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BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) surveillance is recommended for some individuals with a pathogenic or likely pathogenic variant (PV/LPV) in a PDAC susceptibility gene; the recommendation is often dependent on family history of PDAC. This study aimed to describe PDAC family history in individuals with PDAC who underwent genetic testing to determine the appropriateness of including a family history requirement in these recommendations. METHODS: Individuals with PDAC with a germline heterozygous PV/LPV in ATM, BRCA1, BRCA2, EPCAM, MLH1, MSH2, MSH6, PALB2, or PMS2 (PV/LPV carriers) were assessed for family history of PDAC in first-degree relatives (FDRs) or second-degree relatives (SDRs) from nine institutions. A control group of individuals with PDAC without a germline PV/LPV was also assessed. RESULTS: The study included 196 PV/LPV carriers and 1184 controls. In the PV/LPV carriers, 25.5% had an affected FDR and/or SDR compared to 16.9% in the control group (p = .004). PV/LPV carriers were more likely to have an affected FDR compared to the controls (p = .003) but there was no statistical difference when assessing only affected SDRs (p = .344). CONCLUSIONS: Most PV/LPV carriers who developed PDAC did not have a close family history of PDAC and would not have met most current professional societies' recommendations for consideration of PDAC surveillance before diagnosis. However, PV/LPV carriers were significantly more likely to have a family history of PDAC, particularly an affected FDR. These findings support family history as a risk modifier in PV/LPV carriers, and highlight the need to identify other risk factors.
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BACKGROUND: Pancreatic adenocarcinoma (PC) is a highly lethal malignancy with a survival rate of only 12%. Surveillance is recommended for high-risk individuals (HRIs), but it is not widely adopted. To address this unmet clinical need and drive early diagnosis research, we established the Pancreatic Cancer Early Detection (PRECEDE) Consortium. METHODS: PRECEDE is a multi-institutional international collaboration that has undertaken an observational prospective cohort study. Individuals (aged 18-90 years) are enrolled into 1 of 7 cohorts based on family history and pathogenic germline variant (PGV) status. From April 1, 2020, to November 21, 2022, a total of 3,402 participants were enrolled in 1 of 7 study cohorts, with 1,759 (51.7%) meeting criteria for the highest-risk cohort (Cohort 1). Cohort 1 HRIs underwent germline testing and pancreas imaging by MRI/MR-cholangiopancreatography or endoscopic ultrasound. RESULTS: A total of 1,400 participants in Cohort 1 (79.6%) had completed baseline imaging and were subclassified into 3 groups based on familial PC (FPC; n=670), a PGV and FPC (PGV+/FPC+; n=115), and a PGV with a pedigree that does not meet FPC criteria (PGV+/FPC-; n=615). One HRI was diagnosed with stage IIB PC on study entry, and 35.1% of HRIs harbored pancreatic cysts. Increasing age (odds ratio, 1.05; P<.001) and FPC group assignment (odds ratio, 1.57; P<.001; relative to PGV+/FPC-) were independent predictors of harboring a pancreatic cyst. CONCLUSIONS: PRECEDE provides infrastructure support to increase access to clinical surveillance for HRIs worldwide, while aiming to drive early PC detection advancements through longitudinal standardized clinical data, imaging, and biospecimen captures. Increased cyst prevalence in HRIs with FPC suggests that FPC may infer distinct biological processes. To enable the development of PC surveillance approaches better tailored to risk category, we recommend adoption of subclassification of HRIs into FPC, PGV+/FPC+, and PGV+/FPC- risk groups by surveillance protocols.
