The Utilization of JAK2 Molecular Testing at the University of Minnesota Medical Center

2019 ◽  
Vol 152 (Supplement_1) ◽  
pp. S147-S147
Author(s):  
Pawel Mroz ◽  
Cade Arries
Keyword(s):  
Gene Mutation ◽  
Detection Rate ◽  
Medical Center ◽  
Single Gene ◽  
Myeloproliferative Neoplasm ◽  
Pathogenic Mutation ◽  
Molecular Testing ◽  
Mutation Status ◽  
Clinical Indications ◽  
Patient Presentation

Abstract Objectives JAK2 gene mutation status is included in the 2017 WHO diagnostic criteria of a myeloproliferative neoplasm (MPN) and therefore indicated in the diagnostic workup. Overutilization and inappropriate testing, however, can cause harm and lead to medical errors, and most importantly, it can significantly drive up the costs of patients’ care. Here we report an attempt to evaluate the success rate and the associated costs of JAK2 testing as well as to correlate it with clinical indications and patient presentation. Methods We conducted the analysis of next-generation testing orders/results performed at out institution between 9/2/2015 and 7/13/2018. We reviewed the rate of positive results as well as the type of order submitted to laboratory and compared the costs of individual tests. Results We analyzed 3,474 NGS orders/results performed at our institution. Of those, 1,203 were submitted for JAK2 testing, making this the most commonly ordered NGS test. Out of 1,203 results, there were 820 unique patient specimens and 118 tested positive (15%). The JAK2 testing was primarily ordered as part of the NGS MPN panel, which includes JAK2, CALR, and MPL mutation hotspots (70%), the custom panel (23%), JAK2 single gene (5%), or as part of comprehensive myeloid panel (2%). The mutation detection rate was 15%, 12%, 11%, and 15%, respectively. Conclusion Testing for JAK2 gene mutation status is the most commonly ordered NGS test in our laboratory. The detection rate for pathogenic mutation, irrespective of the type of genetic panel ordered, was 11% to 15%. Our analysis of the JAK2 ordering and reporting suggests that the JAK2 testing may be somewhat overutilized at our institution. An ongoing analysis of clinical indications, patient presentation, and associated costs will help to fully elucidate the true utility of this testing and will be included in the poster presentation.

Predictors of Survival in CLL: Multivariate Analyses Reveal Significant Correlation with IgVH Gene Mutation Status, Clinical Stage, and Cellular CD38 (but Not Zap-70) Expression.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5010-5010
Author(s):  
Alicia D. Volkheimer ◽  
Marc C. Levesque ◽  
Bethany E. Beasley ◽  
Louis Diehl ◽  
Youwei Chen ◽  
...  
Keyword(s):  
Gene Mutation ◽  
Doubling Time ◽  
Multivariate Analyses ◽  
Medical Center ◽  
Clinical Stage ◽  
Leukemia Cell ◽  
Mutation Status ◽  
Cd38 Expression ◽  
Binet Stage ◽  
Univariate Analyses

