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BACKGROUND: Lynch Syndrome is among the most common hereditary cancer syndromes and requires ongoing cancer surveillance, repeated screenings and potential risk-reducing surgeries. Despite the importance of continued surveillance, there is limited understanding of patient experiences after initial testing and counseling, the barriers or facilitators they experience adhering to recommendations, and how they want to receive information over time. METHODS: A cross-sectional, observational study was conducted among 127 probands and family members who had received genetic testing for Lynch Syndrome. We conducted semi-structured interviews to determine proband and family member experiences after receiving genetic testing results including their surveillance and screening practices, information needs, and interactions with health care providers. Both closed-ended and open-ended data were collected and analyzed. RESULTS: Both probands (96.9%) and family members (76.8%) received recommendations for follow-up screening and all probands (100%) and most family members (98.2%) who tested positive had completed at least one screening. Facilitators to screening included receiving screening procedure reminders and the ease of making screening and surveillance appointments. Insurance coverage to pay for screenings was a frequent concern especially for those under 50 years of age. Participants commented that their primary care providers were often not knowledgeable about Lynch Syndrome and surveillance recommendations; this presented a hardship in navigating ongoing surveillance and updated information. Participants preferred information from a knowledgeable health care provider or a trusted internet source over social media or support groups. CONCLUSIONS: Probands and family members receiving genetic testing for Lynch Syndrome generally adhered to initial screening and surveillance recommendations. However, factors such as insurance coverage and difficulty finding a knowledgeable healthcare provider presented barriers to receiving recommended follow-up care. There is an opportunity to improve care through better transitions in care, procedures to keep primary care providers informed of surveillance guidelines, and practices so that patients receive reminders and facilitated appointment setting for ongoing screening and surveillance at the time they are due.
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INTRODUCTION: Patients with serrated polyposis syndrome (SPS) and their first-degree relatives (FDRs) have increased colorectal cancer (CRC) risk. Patients with sporadic sessile serrated lesion (SSL) have risk for progression to CRC. Yet familial risks of common extracolonic cancers and even CRC in these cohorts are poorly understood. Our aim was to examine cancer risk for patients with SPS and sporadic SSL and their close and more distant relatives using a large population database. METHODS: Patients with SPS (n = 59) from hereditary patient registries were eligible for study. Sporadic SSL (n = 754) and sex- and age-matched normal colonoscopy controls (n = 1,624) were selected from clinical data linked to the Utah Population Database. Cox models adjusting for the number of relatives, degree of relatedness, and person-years at risk were used to estimate CRC, extracolonic, and any-site adenocarcinoma/carcinoma cancer risk in patients and their relatives. RESULTS: Compared with controls, CRC risk was elevated 10-fold in patients with SPS (P = 0.04) and 5-fold in their FDRs (P = 0.001). Any-site adenoma/carcinoma risk was increased 2.6-fold in FDRs of patients with SPS. No elevated risks of other common extracolonic cancers were observed in SPS and family members. The FDRs, second-degree relatives, and third-degree relatives of patients with both SSL and adenomatous polyps exhibited a 50% increased CRC risk. DISCUSSION: Patients with SPS and their FDRs have an increased CRC risk, confirming other reports. Interestingly, patients with SSL were noted to have an increased risk of prostate cancer. Relatives of individuals with both sporadic SSL and adenomas, irrespective of size or dysplasia on examination, may have an elevated CRC risk, suggesting closer colonoscopy surveillance in this population.
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Adenocarcinoma/diagnóstico , Polipose Adenomatosa do Colo/diagnóstico , Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer/métodos , Predisposição Genética para Doença , Sistema de Registros , Medição de Risco/métodos , Adenocarcinoma/epidemiologia , Polipose Adenomatosa do Colo/etiologia , Polipose Adenomatosa do Colo/genética , Idoso , Colonoscopia/métodos , Neoplasias Colorretais/epidemiologia , Diagnóstico Diferencial , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Linhagem , Estudos Retrospectivos , Fatores de Risco , Síndrome , Utah/epidemiologiaRESUMO
While there are several public repositories of biological sequence variation data and associated annotations, there is little open-source tooling designed specifically for the upkeep of local collections of variant data. Many clinics curate and maintain such local collections and are burdened by frequent changes in the representation of those variants and evolving interpretations of clinical significance. A dictionary of genetic variants from the Huntsman Cancer Institute was analyzed over a period of two years and used to inform the development of LocalVar. This tool uses publicly available ClinVar files to provide the following functionality: auto-complete search bar to pre-empt duplicate entries; single or bulk new variant record entry; auto-detection of duplicate and synonymous variant records; asynchronous suggestion of HGVS expression or variant interpretation updates; extensive edit history tracking; and the easy export of the collection (.csv), edit history (.json), or HGVS synonym bins (.json).