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Adenocarcinoma , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/epidemiologia , Detecção Precoce de Câncer/métodos , Estudos Prospectivos , Predisposição Genética para Doença , Imageamento por Ressonância MagnéticaRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with a dismal survival rate. Screening the general population for early detection of PDAC is not recommended, but because early detection improves survival, high-risk individuals, defined as those meeting criteria based on a family history of PDAC and/or the presence of known pathogenic germline variant genes with PDAC risk, are recommended to undergo screening with MRI and/or endoscopic ultrasound at regular intervals. The Pancreatic Cancer Early Detection (PRECEDE) Consortium was formed in 2018 and is composed of gastroenterologists, geneticists, pancreatic surgeons, radiologists, statisticians, and researchers from 40 sites in North America, Europe, and Asia. The overarching goal of the PRECEDE Consortium is to facilitate earlier diagnosis of PDAC for high-risk individuals to increase survival of the disease. A standardized MRI protocol and reporting template are needed to enhance the quality of screening examinations, improve consistency of clinical management, and facilitate multiinstitutional research. We present a consensus statement to standardize MRI screening and reporting for individuals with elevated risk of pancreatic cancer.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Detecção Precoce de Câncer , Carcinoma Ductal Pancreático/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/genética , Imageamento por Ressonância Magnética , Padrões de Referência , Neoplasias PancreáticasRESUMO
BACKGROUND: Early detection of pancreatic ductal adenocarcinoma (PDAC) is an important goal for improving survival. Individuals who meet published guidelines for surveillance may be underidentified, and family communication about risk represents a pathway to increasing participation in surveillance. We investigated the uptake of and barriers to surveillance in at-risk relatives of clinic patients. METHODS: We conducted a retrospective record review of patients with personal or family history of PDAC evaluated over 12 months. The first relative presenting to clinic (proband) reported surveillance status and reasons for nonparticipation for at-risk relatives. Descriptive analyses and Fisher's exact tests were conducted to evaluate differences in surveillance participation. RESULTS: Among 193 at-risk relatives, 21% were in surveillance. The primary reasons for nonparticipation were lack of awareness (36%) and lack of interest (24%). Neither the sex nor the cancer status of probands impacted surveillance. At-risk relatives with familial pancreatic cancer (FPC) who also carried relevant pathogenic germline variants (PGVs) were more likely to undergo surveillance than those with FPC or PGVs alone (P = .003). Among families with PGVs, 59% of relatives potentially eligible for surveillance had not completed genetic testing. CONCLUSION: PDAC surveillance is underutilized in high-risk families. Communication interventions to address informational needs and decisional support could improve outcomes.
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Adenocarcinoma , Neoplasias Pancreáticas , Adenocarcinoma/diagnóstico , Adenocarcinoma/epidemiologia , Adenocarcinoma/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/genética , Estudos RetrospectivosRESUMO
BACKGROUND: Advances in genetics and sequencing technologies are enabling the identification of more individuals with inherited cancer susceptibility who could benefit from tailored screening and prevention recommendations. While cancer family history information is used in primary care settings to identify unaffected patients who could benefit from a cancer genetics evaluation, this information is underutilized. System-level population health management strategies are needed to assist health care systems in identifying patients who may benefit from genetic services. In addition, because of the limited number of trained genetics specialists and increasing patient volume, the development of innovative and sustainable approaches to delivering cancer genetic services is essential. METHODS: We are conducting a randomized controlled trial, entitled Broadening the Reach, Impact, and Delivery of Genetic Services (BRIDGE), to address these needs. The trial is comparing uptake of genetic counseling, uptake of genetic testing, and patient adherence to management recommendations for automated, patient-directed versus enhanced standard of care cancer genetics services delivery models. An algorithm-based system that utilizes structured cancer family history data available in the electronic health record (EHR) is used to identify unaffected patients who receive primary care at the study sites and meet current guidelines for cancer genetic testing. We are enrolling eligible patients at two healthcare systems (University of Utah Health and New York University Langone Health) through outreach to a randomly selected sample of 2780 eligible patients in the two sites, with 1:1 randomization to the genetic services delivery arms within sites. Study outcomes are assessed through genetics clinic records, EHR, and two follow-up questionnaires at 4 weeks and 12 months after last genetic counseling contactpre-test genetic counseling. DISCUSSION: BRIDGE is being conducted in two healthcare systems with different clinical structures and patient populations. Innovative aspects of the trial include a randomized comparison of a chatbot-based genetic services delivery model to standard of care, as well as identification of at-risk individuals through a sustainable EHR-based system. The findings from the BRIDGE trial will advance the state of the science in identification of unaffected patients with inherited cancer susceptibility and delivery of genetic services to those patients. TRIAL REGISTRATION: BRIDGE is registered as NCT03985852 . The trial was registered on June 6, 2019 at clinicaltrials.gov .