Abstract One of the complexities of chronic lymphocytic leukemia (CLL) is that some patients die early from the disease, while others identically staged by conventional means may live more than two decades. This has led to a search for prognostic indicators that correlate better with eventual survival. Candidate markers include Rai stage, Binet stage, lymphocyte doubling time (DT), immunoglobulin heavy chain V region (IgVH) mutation status, and leukemia cell CD38 and Zap-70 expression. To determine which of these markers correlate best with survival in univariate and multivariate analyses, we examined these parameters in 150 CLL patients from a VA medical center and a university medical center. CLL cells were purified from patients not receiving active treatment with WBC >20,000/uL by deleting T cells, monocytes, neutrophils, and erythrocytes using antibodies against CD2, CD3, CD16, CD36, CD56, and glycophorin A, and centrifugation over ficoll-Hypaque (CLL purity > 97%). In univariate analyses, patients with advanced stage on presentation had shorter survival than those with low stage [14.0 yr for high modified Rai stage vs. 25.3 yr for low stage (p = 0.013), and 13.8 yr, 13.4, and 25.3 yr for Binet stages C, B, and A, respectively (p = 0.033)]. Patients with a lymphocyte DT >3 yr survived twice as long (22.6 yr) as those with a DT <3 yr (11.3 yr) (p = 0.004). There was a strong relationship of IgVH mutation status with survival (median survival 22.6 yr for mutated, 9.4 yr for unmutated; p = 0.0006). Likewise, cellular CD38 expression significantly correlated with survival (CD38 neg 25.3 yr, CD38 pos 13.4 yr, p = 0.008). Zap-70 expression determined by quantitative immunoblot [Zap-70/actin ratio (anti-Zap-70 antibody from Upstate; clone 2F3.2)] was not significantly related to survival (Zap-70 pos 20.8 yr, Zap-70 neg 22.6 yr). Other parameters found not to be related to eventual survival were WBC on presentation, maximum WBC reached before treatment, and time from diagnosis to initial treatment. IgVH mutation status was significantly related to lymphocyte DT, CD38 expression, and Zap-70 expression. In multivariate analyses using the proportional hazards model, IgVH mutation status (p = 0.001), cellular CD38 expression (p = 0.025), and Binet stage (p = 0.026) were significantly associated with survival (with p = 0.0002 overall for these three parameters in the model), but Zap-70 had no significant relationship to survival in the model. Thus, in contrast to other reports, cellular Zap-70 expression does not correlate with various parameters of disease severity (including survival) in our cohort of CLL patients. In summary, our univariate analyses show significant correlations of advanced clinical stage, short lymphocyte doubling time, high CD38 expression, and unmutated IgVH with short survival. However, multivariate analyses show that only IgVH gene mutation status, clinical stage at presentation, and cellular CD38 expression correlate significantly with survival.

scholarly journals Prediction of BRCA Gene Mutation in Breast Cancer Based on Deep Learning and Histopathology Images

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaoxiao Wang ◽  
Chong Zou ◽  
Yi Zhang ◽  
Xiuqing Li ◽  
Chenxi Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Mutation ◽  
Histological Grade ◽  
External Validation ◽  
Pathogenic Mutation ◽  
Tumor Location ◽  
Training Data ◽  
Validation Dataset ◽  
Mutation Status ◽  
Increased Risk

BackgroundBreast cancer is one of the most common cancers and the leading cause of death from cancer among women worldwide. The genetic predisposition to breast cancer may be associated with a mutation in particular genes such as gene BRCA1/2. Patients who carry a germline pathogenic mutation in BRCA1/2 genes have a significantly increased risk of developing breast cancer and might benefit from targeted therapy. However, genetic testing is time consuming and costly. This study aims to predict the risk of gBRCA mutation by using the whole-slide pathology features of breast cancer H&E stains and the patients’ gBRCA mutation status.MethodsIn this study, we trained a deep convolutional neural network (CNN) of ResNet on whole-slide images (WSIs) to predict the gBRCA mutation in breast cancer. Since the dimensions are too large for slide-based training, we divided WSI into smaller tiles with the original resolution. The tile-based classification was then combined by adding the positive classification result to generate the combined slide-based accuracy. Models were trained based on the annotated tumor location and gBRCA mutation status labeled by a designated breast cancer pathologist. Four models were trained on tiles cropped at 5×, 10×, 20×, and 40× magnification, assuming that low magnification and high magnification may provide different levels of information for classification.ResultsA trained model was validated through an external dataset that contains 17 mutants and 47 wilds. In the external validation dataset, AUCs (95% CI) of DL models that used 40×, 20×, 10×, and 5× magnification tiles among all cases were 0.766 (0.763–0.769), 0.763 (0.758–0.769), 0.750 (0.738–0.761), and 0.551 (0.526–0.575), respectively, while the corresponding magnification slides among all cases were 0.774 (0.642–0.905), 0.804 (0.676–0.931), 0.828 (0.691–0.966), and 0.635 (0.471–0.798), respectively. The study also identified the influence of histological grade to the accuracy of the prediction.ConclusionIn this paper, the combination of pathology and molecular omics was used to establish the gBRCA mutation risk prediction model, revealing the correlation between the whole-slide histopathological images and gRCA mutation risk. The results indicated that the prediction accuracy is likely to improve as the training data expand. The findings demonstrated that deep CNNs could be used to assist pathologists in the detection of gene mutation in breast cancer.

