing for patients with SL. This single-center retrospective study characterizes 400 + patients with SL, including IHC results, genetics referrals, and outcomes of genetic testing. Retrospective chart reviews were performed for patients with a pathology-confirmed diagnosis of SL at the University of Michigan between January 2009 and December 2019. 447 patients with 473 SL were identified. Excluding 20 patients with known LS, IHC was conducted in 173 (41%) patients. 92/173 (53%) patients had abnormal results. 69 of these 92 (75%) patients were referred to genetics. 32 additional patients were referred with normal IHC (n = 22) or without IHC (n = 10). Of 101 patients referred, 65 (64%) were seen and 47 (47%) completed genetic testing. 7/47 (15%) had pathogenic variants associated with LS, six with concordant abnormal IHC and one without IHC. Cancer genetics referral of patients with SL, particularly for lesions with abnormal IHC, yields a significant rate of LS diagnosis. Providers should consider genetics referral for patients with SL.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Humanos , Estudos Retrospectivos , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Mutação em Linhagem Germinativa , Testes Genéticos/métodos , Encaminhamento e Consulta , Reparo de Erro de Pareamento de DNA
16.
Eur Urol ; 83(3): 241-248, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36609003

RESUMO

CONTEXT: Prostate cancer (PCa) is a leading cause of death and partially heritable. Genetic risk prediction might be useful for strategies to reduce PCa mortality through early detection and prevention. OBJECTIVE: To review evidence for genetic risk prediction for PCa. EVIDENCE ACQUISITION: A collaborative literature review was conducted using PubMed and Google Scholar. Search terms included genetic, risk, prediction, and "prostate cancer". Articles addressing screening, early detection, or prevention were prioritized, as were studies involving diverse populations. EVIDENCE SYNTHESIS: Rare pathogenic mutations (RPMs), especially in DNA damage repair genes, increase PCa risk. RPMs in BRCA2 are most clearly deleterious, conferring 2-8.6 times higher risk of PCa and a higher risk of aggressive disease. Common genetic variants can be combined into genetic risk scores (GRSs). A high GRS (top 20-25% of the population) confers two to three times higher risk of PCa than average; a very high GRS (top 1-5%) confers six to eight times higher risk. GRSs are not specific for aggressive PCa, possibly due to methodological limitations and/or a field effect of an elevated risk for both low- and high-grade PCa. It is challenging to disentangle genetics from structural racism and social determinants of health to understand PCa racial disparities. GRSs are independently associated with a lethal PCa risk after accounting for family history and race/ancestry. Healthy lifestyle might partially mitigate the risk of lethal PCa. CONCLUSIONS: Genetic risk assessment is becoming more common; implementation studies are needed to understand the implications and to avoid exacerbating healthcare disparities. Men with a high genetic risk of PCa can reasonably be encouraged to adhere to a healthy lifestyle. PATIENT SUMMARY: Prostate cancer risk is inherited through rare mutations and through the combination of hundreds of common genetic markers. Some men with a high genetic risk (especially BRCA2 mutations) likely benefit from early screening for prostate cancer. The risk of lethal prostate cancer can be reduced through a healthy lifestyle.


Assuntos
Próstata , Neoplasias da Próstata , Humanos , Masculino , Detecção Precoce de Câncer , Mutação , Próstata/patologia , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/prevenção & controle , Medição de Risco , Fatores de Risco
17.
Cancer Genet ; 266-267: 15-18, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35644065

RESUMO

Uniparental disomy has long been recognized as a significant cause of genetic disease in imprinting-associated conditions. More recently, it has increasingly been implicated as a potentially significant cause of autosomal recessive disease. Here we report a case of a patient with a history of leukemia and αß hepatosplenic T-cell lymphoma who was diagnosed with ataxia telangiectasia via paired tumor-germline testing at age 20. Germline testing detected a homozygous pathogenic variant in the ATM gene. Parental testing identified this variant only in the mother, leading to suspicion for non-paternity or an atypical cause of autosomal recessive disease. Additional analysis of the proband's sample identified a 54 megabase region at chr11q13.4-q25 with alleles all derived from a single parent, consistent with uniparental isodisomy as causative of autosomal recessive ataxia telangiectasia in this case. This report provides further evidence that uniparental isodisomy should be considered in the potential etiology of autosomal recessive conditions, including in the setting of paired tumor-germline testing. Confirming the method of inheritance is particularly important in cases such as this one where being a heterozygous carrier has medical management implications for cancer screening for relatives as well as for cascade testing and family planning for relatives.