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Aconselhamento Genético , Neoplasias , Criança , Feminino , Testes Genéticos , Humanos , Recém-Nascido , Neoplasias/genética , Neoplasias/terapia , New York , Gravidez , Atenção Primária à SaúdeRESUMO
The originally published version of this Article contained errors in Fig. 2. The numbers below the black arrowheads were incorrect; please see incorrect Figure in associated Correction. These errors have now been corrected in the PDF and HTML versions of the Article.
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PURPOSE: Clinical sequencing emerging in health care may result in secondary findings (SFs). METHODS: Seventy-four of 6240 (1.2%) participants who underwent genome or exome sequencing through the Clinical Sequencing Exploratory Research (CSER) Consortium received one or more SFs from the original American College of Medical Genetics and Genomics (ACMG) recommended 56 gene-condition pair list; we assessed clinical and psychosocial actions. RESULTS: The overall adjusted prevalence of SFs in the ACMG 56 genes across the CSER consortium was 1.7%. Initially 32% of the family histories were positive, and post disclosure, this increased to 48%. The average cost of follow-up medical actions per finding up to a 1-year period was $128 (observed, range: $0-$678) and $421 (recommended, range: $141-$1114). Case reports revealed variability in the frequency of and follow-up on medical recommendations patients received associated with each SF gene-condition pair. Participants did not report adverse psychosocial impact associated with receiving SFs; this was corroborated by 18 participant (or parent) interviews. All interviewed participants shared findings with relatives and reported that relatives did not pursue additional testing or care. CONCLUSION: Our results suggest that disclosure of SFs shows little to no adverse impact on participants and adds only modestly to near-term health-care costs; additional studies are needed to confirm these findings.
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Testes Genéticos/economia , Achados Incidentais , Sequenciamento Completo do Genoma/ética , Adulto , Tomada de Decisões/ética , Revelação , Exoma , Feminino , Testes Genéticos/ética , Testes Genéticos/normas , Genômica/métodos , Custos de Cuidados de Saúde , Conhecimentos, Atitudes e Prática em Saúde , Pessoal de Saúde , Sequenciamento de Nucleotídeos em Larga Escala/ética , Humanos , Intenção , Masculino , Pacientes , Prevalência , Sequenciamento Completo do Genoma/economiaRESUMO
The amount of information produced by genomic sequencing is vast, technically complicated, and can be difficult to interpret. Appropriately tailoring genomic information for non-geneticists is an essential next step in the clinical use of genomic sequencing. To initiate development of a framework for genomic results communication, we conducted eighteen qualitative interviews with oncologists who had referred adult cancer patients to a matched tumor-normal tissue genomic sequencing study. In our qualitative analysis, we found varied levels of clinician knowledge relating to sequencing technology, the scope of the tumor genomic sequencing study, and incidental germline findings. Clinicians expressed a perceived need for more genetics education. Additionally, they had a variety of suggestions for improving results reports and possible resources to aid in results interpretation. Most clinicians felt genetic counselors were needed when incidental germline findings were identified. Our research suggests that more consistent genetics education is imperative in ensuring the proper utilization of genomic sequencing in cancer care. Clinician suggestions for results interpretation resources and results report modifications could be used to improve communication. Clinicians' perceived need to involve genetic counselors when incidental germline findings were found suggests genetic specialists could play a critical role in ensuring patients receive appropriate follow-up.