Multigene Combined Detection by RT-qPCR Using Cytological Specimens

2021 ◽  
pp. 1-10
Author(s):  
Yang Ma ◽  
Jingxia Zhao ◽  
Yun Du ◽  
Rui Wang ◽  
Xiaokun Ji ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Smoking Status ◽  
Single Gene ◽  
Rna Extraction ◽  
Pcr Amplification ◽  
Driver Mutations ◽  
Amplification Refractory Mutation System ◽  
Driver Genes ◽  
Mutation Status ◽  
Pik3ca Mutations

<b><i>Objective:</i></b> The aim of the study was to investigate the mutation status of multiple driver genes by RT-qPCR and their significance in advanced lung adenocarcinoma using cytological specimens. <b><i>Materials and Methods:</i></b> 155 cytological specimens that had been diagnosed with lung adenocarcinoma in the Fourth Hospital of Hebei Medical University were selected from April to November 2019. The cytological specimens included serous cavity effusion and fine-needle aspiration biopsies. Among cytological specimens, 108 cases were processed by using the cell block method (CBM), and 47 cases were processed by the disposable membrane cell collector method (MCM) before DNA/RNA extraction. Ten drive genes of EGFR, ALK, ROS1, BRAF, KRAS, NRAS, HER2, RET, PIK3CA, and MET were combined detected at one step by the amplification refractory mutation system and ABI 7500 RT-qPCR. <b><i>Results:</i></b> The purity of RNA (<i>p</i> = 0.005) and DNA (<i>p</i> = 0.001) extracted by using the MCM was both significantly higher than that extracted by using the CBM. Forty-seven cases of fresh cell specimens processed by the MCM all succeeded in multigene detections, while of 108 specimens processed by the CBM, 6 cases failed in multigene detections. Among 149 specimens, single-gene mutation rates of EGFR, ALK, ROS1, RET, HER2, MET, KRAS, NRAS, BRAF, and PIK3CA mutations were 57.71%, 6.04%, 3.36%, 2.68%, 2.01%, 2.01%, 1.34%, 0.67%, 0% and 0% respectively, and 6 cases including 2 coexistence mutations. We found that mutation status was correlated with gender (<i>p</i> = 0.047), but not correlated with age (<i>p</i> = 0.141) and smoking status (<i>p</i> = 0.083). We found that the EGFR mutation status was correlated with gender (<i>p</i> = 0.003), age (<i>p</i> = 0.015) and smoking habits (<i>p</i> = 0.007), and ALK mutation status was correlated with age (<i>p</i> = 0.002). <b><i>Conclusion:</i></b> Compared with the CBM, the MCM can improve the efficiency of DNA/RNA extraction and PCR amplification by removing impurities and enriching tumor cells. And we speculate that the successful detection rate of fresh cytological specimens was higher than that of paraffin-embedded specimens. EGFR, ALK, and ROS1 mutations were the main driver mutations in patients with advanced lung adenocarcinoma. We speculate that EGFR and ALK are more prone to concomitant mutations, respectively. Targeted therapies for patients with coexisting mutations need further study.

Prognostic factors and survival after whole-brain radiotherapy for initial brain metastases arising from non-small cell lung cancer

2021 ◽  
pp. 1-6
Author(s):  
Yukinori Okada ◽  
Mariko Kobayashi ◽  
Mio Shinozaki ◽  
Tatsuyuki Abe ◽  
Naoki Nakamura
Keyword(s):  
Prognostic Factors ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Gene Mutation ◽  
Stage Iv ◽  
Whole Brain Radiotherapy ◽  
Hazard Ratio ◽  
Small Cell Lung ◽  
Mutation Status ◽  
Brain Radiotherapy