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Bases de Dados Genéticas , Variação Genética , Humanos , Genoma HumanoRESUMO
PURPOSE: National Comprehensive Cancer Network guidelines for germline genetic testing have included pancreatic cancer in the context of additional family cancer history for many years but this was not recommended for patients with pancreatic ductal adenocarcinoma (PDAC) independent of a family history until 2019. This hypothesis-generating study reports the results from multigene panel testing for PDAC patients at an academic medical center. PATIENTS AND METHODS: This prospective longitudinal feasibility study examined responses to genetic counseling and multigene panel testing among PDAC and breast or ovarian cancer (BrOv) patients between October 2016 and November 2017. Pre- and post-test surveys assessed perceptions of genetic risk and testing, recall, comprehension, and emotional reactions to results using open-ended and closed-ended items. RESULTS: Forty-six BrOv and 33 PDAC patients were enrolled, and 44 BrOv and 31 PDAC participants underwent genetic testing. Seven pathogenic variants were identified in six BrOv participants (13.6%), and three pathogenic variants were identified in three PDAC participants (9.7%). The majority of both cohorts expressed similar attitudes about the importance of genetic testing for their personal and family medical management and expressed accurate understanding of implications of their results. Although sample size was small, there were no significant differences between the BrOv and PDAC cohorts for positive or negative emotions. CONCLUSION: This study points to high rates of positive emotions and low rates of negative emotions following genetic test results, suggesting that the emotional reactions to genetic test results are similar for patients with BrOv and PDAC, despite poor prognosis with PDAC diagnoses. Because of the unique needs of the PDAC population following diagnosis, a multidisciplinary approach to germline genetic testing following diagnosis may result in best patient and family member outcomes.
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Neoplasias da Mama/diagnóstico , Neoplasias da Mama/psicologia , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/psicologia , Testes Genéticos/métodos , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/psicologia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/psicologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/genética , Carcinoma Ductal Pancreático/genética , Estudos de Viabilidade , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Neoplasias Pancreáticas/genética , Estudos ProspectivosRESUMO
Germline variants in tumor suppressor genes (TSGs) can result in RNA mis-splicing and predisposition to cancer. However, identification of variants that impact splicing remains a challenge, contributing to a substantial proportion of patients with suspected hereditary cancer syndromes remaining without a molecular diagnosis. To address this, we used capture RNA-sequencing (RNA-seq) to generate a splicing profile of 18 TSGs (APC, ATM, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NF1, PALB2, PMS2, PTEN, RAD51C, RAD51D, and TP53) in 345 whole-blood samples from healthy donors. We subsequently demonstrated that this approach can detect mis-splicing by comparing splicing profiles from the control dataset to profiles generated from whole blood of individuals previously identified with pathogenic germline splicing variants in these genes. To assess the utility of our TSG splicing profile to prospectively identify pathogenic splicing variants, we performed concurrent capture DNA and RNA-seq in a cohort of 1000 patients with suspected hereditary cancer syndromes. This approach improved the diagnostic yield in this cohort, resulting in a 9.1% relative increase in the detection of pathogenic variants, demonstrating the utility of performing simultaneous DNA and RNA genetic testing in a clinical context.
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Familial adenomatous polyposis (FAP) syndrome is a complex entity, which includes FAP, attenuated FAP, and MUTYH-associated polyposis. These patients are at significant risk for colorectal cancer and carry additional risks for extracolonic malignancies. In this guideline, we reviewed the most recent literature to formulate recommendations on the role of endoscopy in this patient population. Relevant clinical questions were how to identify high-risk individuals warranting genetic testing, when to start screening examinations, what are appropriate surveillance intervals, how to identify endoscopically high-risk features, and what is the role of chemoprevention. A systematic literature search from 2005 to 2018 was performed, in addition to the inclusion of seminal historical studies. Most studies were from worldwide registries, which have compiled years of data regarding the natural history and cancer risks in this cohort. Given that most studies were retrospective, recommendations were based on epidemiologic data and expert opinion. Management of colorectal polyps in FAP has not changed much in recent years, as colectomy in FAP is the standard of care. What is new, however, is the developing body of literature on the role of endoscopy in managing upper GI and small-bowel polyposis, as patients are living longer and improved endoscopic technologies have emerged.