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Atitude do Pessoal de Saúde , Aconselhamento Genético , Testes Genéticos , Neoplasias/genética , Oncologistas/estatística & dados numéricos , Adulto , Competência Clínica , Feminino , Genômica , Humanos , Achados Incidentais , Oncologia/normasAssuntos
Detecção Precoce de Câncer/normas , Endossonografia/normas , Testes Genéticos/normas , Anamnese/normas , Neoplasias Pancreáticas/diagnóstico , Adulto , Idoso , Tomada de Decisão Clínica , Feminino , Predisposição Genética para Doença , Hereditariedade , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Linhagem , Valor Preditivo dos Testes , Prognóstico , Fatores de RiscoRESUMO
Next generation sequencing technology is increasingly utilized in oncology with the goal of targeting therapeutics to improve response and reduce side effects. Interpretation of tumor mutations requires sequencing of paired germline DNA, raising questions about incidental germline findings. We describe our experiences as part of a research team implementing a protocol for whole genome sequencing (WGS) of tumors and paired germline DNA known as the Michigan Oncology Sequencing project (MI-ONCOSEQ) that includes options for receiving incidental germline findings. Genetic counselors (GCs) discuss options for return of results with patients during the informed consent process and document family histories. GCs also review germline findings and actively participate in the multi-disciplinary Precision Medicine Tumor Board (PMTB), providing clinical context for interpretation of germline results and making recommendations about disclosure of germline findings. GCs have encountered ethical and counseling challenges with participants, described here. Although GCs have not been traditionally involved in molecular testing of tumors, our experiences with MI-ONCOSEQ demonstrate that GCs have important applicable skills to contribute to multi-disciplinary care teams implementing precision oncology. Broader use of WGS in oncology treatment decision making and American College of Medical Genetics and Genomics (ACMG) recommendations for active interrogation of germline tissue in tumor-normal dyads suggests that GCs will have future opportunities in this area outside of research settings.
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Aconselhamento Genético , Neoplasias/genética , Humanos , Papel ProfissionalRESUMO
BACKGROUND: Genetic testing is recommended for all pancreatic ductal adenocarcinoma (PDAC) patients. Prior research demonstrates that multidisciplinary pancreatic cancer clinics (MDPCs) improve treatment- and survival-related outcomes for PDAC patients. However, limited information exists regarding the utility of integrated genetics in the MDPC setting. We hypothesized that incorporating genetics in an MDPC serving both PDAC patients and high-risk individuals (HRI) could: (1) improve compliance with guideline-based genetic testing for PDAC patients, and (2) optimize HRI identification and PDAC surveillance participation to improve early detection and survival. METHODS: Demographics, genetic testing results, and pedigrees were reviewed for PDAC patients and HRI at one institution over 45 months. Genetic testing analyzed 16 PDAC-associated genes at minimum. RESULTS: Overall, 969 MDPC subjects were evaluated during the study period; another 56 PDAC patients were seen outside the MDPC. Among 425 MDPC PDAC patients, 333 (78.4%) completed genetic testing; 29 (8.7%) carried a PDAC-related pathogenic germline variant (PGV). Additionally, 32 (9.6%) met familial pancreatic cancer (FPC) criteria. These PDAC patients had 191 relatives eligible for surveillance or genetic testing. Only 2/56 (3.6%) non-MDPC PDAC patients completed genetic testing (p < 0.01). Among 544 HRI, 253 (46.5%) had a known PGV or a designation of FPC, and were eligible for surveillance at baseline; of the remainder, 15/291 (5.2%) were eligible following genetic testing and PGV identification. CONCLUSION: Integrating genetics into the multidisciplinary setting significantly improved genetic testing compliance by reducing logistical barriers for PDAC patients, and clarified cancer risks for their relatives while conserving clinical resources. Overall, we identified 206 individuals newly eligible for surveillance or genetic testing (191 relatives of MDPC PDAC patients, and 15 HRI from this cohort), enabling continuity of care for PDAC patients and at-risk relatives in one clinic.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Predisposição Genética para Doença , Neoplasias Pancreáticas/patologia , Testes Genéticos , Carcinoma Ductal Pancreático/patologia , Neoplasias PancreáticasRESUMO
