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1.
Sci Rep ; 11(1): 24501, 2021 12 30.
Article in English | MEDLINE | ID: covidwho-1592860

ABSTRACT

During the COVID-19 pandemic, breast and ovarian cancer survivors experienced more anxiety and depression than before the pandemic. Studies have not investigated the similarities of this trend among BRCA1/2-positive women who are considered high risk for these cancers. The current study examines the impact of COVID-19 experiences on anxiety and depression in a sample of BRCA1/2-positive women in the U.S. 211 BRCA1/2-positive women from medically underserved backgrounds completed an online survey. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression for associations between COVID-19 experiences and self-reported anxiety and depression stratified by demographic factors. Overall, women who reported COVID-19 stigma or discrimination (aOR, 5.14, 95% CI [1.55, 17.0]) experienced significantly more depressive symptoms than women who did not report this experience. Racial/ethnic minority women caring for someone at home during COVID-19 were 3.70 times more likely (95% CI [1.01, 13.5]) to report high anxiety while non-Hispanic white women were less likely (aOR, 0.34, 95% CI [0.09, 1.30], p interaction = 0.011). To date, this is the first study to analyze anxiety and depression considering several COVID-19 predictors among BRCA1/2-positive women. Our findings can be used to inform future research and advise COVID-19-related mental health resources specific to these women.


Subject(s)
Breast Neoplasms , COVID-19 , Pandemics , Anxiety , BRCA1 Protein/genetics , BRCA2 Protein/genetics , Breast Neoplasms/epidemiology , Breast Neoplasms/psychology , COVID-19/epidemiology , COVID-19/psychology , Cross-Sectional Studies , Depression , Female , Humans , Middle Aged , Risk Factors , Self Report , United States/epidemiology
2.
Cancer Prev Res (Phila) ; 14(11): 1021-1032, 2021 11.
Article in English | MEDLINE | ID: covidwho-1463067

ABSTRACT

Up to 10% of patients with pancreatic ductal adenocarcinoma (PDAC) carry underlying germline pathogenic variants in cancer susceptibility genes. The GENetic Education Risk Assessment and TEsting (GENERATE) study aimed to evaluate novel methods of genetic education and testing in relatives of patients with PDAC. Eligible individuals had a family history of PDAC and a relative with a germline pathogenic variant in APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, or TP53 genes. Participants were recruited at six academic cancer centers and through social media campaigns and patient advocacy efforts. Enrollment occurred via the study website (https://GENERATEstudy.org) and all participation, including collecting a saliva sample for genetic testing, could be done from home. Participants were randomized to one of two remote methods that delivered genetic education about the risks of inherited PDAC and strategies for surveillance. The primary outcome of the study was uptake of genetic testing. From 5/8/2019 to 5/6/2020, 49 participants were randomized to each of the intervention arms. Overall, 90 of 98 (92%) of randomized participants completed genetic testing. The most frequently detected pathogenic variants included those in BRCA2 (N = 15, 17%), ATM (N = 11, 12%), and CDKN2A (N = 4, 4%). Participation in the study remained steady throughout the onset of the Coronavirus disease (COVID-19) pandemic. Preliminary data from the GENERATE study indicate success of remote alternatives to traditional cascade testing, with genetic testing rates over 90% and a high rate of identification of germline pathogenic variant carriers who would be ideal candidates for PDAC interception approaches. PREVENTION RELEVANCE: Preliminary data from the GENERATE study indicate success of remote alternatives for pancreatic cancer genetic testing and education, with genetic testing uptake rates over 90% and a high rate of identification of germline pathogenic variant carriers who would be ideal candidates for pancreatic cancer interception.


Subject(s)
BRCA1 Protein/genetics , BRCA2 Protein/genetics , Genetic Predisposition to Disease , Genetic Testing/methods , Germ-Line Mutation , Pancreatic Neoplasms/genetics , Risk Assessment/methods , Adolescent , Adult , Aged , Aged, 80 and over , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Pancreatic Ductal/therapy , Female , Humans , Male , Middle Aged , Models, Genetic , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/therapy , Patient Participation , Risk Factors , Surveys and Questionnaires , Telemedicine , Young Adult
3.
Cell ; 184(4): 1064-1080.e20, 2021 02 18.
Article in English | MEDLINE | ID: covidwho-1086818

ABSTRACT

Understanding the functional consequences of single-nucleotide variants is critical to uncovering the genetic underpinnings of diseases, but technologies to characterize variants are limiting. Here, we leverage CRISPR-Cas9 cytosine base editors in pooled screens to scalably assay variants at endogenous loci in mammalian cells. We benchmark the performance of base editors in positive and negative selection screens, identifying known loss-of-function mutations in BRCA1 and BRCA2 with high precision. To demonstrate the utility of base editor screens to probe small molecule-protein interactions, we screen against BH3 mimetics and PARP inhibitors, identifying point mutations that confer drug sensitivity or resistance. We also create a library of single guide RNAs (sgRNAs) predicted to generate 52,034 ClinVar variants in 3,584 genes and conduct screens in the presence of cellular stressors, identifying loss-of-function variants in numerous DNA damage repair genes. We anticipate that this screening approach will be broadly useful to readily and scalably functionalize genetic variants.