Abstract Aim: To identify prognostic factors and investigate patient survival after whole-brain radiotherapy (WBRT) for initial brain metastases arising from non-small cell lung cancer (NSCLC). Methods: Patients diagnosed with NSCLC between 1 January 2010 and 30 September 2019, and who received WBRT upon first developing a brain metastasis, were investigated. Overall survival was determined as related to age, sex, duration between initial examination and brain metastasis detection, stage at the first examination, presence of metastases outside the brain, blood analysis findings, brain metastasis symptoms, radiotherapy dose and completion, imaging findings, therapeutic course of chemotherapy and/or radiation therapy, histological type, and gene mutation status. Results: Thirty-one consecutive patients (20 men and 11 women) with a mean age of 63·8 years and median survival of 129 days were included. Multivariate analysis with stepwise testing was performed to investigate differences in survival according to gene mutation status, lactate dehydrogenase (LDH) level, irradiation dose, WBRT completion and Stage status. Of these, a statistically significant difference in survival was observed in patients with gene mutation status (hazard ratio: 0·31, 95% CI: 0·11–0·86, p = 0·025), LDH levels <230 vs. ≥230 IU/L (hazard ratio: 4·08, 95% CI: 1·45–11·5, p < 0·01) received 30 Gy, 30 Gy/10 fractions to 35 Gy/14 fractions, and 37·5 Gy/15 fractions (hazard ratio: 0·26, 95% CI: 0·09–0·71, p < 0·01), and stage IV versus non-stage IV (hazard ratio: 0·13, 95 CI:0·02–0·64, p < 0·01) Findings: Gene mutation, LDH, radiation dose and Stage are prognostic factors for patients with initial brain metastases who are treated with WBRT.

Synaptic transmission reversibly conditioned by single-gene mutation in Drosophila melanogaster

Nature ◽  
1976 ◽  
Vol 259 (5543) ◽  
pp. 489-491 ◽  
Author(s):  
KAZUO IKEDA ◽  
SEIJI OZAWA ◽  
SUSUMU HAGIWARA
Keyword(s):  
Drosophila Melanogaster ◽  
Synaptic Transmission ◽  
Gene Mutation ◽  
Single Gene ◽  
Single Gene Mutation

scholarly journals Case of Small Vessel Disease Associated with COL4A1 Mutations following Trauma

2015 ◽  
Vol 7 (2) ◽  
pp. 142-147 ◽  
Author(s):  
Joao McONeil Plancher ◽  
Robert B. Hufnagel ◽  
Achala Vagal ◽  
Katrina Peariso ◽  
Howard M. Saal ◽  
...  
Keyword(s):  
Contrast Enhancement ◽  
Head Trauma ◽  
Small Vessel Disease ◽  
Genetic Disorder ◽  
Single Gene ◽  
Young Patients ◽  
Pathogenic Mutation ◽  
Small Vessel ◽  
Vessel Disease ◽  
History Of

With this case report, we would like to heighten the awareness of clinicians about COL4A1 as a single-gene disorder causing cerebral small vessel disease and describe a previously unreported pathogenic missense substitution in COL4A1 (p.Gly990Val) and a new clinical presentation. We identified a heterozygous putatively pathogenic mutation of COL4A1 in a 50-year-old female with a history of congenital cataracts and glaucoma who presented with multiple diffusion-positive infarcts and areas of contrast enhancement following mild head trauma. We believe that this presentation of multiple areas of acute brain and vascular injury in the setting of mild head trauma is a new manifestation of this genetic disorder. Imaging findings of multiple acute infarcts and regions of contrast enhancement with associated asymptomatic old deep microhemorrhages and leukomalacia in adults after head trauma should raise a high suspicion for a COL4A1 genetic disorder. Radiographic patterns of significant leukoaraiosis and deep microhemorrhages can also be seen in patients with long-standing vasculopathy associated with hypertension, which our patient lacked. Our findings demonstrate the utility of genetic screening for COL4A1 mutations in young patients who have small vessel vasculopathy on brain imaging but who do not have significant cardiovascular risk factors.

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