Since its inception two years ago, the international, multicenter Pancreatic Cancer Early Detection (PRECEDE) Consortium has enrolled high-risk individuals (HRI) undergoing pancreatic ductal adenocarcinoma (PDAC) surveillance. Herein we aim to evaluate enrollment disparities in PRECEDE. Data on HRIs enrolled between May 2020 and March 2022 were collected, with HRIs defined as participants enrolled in PRECEDE meeting guideline-based criteria for PDAC surveillance. Of 1,273 HRIs enrolled, 1,113 were eligible for inclusion, with 47.2% meeting familial pancreatic cancer criteria without a known pathogenic variant (PV) and the remainder having a pathogenic variant in a PDAC-risk gene (CDKN2A, STK11, PRSS1, BRCA1, BRCA2, PALB2, ATM, MLH1, MSH2, MSH6, PMS2, or EPCAM). Study participants were predominantly from the United States (82.7%), the most common age range at enrollment was 60-69 years (37.4%), and a non-PDAC cancer was present in 32.4%. There were racial/ethnic- and sex-based disparities among enrolled subjects, as the majority of participants were female (65.9%) and self-reported white (87.7%), with only 2.9% having Hispanic ethnicity. While more than 97% of participants consented to utilize imaging data and biosamples for research, there was no difference in rate of consent based on race/ethnicity, sex, or age, thereby demonstrating uniform participation in research activities among all subgroups after enrollment. Ensuring that diversity of HRIs in PDAC surveillance programs mirrors the communities served by participating centers is important. Substantial racial/ethnic- and sex-based disparities persist among recently enrolled HRIs undergoing PDAC surveillance, and therefore reducing these disparities will be a major focus of the PRECEDE Consortium moving forward. PREVENTION RELEVANCE: Pancreatic cancer surveillance is critical to decreasing pancreatic cancer mortality; therefore, it is important that pancreatic cancer surveillance studies enroll diverse patients. We demonstrate that substantial racial/ethnic- and sex-based disparities exist amongst enrollment in the international PRECEDE consortium, highlighting the dire need for future efforts to reduce these disparities. See related Spotlight, p. 305.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Masculino , Feminino , Estados Unidos , Pessoa de Meia-Idade , Idoso , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/genética , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/epidemiologia , Carcinoma Ductal Pancreático/genética , Pâncreas/patologia , Etnicidade , Neoplasias PancreáticasRESUMO
Changing practice guidelines and recommendations have important implications for cancer survivors. This study investigated genetic testing patterns and outcomes and reported family history of pancreatic cancer (FHPC) in a large registry population of breast cancer (BC) patients. Variables including clinical and demographic characteristics, FHPC in a first or second-degree relative, and genetic testing outcomes were analyzed for BC patients diagnosed between 2010 and 2018 in the NYU Langone Health Breast Cancer Database. Among 3334 BC patients, 232 (7%) had a positive FHPC. BC patients with FHPC were 1.68 times more likely to have undergone genetic testing (p < 0.001), but 33% had testing for BRCA1/2 only and 44% had no genetic testing. Pathogenic germline variants (PGV) were identified in 15/129 (11.6%) BC patients with FHPC, and in 145/1315 (11.0%) BC patients without FHPC. Across both groups, updates in genetic testing criteria and recommendations could impact up to 80% of this cohort. Within a contemporary cohort of BC patients, 7% had a positive FHPC. The majority of these patients (56%) had no genetic testing, or incomplete testing by current standards, suggesting under-diagnosis of PC risk. This study supports recommendations for survivorship care that incorporate ongoing genetic risk assessment and counseling.