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Polipose Adenomatosa do Colo , Neoplasias Colorretais , Polipose Adenomatosa do Colo/genética , Endoscopia Gastrointestinal , Testes Genéticos , Humanos , Guias de Prática Clínica como Assunto , Estudos Retrospectivos , Sociedades Médicas , Estados UnidosRESUMO
OBJECTIVES: To explore patterns of communication among families with a Lynch syndrome diagnosis and understand what resources could facilitate family communication. METHODS: 127 probands (i.e., first person in family with identified mutation) and family members participated in semi-structured interviews about: how they learned about the Lynch syndrome diagnosis, with whom they shared genetic test results, confidence in sharing results with other family members, and helpfulness of educational resources. RESULTS: Both probands and family members were most likely to share genetic test results with parents and siblings, and least likely to share results with aunts, uncles, and cousins. Most participants felt very confident sharing their test results with family members, but reported that certain topics such as cancer risk were challenging to convey. Probands reported the most helpful resources to be access to a specialty clinic or website, while family members described general printed materials as most helpful. CONCLUSIONS: Families affected by Lynch syndrome may experience barriers to communication with more distant relatives, and may benefit from receiving specific resources (e.g., websites about Lynch syndrome, print materials) to facilitate family communication. PRACTICE IMPLICATIONS: Providers could emphasize the need to share information with more distant family members and provide appropriate supportive resources.
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Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Comunicação , Família/psicologia , Testes Genéticos/métodos , Disseminação de Informação , Educação de Pacientes como Assunto/métodos , Adulto , Idoso , Neoplasias Colorretais Hereditárias sem Polipose/genética , Barreiras de Comunicação , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Entrevistas como Assunto , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Genes associated with hereditary breast and ovarian cancer (HBOC) and colorectal cancer (CRC) predisposition have been shown to play a role in pancreatic cancer susceptibility. Growing evidence suggests that pancreatic cancer may be useful as a sentinel cancer to identify families that could benefit from HBOC or CRC surveillance, but to date pancreatic cancer is only considered an indication for genetic testing in the context of additional family history. METHODS: Preliminary data generated at the Huntsman Cancer Hospital (HCH) included variants identified on a custom 34-gene panel or 59-gene panel including both known HBOC and CRC genes for respective sets of 66 and 147 pancreatic cancer cases, unselected for family history. Given the strength of preliminary data and corresponding literature, 61 sequential pancreatic cancer cases underwent a custom 14-gene clinical panel. Sequencing data from HCH pancreatic cancer cases, pancreatic cancer cases of the Cancer Genome Atlas (TCGA), and an unselected pancreatic cancer screen from the Mayo Clinic were combined in a meta-analysis to estimate the proportion of carriers with pathogenic and high probability of pathogenic variants of uncertain significance (HiP-VUS). RESULTS: Approximately 8.6% of unselected pancreatic cancer cases at the HCH carried a variant with potential HBOC or CRC screening recommendations. A meta-analysis of unselected pancreatic cancer cases revealed that approximately 11.5% carry a pathogenic variant or HiP-VUS. CONCLUSION: With the inclusion of both HBOC and CRC susceptibility genes in a panel test, unselected pancreatic cancer cases act as a useful sentinel cancer to identify asymptomatic at-risk relatives who could benefit from relevant HBOC and CRC surveillance measures.