Subject(s)
Gene Editing , Genetic Variation , High-Throughput Nucleotide Sequencing , Alleles , BRCA1 Protein/genetics , BRCA2 Protein/genetics , Base Sequence , Catalytic Domain , Cell Line, Tumor , Humans , Loss of Function Mutation , Mutagenesis/genetics , Myeloid Cell Leukemia Sequence 1 Protein/genetics , Point Mutation/genetics , Poly(ADP-ribose) Polymerases/chemistry , Poly(ADP-ribose) Polymerases/genetics , Reproducibility of Results , Selection, Genetic , bcl-X Protein/genetics
4.
Expert Rev Mol Diagn ; 21(1): 101-107, 2021 01.
Article in English | MEDLINE | ID: covidwho-962282

ABSTRACT

Background: The SARS-CoV-2 pandemic introduced a global distraction effect in cancer patients' care. The aim of this study was to explore the effect of the pandemic on the largest molecular diagnostics center for cancer patients and high-risk individuals in Serbia.Research design and methods: EGFR, KRAS/NRAS, BRAF, and BRCA1/2 mutation testing were performed by qPCR and NGS. NGS was used for panel testing of hereditary breast/ovarian cancer and cancers associated with Lynch syndrome. The analytical output during the state of emergency (SoE) was compared to the period before and after the outbreak using one-way ANOVA. Statistical significance was set at p < 0.05.Results: A 38% reduction in the number of analysis was detected during the SoE. After the SoE, a 19% reduction was noted compared to SoE and 50% compared to the period before the SoE (p = 0.038). Three of the 48 scheduled appointments for pretest genetic counseling were carried out during the SoE, but the number of NGS tests increased by 50%.Conclusions: The SARS-CoV-2 pandemic had a profound negative effect on the diagnostic output of our centralized molecular diagnostics center. The only positive effect was shortening of waiting lists for hereditary cancer patients and high-risk individuals.


Subject(s)
Breast Neoplasms/diagnosis , Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis , Mutation , Ovarian Neoplasms/diagnosis , BRCA1 Protein/genetics , BRCA2 Protein/genetics , Breast Neoplasms/genetics , COVID-19 , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , DNA Mutational Analysis , ErbB Receptors/genetics , Female , GTP Phosphohydrolases/genetics , Genetic Counseling , Genetic Predisposition to Disease , Humans , Liquid Biopsy , Membrane Proteins/genetics , Ovarian Neoplasms/genetics , Pandemics , Pathology, Molecular , Pharmacogenetics , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Serbia/epidemiology
5.
Eur J Med Genet ; 63(12): 104098, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-917288

ABSTRACT

INTRODUCTION: Mainstreamed genetic testing (MGT) obviates the need for a cancer genetics consultation, since trained oncologists (O) and gynaecologists (G) provide counseling, prescribe testing and deliver results. We report results from our MGT program and emphasize its utility during the COVID-19 lockdown, when cancer genetics clinics had suspended their activity. METHODS: An MGT pathway for breast and ovarian cancer (BC/OC) patients was established in Jan-2018 between the Assistance Publique - Hôpitaux de Paris.Sorbonne Université Cancer Genetics team and the Oncology/Gynecology departments at one teaching and two regional hospitals. Trained O + G evaluated patients with the Manchester Scoring System. A 12-point threshold was recommended for testing. Next-generation sequencing of BRCA1, BRCA2, PALB2, RAD51C and RAD51D was performed. Results were delivered to the patient by O/G. Pathogenic variants (PV) carriers were referred to the genetics clinic. Results are reported for the 2nd-Jan-2018 to 1st-June-2020 period. That includes the eight-week COVID-19 lockdown and three-week de-confinement phase 1. RESULTS: Results were available for 231/234 patients. Twenty-eight (12.1%) carried a PV. Of the 27 patients tested during the COVID-19 period, three carried a PV, two in BRCA1 and one in RAD51C. The clinical impact was immediate for the two BRCA1 BC cases undergoing neo-adjuvant chemotherapy, since double mastectomy and salpingo-oophorectomy will now be performed using two-step strategies. CONCLUSIONS: MGT guaranteed care continuity in BC/OC patients during the critical phases of the COVID-19 pandemic, with immediate implications for PV carriers. More broadly, we report for the first time the successful implementation of MGT in France.