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Neoplasias da Mama Masculina/mortalidade , Neoplasias da Mama/mortalidade , Testes Genéticos/normas , Neoplasias Pancreáticas/diagnóstico , Guias de Prática Clínica como Assunto , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Neoplasias da Mama Masculina/genética , Neoplasias da Mama Masculina/terapia , Sobreviventes de Câncer/estatística & dados numéricos , Detecção Precoce de Câncer/métodos , Detecção Precoce de Câncer/normas , Detecção Precoce de Câncer/estatística & dados numéricos , Feminino , Aconselhamento Genético/normas , Aconselhamento Genético/estatística & dados numéricos , Predisposição Genética para Doença , Testes Genéticos/estatística & dados numéricos , Humanos , Estudos Longitudinais , Masculino , Anamnese/estatística & dados numéricos , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/prevenção & controle , Sistema de Registros/estatística & dados numéricos , SobrevivênciaAssuntos
Adenoma Oxífilo/diagnóstico , Síndrome de Birt-Hogg-Dubé/diagnóstico , Neoplasias Renais/diagnóstico , Adenoma Oxífilo/complicações , Síndrome de Birt-Hogg-Dubé/complicações , Feminino , Humanos , Neoplasias Renais/complicações , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Linhagem , FenótipoRESUMO
Genetic testing (GT) for inherited cancer predisposition is most informative when initiated in individuals with cancer, thus standard practice recommends GT start in an affected individual. This strategy can be frustrating for unaffected consultands and providers. Retrospective review of cases was performed to compare outcomes of testing the unaffected consultand and recommending that testing start in an affected relative. Records from cancer-free consultands (N = 101), presenting to the University of Michigan Cancer Genetics Clinic between 6/1/2011 and 12/30/2011 were reviewed. All genetics records for these consultands were reviewed through 3/31/2013 for GT recommendations (117 total). The unaffected consultand was offered testing in 14.5 % of cases, testing was completed in 64.7 % of these with one mutation identified. Of consultands tested initially, 70.5 % received cancer-screening recommendations based on family history and test results. Testing was recommended to start in an affected family member in 30.7 % of cases. Fifty percent returned to clinic with information on an affected family member; 83.3 % documented that their family member underwent GT with one mutation identified. Consultands reported the affected family member refused testing in 22.2 % and two of these consultands subsequently pursued GT, identifying one mutation. Fifty percent of cases where testing the family member first was recommended were lost to follow-up with 66.6 % of these never given cancer-screening recommendations. Cancer genetic risk evaluation of healthy consultands should consider the option of pursuing GT in the unaffected consultand and should implement a plan for tailored risk management in the absence of informative genetic evaluation within the family.
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Detecção Precoce de Câncer , Testes Genéticos , Síndromes Neoplásicas Hereditárias/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Família , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
CONTEXT: Mutations in the genes encoding subunits of the succinate dehydrogenase complex cause hereditary paraganglioma syndromes. Although the phenotypes associated with the more commonly mutated genes, SDHB and SDHD, are well described, less is known about SDHC-associated paragangliomas. OBJECTIVE: To describe functionality, penetrance, number of primary tumors, biological behavior, and location of paragangliomas associated with SDHC mutations. DESIGN: Families with an SDHC mutation were identified through a large cancer genetics registry. A retrospective chart review was conducted with a focus on patient and tumor characteristics. In addition, clinical reports on SDHC-related paragangliomas were identified in the medical literature to further define the phenotype and compare findings. SETTING: A cancer genetics clinic and registry at a tertiary referral center. PATIENTS: Eight index patients with SDHC-related paraganglioma were identified. RESULTS: Three of the eight index patients had mediastinal paraganglioma and four of the eight patients had more than one paraganglioma. Interestingly, the index patients were the only affected individuals in all families. When combining these index cases with reported cases in the medical literature, the mediastinum is the second most common location for SDHC-related paraganglioma (10% of all tumors), occurring in up to 13% of patients. CONCLUSIONS: Our findings suggest that thoracic paragangliomas are common in patients with SDHC mutations, and imaging of this area should be included in surveillance of mutation carriers. In addition, the absence of paragangliomas among at-risk relatives of SDHC mutation carriers suggests a less penetrant phenotype as compared to SDHB and SDHD mutations.
