Genetic Screening for von Hippel-Lindau Gene Mutations in Non-syndromic Pheochromocytoma: Low Prevalence and False-positives or Misdiagnosis Indicate a Need for Caution

Abstract Objectives: Concurrent hearing and genetic screening of newborns is expected to play an important role in the early detection and diagnosis of congenital deafness, which triggers an intervention, as well as in predicting late-onset and progressive hearing loss and identifying individuals who are at risk of drug-induced hearing loss (HL).Methods: A Deafness Gene Variant Detection Array Kit covering fifteen variants in four genes was used to screen for deafness genes in 18001 infants.Results: A total of 108 neonates did not pass the second hearing screening. In addition, 912 (5.07%) screened positive for deafness-associated variants, including 78 (0.43%) genetically referred and 834 (4.63%) genetic deafness-associated variant carriers. Of the 912 screened positive cases, 880 passed the hearing screening, and 32 failed. A total of 62 (0.34%) cases carried the mtDNA 12S rRNA variants. A total of 108 cases did not pass the hearing screening and underwent a hearing diagnostic examination. An expanded DNA test identified 17 patients who possessed deafness gene mutations, increasing the detection rate to 5.16%.Conclusion: Early detection, diagnosis, and interventions are necessary for newborns who are susceptible to deafness. A good strategy is to use a small panel to quickly screen all subjects and then apply an extended panel to study the cause of deafness in affected patients.

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Abstract P4-03-06: Limitations of direct-to-consumer genetic screening for HBOC: False negatives, false positives and everything in between

10.1158/1538-7445.sabcs18-p4-03-06 ◽

2019 ◽

Cited By ~ 2

Author(s):

ED Esplin ◽

E Haverfield ◽

S Yang ◽

B Herrera ◽

M Anderson ◽

...

Keyword(s):

Genetic Screening ◽

False Positives ◽

False Negatives ◽

Direct To Consumer

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Prospective assessment of circulating endothelial cells (CECs) as early markers of clear cell renal cell carcinoma (CCRCC) progression in first line setting: The Circles study (SOGUG 2011-01).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.tps4685 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. TPS4685-TPS4685 ◽

Cited By ~ 1

Author(s):

Daniel E. Castellano ◽

Emilio Esteban ◽

Luis Leon ◽

Laura Basterretxea ◽

Arancha Gonzalez ◽

...

Keyword(s):

Tumor Progression ◽

Renal Cell ◽

Clear Cell ◽

Cox Model ◽

Gene Mutations ◽

Circulating Endothelial Cells ◽

Tumor Evolution ◽

First Line ◽

Cell Renal Cell Carcinoma ◽

Von Hippel Lindau

TPS4685 Background: Since the identification of Von Hippel Lindau (VHL) gene mutations as a critical step in the development of most Clear Cell Renal Cell Carcinomas (CCRCC), neoangionesis inhibition has become a cornerstone in their treatment. Despite the proven efficacy of antiangiogenic drugs, most patients will not achieve partial response by RECIST criteria. Thus, to accurately determine tumor progression is a challenging question incompletely answered by traditional radiological assessment. In recent years CECs counts have been proposed as surrogate biomarkers of angiogenesis that could be used for monitoring tumor evolution while on targeted therapies. We aim to figure out if CECs elevations could anticipate radiological progression in CCRCC. Methods: An observational prospective study is being performed in 10 institutions members of the Spanish Oncology Genitourinary group (SOGUG). Patients older than 18 years with histologically proven CCRCC on first line treatment with any targeted drug who have not progressed after 3 months of therapy are considered elegible. Recruitment begun on August the 1st 2011 and 15 of the 75 scheduled patients have been included so far. CECs are periodically collected in peripheral blood every 6 weeks for 15 months or radiological tumor progression, whatever occurs first. Median CEC values will be calculated and stated by descriptive statistics (Cellsearch, VERIDEX). To explore the evolution of CECs counts along treatment a linear model will be constructed. An association among CECs counts changes and time to progression will be analyzed with Cox model.