Subject(s)
Breast Neoplasms/genetics , COVID-19/epidemiology , Genetic Testing , Hereditary Breast and Ovarian Cancer Syndrome/genetics , Ovarian Neoplasms/genetics , Pandemics , Adult , Aged , Aged, 80 and over , BRCA1 Protein/genetics , BRCA2 Protein/genetics , Breast Neoplasms/drug therapy , Breast Neoplasms/surgery , DNA-Binding Proteins/genetics , Fanconi Anemia Complementation Group N Protein/genetics , Female , Genetic Counseling , Genetic Predisposition to Disease , High-Throughput Nucleotide Sequencing , Humans , Male , Mastectomy , Middle Aged , Neoadjuvant Therapy , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/surgery , Paris/epidemiology , Salpingo-oophorectomy , Young Adult
6.
J Immunother Cancer ; 8(2)2020 08.
Article in English | MEDLINE | ID: covidwho-712954

ABSTRACT

To report a multi-institutional case series of patients with advanced microsatellite instability high (MSI-H) prostate adenocarcinoma identified with clinical cell-free DNA (cfDNA) next-generation sequencing (NGS) testing and treated with immune checkpoint inhibitors. Retrospective analysis of patients with metastatic castration-resistant prostate cancer (mCRPC) and MSI-H tumor detected by a commercially available cfDNA NGS assay Guardant360 (G360, Guardant Health) at eight different Academic Institutions in the USA, from September 2018 to April 2020. From a total of 14 MSI-H metastatic prostate cancer patients at participating centers, nine patients with mCRPC with 56% bone, 33% nodal, 11% liver and 11% soft-tissue metastases and a median PSA of 29.3 ng/dL, were treated with pembrolizumab after 2 lines of therapy for CRPC. The estimated median time on pembrolizumab was 9.9 (95% CI 1.0 to 18.8) months. Four patients (44%) achieved PSA50 after a median of 4 (3-12) weeks after treatment initiation including three patients with >99% PSA decline. Among the patients evaluable for radiographic response (n=5), the response rate was 60% with one complete response and two partial responses. Best response was observed after a median of 3.3 (1.4-7.6) months. At time of cut-off, four patients were still on pembrolizumab while four patients discontinued therapy due to progressive disease and one due to COVID-19 infection. Half of the patients with PSA50 had both MSI-H and pathogenic alterations in BRCA1 and BRCA2 in their G360 assays. The use of liquid biopsy to identify metastatic prostate cancer patients with MSI-H is feasible in clinical practice and may overcome some of the obstacles associated with prostate cancer tumor tissue testing. The robust activity of pembrolizumab in selected patients supports the generalized testing for MSI-H.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Microsatellite Instability , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/genetics , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Agents, Immunological/adverse effects , BRCA1 Protein/genetics , BRCA2 Protein/genetics , Biomarkers, Tumor/genetics , COVID-19 , Circulating Tumor DNA/blood , Coronavirus Infections , Humans , Liquid Biopsy , Male , Middle Aged , Mutation , Pandemics , Pneumonia, Viral , Prostatic Neoplasms/pathology
8.
Mol Biol Rep ; 47(6): 4857-4860, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-209514

ABSTRACT

The first person-to-person transmission of the 2019-novel coronavirus in Italy on 21 February 2020 led to an infection chain that represents one of the largest known COVID-19 outbreaks outside Asia. Hospitals have been forced to reorganized their units in response to prepare for an unforeseen healthcare emergency. In this context, our laboratory (Molecular and Genomic Diagnostics Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS) re-modulated its priorities by temporarily interrupting most of the molecular tests guaranteeing only those considered "urgent" and not postponable. In particular, this paper details changes regarding the execution of germline BRCA (gBRCA) testing in our laboratory. A substantial reduction in gBRCA testing (about 60%) compared to the first 2 months of the current year was registered, but the requests have not been reset. The requesting physicians were mainly gynaecologists and oncologists. These evidences further emphasize the new era of gBRCA testing in the management of cancer patients and confirms definitively the integration of gBRCA testing/Next Generation Sequencing (NGS) into clinical oncology. Finally, a re-organization of gBRCA testing in our Unit, mainly related to delayed and reduced arrival of tests was necessary, ensuring, however, a high-quality standard and reliability, mandatory for gBRCA testing in a clinical setting.


Subject(s)
BRCA2 Protein/genetics , Breast Neoplasms/diagnosis , Coronavirus Infections/epidemiology , Early Detection of Cancer/statistics & numerical data , Ovarian Neoplasms/diagnosis , Pandemics , Pneumonia, Viral/epidemiology , Betacoronavirus/genetics , Betacoronavirus/pathogenicity , Biomarkers, Tumor/genetics , Breast Neoplasms/genetics , Breast Neoplasms/pathology , COVID-19 , COVID-19 Testing , Clinical Laboratory Techniques/statistics & numerical data , Coronavirus Infections/blood , Coronavirus Infections/diagnosis , Coronavirus Infections/pathology , Early Detection of Cancer/methods , Early Diagnosis , Female , Genomics/methods , High-Throughput Nucleotide Sequencing/statistics & numerical data , Humans , Italy/epidemiology , Mutation , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Pneumonia, Viral/blood , Pneumonia, Viral/diagnosis , Pneumonia, Viral/pathology , Referral and Consultation/statistics & numerical data , SARS-CoV-2
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