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Neoplasias de Cabeça e Pescoço/genética , Neoplasias do Mediastino/genética , Proteínas de Membrana/genética , Síndromes Neoplásicas Hereditárias/genética , Paraganglioma/genética , Adolescente , Adulto , Família , Feminino , Predisposição Genética para Doença , Neoplasias de Cabeça e Pescoço/epidemiologia , Humanos , Masculino , Neoplasias do Mediastino/epidemiologia , Mutação , Síndromes Neoplásicas Hereditárias/epidemiologia , Paraganglioma/epidemiologia , Penetrância , Fenótipo , Sistema de Registros/estatística & dados numéricos , Estudos Retrospectivos , Síndrome , Adulto JovemRESUMO
IMPORTANCE Sebaceous neoplasms (SNs) define the Muir-Torre syndrome variant of Lynch syndrome (LS), which is associated with increased risk for colon and other cancers necessitating earlier and more frequent screening to reduce morbidity and mortality.Immunohistochemical (IHC) staining for mismatch repair (MMR) proteins in SNs can be used to screen for LS, but data on subsequent germline genetic testing to confirm LS diagnosis are limited.OBJECTIVE To characterize the utility of IHC screening of SNs in identification of germline MMR mutations confirming LS.DESIGN, SETTING, AND PARTICIPANTS Retrospective study at 2 academic cancer centers of 86 adult patients referred for clinical genetics evaluation after diagnosis of SN.MAIN OUTCOMES AND MEASURES Results of tumor IHC testing and germline genetic testing were reviewed to determine positive predictive value and sensitivity of IHC testing in diagnosis of LS. Clinical variables, including age at diagnosis of SN, clinical diagnostic criteria for LS and Muir-Torre syndrome, and family history characteristics were compared between mutation carriers and noncarriers.RESULTS Of 86 patients with SNs, 25 (29%) had germline MMR mutations confirming LS.Among 77 patients with IHC testing on SNs, 38 (49%) had loss of staining of 1 or more MMR proteins and 14 had germline MMR mutations. Immunohistochemical analysis correctly identified 13 of 16 MMR mutation carriers, corresponding to 81% sensitivity. Ten of 12 patients(83%) with more than 1 SN had MMR mutations. Fifty-two percent of MMR mutation carriers did not meet clinical diagnostic criteria for LS, and 11 of 25 (44%) did not meet the clinical definition of Muir-Torre syndrome. CONCLUSIONS AND RELEVANCE Immunohistochemical screening of SNs is effective in identifying patients with germline MMR mutations and can be used as a first-line test when LSis suspected. Abnormal IHC results, including absence of MSH2, are not diagnostic of LS and should be interpreted cautiously in conjunction with family history and germline genetic testing. Use of family history to select patients for IHC screening has substantial limitations,suggesting that universal IHC screening of SNs merits further study. Clinical genetics evaluation is warranted for patients with abnormal IHC test results, normal IHC test results with personal or family history of other LS-associated neoplasms, and/or multiple SNs.