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Mutational status and thromboembolic risk in lung, gastrointestinal and breast cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e23147 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e23147-e23147

Author(s):

Marco Platania ◽

Federico Nichetti ◽

Filippo G. De Braud

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Clinical Manifestations ◽

Gene Mutations ◽

Molecular Profile ◽

Breast Cancer Patients ◽

Vein Thrombosis ◽

Mutational Status ◽

Cancer Associated Thrombosis ◽

Low Prevalence

e23147 Background: Cancer-Associated Thrombosis (CAT) is one of the most threatening complications of cancer. Recent evidences suggested a link between the molecular profile of solid tumors and the incidence of CAT. The aim of this study was to explore the relationship between the mutational status of breast, lung and gastrointestinal cancer patients and the risk of CAT. Methods: We retrospectively evaluated the molecular profile, analysed as per clinical practice, of all consecutive patients hospitalized at the National Cancer Institute’s Department in Milan from October 2017 to November 2018. Patients with previous thromboembolic events and patients under anticoagulant therapy at cancer diagnosis were excluded. Due to death as competing risk, the Fine and Gray proportional regression model was used to detect statistical association and estimate relative risk. Results: The resulting cohort consisted of 484 patients, of whom 47% had gastrointestinal cancers, 18% had lung cancer and 15% had breast cancer. Molecular investigations were available for 375 (77%) patients; in particular, a 50-gene Next Generation Sequencing (NGS) panel was performed on 148 (31%) patients. After a median follow up of 17 months, 118 patients (24%) exhibited clinical manifestations of thrombosis (i.e. deep vein thrombosis, pulmonary thromboembolism, splanchnic thrombosis, disseminated intravascular coagulation, arterial thrombosis) and 117 (24%) patients deceased without thrombotic events. A statistically significant association was observed between incidence of CAT and presence of TP53 (HR 0.50, p = 0.04), c-KIT (HR 4.30, p = 0.041), and SMAD4 (HR 3.19, p = 0.029) mutations. No significant association was detected for KRAS and MET gene mutations, even if HRs were >2. Conclusions: In this study, the mutational status of TP53, SMAD4 and c-KIT genes was statistically associated to the risk of thrombosis. Due to methodological limits and low prevalence of mutations, large prospective studies are warranted, with the aim of better defining the role of oncogenes in CAT risk.

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Contrasting clinical manifestations of SDHB and VHL associated chromaffin tumours

Endocrine Related Cancer ◽

10.1677/erc-08-0239 ◽

2009 ◽

Vol 16 (2) ◽

pp. 515-525 ◽

Cited By ~ 25

Author(s):

Umasuthan Srirangalingam ◽

Bernard Khoo ◽

Lisa Walker ◽

Fiona MacDonald ◽

Robert H Skelly ◽

...

Keyword(s):