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Neoplasias da Mama/genética , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Neoplasias Ovarianas/genética , Neoplasias Pancreáticas/genética , Adulto , Idoso , Feminino , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND AND OBJECTIVES: Biliary tract cancers (BTC) including, cholangiocarcinoma (CC) and gallbladder cancer (GBC), are rare and highly fatal malignancies. The etiology and inherited susceptibility of both malignancies are poorly understood. We quantified the risk of BTC in first-degree (FDR), second-degree (SDR), and first cousin (FC) relatives of individuals with BTC, stratified by tumor subsite. METHODS: BTC diagnosed between 1980 and 2011 were identified from the Utah Cancer Registry and linked to pedigrees from the Utah Population Database. Age- and gender-matched BTC-free controls were selected to form the comparison group for determining BTC risk in relatives using Cox regression analysis. RESULTS: Of the 1302 index patients diagnosed with BTC, 550 (42.2 %) were located in the gallbladder and 752 (57.8 %) were cholangiocarcinomas. There was no elevated risk of BTC (all subsites combined) in FDRs (HR 0.94, 95 % CI 0.29-3.0), SDRs (HR 0.25, 95 % CI 0.06-1.03), and FCs (HR 0.96, 95 % CI 0.61-1.51) of BTC cases compared to cancer-free controls. Similarly, no increased familial risk of GBC or CC was found in relatives of BTC patients stratified by tumor subsite compared to relatives of controls. CONCLUSIONS: Relatives of BTC patients are not at an increased risk of GBC or CC in a statewide population. This suggests that biliary tract cancer risk is not associated with a familial predisposition and may be mitigated more strongly by environmental modifiers.
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Adenocarcinoma/genética , Neoplasias dos Ductos Biliares/genética , Colangiocarcinoma/genética , Família , Neoplasias da Vesícula Biliar/genética , Linhagem , Sistema de Registros , Adenocarcinoma/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/epidemiologia , Ductos Biliares Extra-Hepáticos , Ductos Biliares Intra-Hepáticos , Neoplasias do Sistema Biliar/epidemiologia , Neoplasias do Sistema Biliar/genética , Colangiocarcinoma/epidemiologia , Feminino , Neoplasias da Vesícula Biliar/epidemiologia , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Utah/epidemiologia , Adulto JovemRESUMO
OBJECTIVES: Acupuncture needle manipulation causes mechanical deformation of connective tissue, which in turn results in mechanical stimulation of fibroblasts, with active changes in cell shape and autocrine purinergic signaling. We have previously shown using ultrasound elastography in humans that acupuncture needle manipulation causes measurable movement of tissue up to several centimeters away from the needle. The goal of this study was to quantify the spatial pattern of tissue displacement and deformation (shear strain) in response to acupuncture needling along an intermuscular connective tissue plane compared with needling over the belly of a muscle. DESIGN: Eleven (11) healthy human subjects underwent a single testing session during which robotic acupuncture needling was performed while recording tissue displacement using ultrasound. Outcome measures were axial and lateral tissue displacement as well as lateral shear strain calculated using ultrasound elastography postprocessing. RESULTS: Tissue displacement and strain extended further in the longitudinal direction when needling between muscles, and in the transverse direction when needling over the belly of a muscle. CONCLUSIONS: The anisotropic tissue motion observed in this study may influence the spatial distribution of local connective tissue cellular responses following acupuncture needle manipulation.
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Terapia por Acupuntura/instrumentação , Terapia por Acupuntura/métodos , Tecido Conjuntivo/fisiologia , Movimento/fisiologia , Músculo Esquelético/fisiologia , Adulto , Anisotropia , Técnicas de Imagem por Elasticidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Robótica/instrumentação , Robótica/métodos , Coxa da Perna/fisiologia , Adulto JovemRESUMO
Fibroblasts in whole areolar connective tissue respond to static stretching of the tissue by expanding and remodeling their cytoskeleton within minutes both ex vivo and in vivo. This study tested the hypothesis that the mechanism of fibroblast expansion in response to tissue stretch involves extracellular ATP signaling. In response to tissue stretch ex vivo, ATP levels in the bath solution increased significantly, and this increase was sustained for 20 min, returning to baseline at 60 min. No increase in ATP was observed in tissue incubated without stretch or tissue stretched in the presence of the Rho kinase inhibitor Y27632. The increase in fibroblast cross sectional area in response to tissue stretch was blocked by both suramin (a purinergic receptor blocker) and apyrase (an enzyme that selectively degrades extracellular ATP). Furthermore, connexin channel blockers (octanol and carbenoxolone), but not VRAC (fluoxetine) or pannexin (probenecid) channel blockers, inhibited fibroblast expansion. Together, these results support a mechanism in which extracellular ATP signaling via connexin hemichannels mediate the active change in fibroblast shape that occurs in response to a static increase in tissue length.