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Reparo de Erro de Pareamento de DNA/genética , Mutação em Linhagem Germinativa , Síndrome de Muir-Torre/diagnóstico , Síndrome de Muir-Torre/genética , Proteínas Adaptadoras de Transdução de Sinal/análise , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenosina Trifosfatases/análise , Adenosina Trifosfatases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Antígenos de Neoplasias/análise , Antígenos de Neoplasias/genética , Moléculas de Adesão Celular/análise , Moléculas de Adesão Celular/genética , Enzimas Reparadoras do DNA/análise , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/análise , Proteínas de Ligação a DNA/genética , Molécula de Adesão da Célula Epitelial , Feminino , Testes Genéticos , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS/análise , Proteína 2 Homóloga a MutS/genética , Proteínas Nucleares/análise , Proteínas Nucleares/genética , Valor Preditivo dos Testes , Estudos RetrospectivosRESUMO
PURPOSE: Adrenocortical carcinoma (ACC) is a hallmark cancer in families with Li Fraumeni syndrome (LFS) caused by mutations in the TP53 gene. The prevalence of germline TP53 mutations in children diagnosed with ACC ranges from 50-97%. Although existing criteria advocate for TP53 testing in all patients with ACC regardless of age at diagnosis, the overall prevalence of germline mutations in patients diagnosed with ACC has not been well studied. PATIENTS AND METHODS: A total of 114 patients with confirmed ACC evaluated in the University of Michigan Endocrine Oncology Clinic were prospectively offered genetic counseling and TP53 genetic testing, regardless of age at diagnosis or family history. Ninety-four of the 114 patients met with a genetic counselor (82.5%), with 53 of 94 (56.4%) completing TP53 testing; 9.6% (nine of 94) declined testing. The remainder (32 of 94; 34%) expressed interest in testing but did not pursue it for various reasons. RESULTS: Four of 53 patients in this prospective, unselected series were found to have a TP53 mutation (7.5%). The prevalence of mutations in those diagnosed over age 18 was 5.8% (three of 52). There were insufficient data to estimate the prevalence in those diagnosed under age 18. None of these patients met clinical diagnostic criteria for classic LFS. Three of the families met criteria for Li Fraumeni-like syndrome; one patient met no existing clinical criteria for LFS or Li Fraumeni-like syndrome. Three of the four patients with mutations were diagnosed with ACC after age 45. CONCLUSIONS: Genetic counseling and germline testing for TP53 should be offered to all patients with ACC. Restriction on age at diagnosis or strength of the family history would fail to identify mutation carriers.
Assuntos
Neoplasias do Córtex Suprarrenal/genética , Carcinoma Adrenocortical/genética , Genes p53/genética , Mutação em Linhagem Germinativa , Adolescente , Neoplasias do Córtex Suprarrenal/diagnóstico , Neoplasias do Córtex Suprarrenal/epidemiologia , Carcinoma Adrenocortical/diagnóstico , Carcinoma Adrenocortical/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Frequência do Gene , Aconselhamento Genético , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Prevalência , Estudos Prospectivos , Adulto JovemRESUMO
PURPOSE: Adrenocortical carcinoma (ACC) is an endocrine malignancy with a poor prognosis. The association of adult-onset ACC with inherited cancer predisposition syndromes is poorly understood. Our study sought to define the prevalence of Lynch syndrome (LS) among patients with ACC. PATIENTS AND METHODS: One hundred fourteen patients with ACC were evaluated in a specialized endocrine oncology clinic and were prospectively offered genetic counseling and clinical genetics risk assessment (group 1). In addition, families with known mismatch repair (MMR) gene mutations that were recorded in the University of Michigan Cancer Genetics Registry were retrospectively reviewed for the presence of ACC (group 2). ACC tumors from patients with LS were tested for microsatellite instability and immunohistochemistry (IHC) to evaluate for MMR deficiency. RESULTS: Ninety-four (82.5%) of 114 patients with ACC underwent genetic counseling (group 1). Three individuals (3.2%) had family histories suggestive of LS. All three families were found to have MMR gene mutations. Retrospective review of an additional 135 MMR gene-positive probands identified two with ACC (group 2). Four ACC tumors were available (group 1, 3; group 2, 1). All four tumors were microsatellite stable; three had IHC staining patterns consistent with germline mutation status. CONCLUSION: The prevalence of LS among patients with ACC is 3.2%, which is comparable to the prevalence of LS in colorectal and endometrial cancer. Patients with ACC and a personal or family history of LS tumors should be strongly considered for genetic risk assessment. IHC screening of all ACC tumors may be an effective strategy for identifying patients with LS.