Malignant Disease ◽

Tumour Size ◽

Age At Onset ◽

Clinical Manifestations ◽

Gene Mutations ◽

Catecholamine Secretion ◽

Renal Cell Carcinomas ◽

Von Hippel Lindau ◽

Increased Risk ◽

Multifocal Disease

Mutations in succinate dehydrogense-B (SDHB) and the von Hippel-Lindau (VHL) genes result in an increased risk of developing chromaffin tumours via a common aetiological pathway. The aim of the present retrospective study was to compare the clinical phenotypes of disease in subjects developing chromaffin tumours as a result of SDHB mutations or VHL disease. Thirty-one subjects with chromaffin tumours were assessed; 16 subjects had SDHB gene mutations and 15 subjects had a diagnosis of VHL. VHL-related tumours were predominantly adrenal phaeochromocytomas (22/26; 84.6%), while SDHB-related tumours were predominantly extra-adrenal paragangliomas (19/25; 76%). Median age at onset of the first chromaffin tumour was similar in the two cohorts. Tumour size was significantly larger in the SDHB cohort in comparison with the VHL cohort (P=0.002). Multifocal disease was present in 9/15 (60%) of the VHL cohort (bilateral phaeochromocytomas) and only 3/16 (19%) of the SDHB cohort, while metastatic disease was found in 5/16 (31%) of the SDHB cohort but not in the VHL cohort to date. The frequency of symptoms, hypertension and the magnitude of catecholamine secretion appeared to be greater in the SDHB cohort. Renal cell carcinomas were a feature in 5/15 (33%) of the VHL cohort and 1/16 (6%) of the SDHB cohort. These data indicate that SDHB-related tumours are predominantly extra-adrenal in location and associated with higher catecholamine secretion and more malignant disease, in subjects who appear more symptomatic. VHL-related tumours tend to be adrenal phaeochromocytomas, frequently bilateral and associated with a milder phenotype.

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Cigarette smoking, von Hippel–Lindau gene mutations and sporadic renal cell carcinoma

British Journal of Cancer ◽

10.1038/sj.bjc.6603281 ◽

2006 ◽

Vol 95 (3) ◽

pp. 374-377 ◽

Cited By ~ 16

Author(s):

B A C van Dijk ◽

L J Schouten ◽

E Oosterwijk ◽

C A Hulsbergen-van de Kaa ◽

L A L M Kiemeney ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cigarette Smoking ◽

Cell Carcinoma ◽

Renal Cell ◽

Gene Mutations ◽

Von Hippel Lindau ◽

Sporadic Renal Cell Carcinoma

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rs779805 Von Hippel-Lindau Gene Polymorphism Induced/Related Polycythemia Entity, Clinical Features, Cancer Association, and Familiar Characteristics

Pathology & Oncology Research ◽

10.3389/pore.2021.1609987 ◽

2021 ◽

Vol 27 ◽

Author(s):

Gyula Remenyi ◽

Zsuzsanna Bereczky ◽

Réka Gindele ◽

Aniko Ujfalusi ◽

Arpad Illes ◽

...

Keyword(s):

Risk Factors ◽

Colon Cancer ◽

Gene Mutations ◽

Tissue Oxygen ◽

Blood Cell Count ◽

Von Hippel Lindau ◽

The Family ◽

Red Blood Cell Count ◽

Vhl Disease ◽

Secondary Causes

Increased red blood cell count may result from primary erythrocytosis (polycythemia vera), but it is often due to secondary causes with increased erythropoietin levels. Secondary erythrocytosis may also be congenital due to different gene mutations of hemoglobin, hemoglobin stabilization proteins, EPO receptors, or oxygen sensing pathways. Von Hippel- Lindau gene mutation causes altered tissue oxygen sensation in VHL disease, usually with normal hemoglobin. Germline VHL mutations associate with classical VHL disease and represent genetic susceptibility for pheochromocytoma. VHL polymorphisms are mostly considered an innocent phenomenon. Still, some data indicate that these polymorphisms are not always harmless and can occur with prostate, renal, and colon cancer or even with isolated erythrocytosis. Seventy-eight patients referred to our department with elevated hemoglobin were screened for VHL mutations. There were no classical somatic VHL mutations. However, we found heterozygous (GA) or homozygous (AA) rs779805 VHL c.-195G>A polymorphism accompanied by erythrocytosis. These patients are Jak-2 negative, with normal or elevated EPO levels, sometimes with family accumulations and often phlebotomy needs, and in some cases with malignancies in the family. No other cause of erythrocytosis was found. We use phlebotomy regularly, and for those with cardiovascular risk factors, we recommend aspirin.