Assuntos
Ataxia Telangiectasia , Linfoma de Células T , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Adulto , Ataxia Telangiectasia/diagnóstico , Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Células Germinativas , Humanos , Linfoma de Células T/genética , Mutação , Dissomia Uniparental/genética , Adulto Jovem
18.
Fam Cancer ; 21(3): 375-385, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-34545504

RESUMO

Advances in cancer genetics have increased germline pathogenic/likely pathogenic variant (PV/LPV) detection rates. More data is needed to inform which patients with previously uninformative results could benefit most from retesting, especially beyond breast/ovarian cancer populations. Here, we describe retesting outcomes and predictors of PV/LPVs in a cohort of patients unselected by cancer diagnosis. Retrospective chart reviews were conducted for patients at a cancer genetics clinic between 1998 and 2019 who underwent genetic testing (GT) on ≥ 2 dates with ≥ 1 year between tests, with no PV/LPVs on first-line GT. Demographics, retesting indications, and GT details were reviewed to evaluate predictive factors of PV/LPV identification. 139 patients underwent retesting, of whom 24 (17.3%) had a PV/LPV, encompassing 15 genes. 14 PV/LPV carriers (58.3%) only returned for retesting after personal or familial history changes (typically new cancer diagnoses), while 10 (41.7%) retested due to updated GT availability. No specific GT method was most likely to identify PV/LPVs and no specific clinical factors were predictive of a PV/LPV. The identified PV/LPVs were consistent with patients' personal or family histories, but were discordant with the initial referral indication for GT. For 16 (66.7%) PV/LPV carriers, the genetic diagnosis changed clinical management. This study adds to the limited body of literature on retesting outcomes beyond first-line BRCA analysis alone and confirms the utility of multigene panel testing. Retesting certain affected individuals when updated GT is available could result in earlier PV/LPV identification, significantly impacting screening recommendations and potentially reducing cancer-related morbidity and mortality.


Assuntos
Neoplasias da Mama , Neoplasias Ovarianas , Neoplasias da Mama/genética , Feminino , Predisposição Genética para Doença , Testes Genéticos/métodos , Humanos , Neoplasias Ovarianas/genética , Estudos Retrospectivos
19.
Cancer Res Commun ; 2(4): 220-232, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-36187937

RESUMO

Ewing sarcoma is a fusion oncoprotein-driven primary bone tumor. A subset of patients (~10%) with Ewing sarcoma are known to harbor germline variants in a growing number of genes involved in DNA damage repair. We recently reported our discovery of a germline mutation in the DNA damage repair protein BARD1 (BRCA1-associated RING domain-1) in a patient with Ewing sarcoma. BARD1 is recruited to the site of DNA double stranded breaks via the poly(ADP-ribose) polymerase (PARP) protein and plays a critical role in DNA damage response pathways including homologous recombination. We thus questioned the impact of BARD1 loss on Ewing cell sensitivity to DNA damage and the Ewing sarcoma transcriptome. We demonstrate that PSaRC318 cells, a novel patient-derived cell line harboring a pathogenic BARD1 variant, are sensitive to PARP inhibition and by testing the effect of BARD1 depletion in additional Ewing sarcoma cell lines, we confirm that BARD1 loss enhances cell sensitivity to PARP inhibition plus radiation. Additionally, RNA-seq analysis revealed that loss of BARD1 results in the upregulation of GBP1 (guanylate-binding protein 1), a protein whose expression is associated with variable response to therapy depending on the adult carcinoma subtype examined. Here, we demonstrate that GBP1 contributes to the enhanced sensitivity of BARD1 deficient Ewing cells to DNA damage. Together, our findings demonstrate the impact of loss-of function mutations in DNA damage repair genes, such as BARD1, on Ewing sarcoma treatment response.


Assuntos
Neoplasias Ósseas , Tumores Neuroectodérmicos Primitivos Periféricos , Sarcoma de Ewing , Humanos , Sarcoma de Ewing/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Dano ao DNA/genética , Reparo do DNA/genética , Neoplasias Ósseas/genética , Poli(ADP-Ribose) Polimerases/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/genética , Proteínas de Ligação ao GTP/genética , Proteína BRCA1/genética
20.
Elife ; 102021 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-34586069

RESUMO

A new software package provides more accurate cancer risk prediction profiles and has the ability to integrate more genes and cancer types in the future.


Assuntos
Neoplasias , Humanos , Neoplasias/epidemiologia , Neoplasias/genética , Linhagem
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