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Concurrent Hearing and Genetic Screening among Newborns in Ningbo, China

Computational and Mathematical Methods in Medicine ◽

10.1155/2022/1713337 ◽

2022 ◽

Vol 2022 ◽

pp. 1-8

Author(s):

Cao Guomei ◽

Zhang Luyan ◽

Dai Lingling ◽

Huang Chunhong ◽

Chen Shan

Keyword(s):

Carrier Frequency ◽

Genetic Variants ◽

Genetic Screening ◽

Gene Mutations ◽

Hearing Screening ◽

Screening Tests ◽

Genomic Epidemiology ◽

Deafness Gene ◽

Hearing Test ◽

Insight Into

Objective. To detect the carrier rates of deafness gene variants in populations in Ningbo and analyze the risk of hereditary hearing loss through concurrent hearing and genetic screening tests. Methods. Two thousand one hundred and seventy-four newborns were enrolled from November 2018 to August 2019. All subjects underwent hearing screening and newborn deafness genetic screening with 15 variants in 4 genes, and the positive sites were simultaneously verified by sequencing. Results. The total carrier rate of genetic variants in Ningbo reached 4.32%, when GJB2 c.235delC was the variant with the highest prevalence (2.12%), approximately accounting for 48.9% of the total carrier frequency. The carrier frequency of SLC26A4 c.919-2A>G was 0.87%, while the most common variant in mitochondrial DNA (mtDNA) MT-RNR1 gene was m.1555A>G, and its carrier frequency was 0.184%. In the OAE testing, 92 newborns passing hearing screening were tested positively for variants in 4 genes, and 2 of 42 newborns who failed in the first hearing test were found to mutate in 4 genes. Conclusion. Herein, the results concerning the carrier rates for deafness gene mutations of Ningbo population are reported. Our study is beneficial to the insight into the deafness genomic epidemiology for deafness genes in Ningbo population and provides the reference for healthcare in Ningbo.

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Testing for coronavirus (SARS-CoV-2) infection in populations with low infection prevalence: the largely ignored problem of false positives and the value of repeat testing

10.1101/2020.08.19.20178137 ◽

2020 ◽

Author(s):

Cathie Sudlow ◽

Peter Diggle ◽

Oliver Warlow ◽

David Seymour ◽

Ben Gordon ◽

...

Keyword(s):

False Positives ◽

Infection Prevalence ◽

Test Accuracy ◽

Single Test ◽

False Negatives ◽

Repeat Testing ◽

Confirmatory Testing ◽

Test Specificity ◽

Low Prevalence ◽

The Impact

Background: Calls are increasing for widespread SARS-CoV-2 infection testing of people from populations with a very low prevalence of infection. We quantified the impact of less than perfect diagnostic test accuracy on populations, and on individuals, in low prevalence settings, focusing on false positives and the role of confirmatory testing. Methods: We developed a simple, interactive tool to assess the impact of different combinations of test sensitivity, specificity and infection prevalence in a notional population of 100,000. We derived numbers of true positives, true negatives, false positives and false negatives, positive predictive value (PPV, the percentage of test positives that are true positives) and overall test accuracy for three testing strategies: (1) single test for all; (2) add repeat testing in test positives; (3) add further repeat testing in those with discrepant results. We also assessed the impact on test results for individuals having one, two or three tests under these three strategies. Results: With sensitivity of 80%, infection prevalence of 1 in 2,000, and specificity 99.9% on all tests, PPV in the tested population of 100,000 will be only 29% with one test, increasing to >99.5% (100% when rounded to the nearest %) with repeat testing in strategies 2 or 3. More realistically, if specificity is 95% for the first and 99.9% for subsequent tests, single test PPV will be only 1%, increasing to 86% with repeat testing in strategy 2, or 79% with strategy 3 (albeit with 6 fewer false negatives than strategy 2). In the whole population, or in particular individuals, PPV increases as infection becomes more common in the population but falls to unacceptably low levels with lower test specificity. Conclusion: To avoid multiple unnecessary restrictions on whole populations, and in particular individuals, from widespread population testing for SARS-CoV-2, the crucial roles of extremely high test specificity and of confirmatory testing must be fully appreciated and incorporated into policy decisions.

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