tbuckley/cabot-search huggingface dataset:
IDH1 mutation in prostate cancer: R132H and beyond.
Authors: Amber Lea Flaherty, Jamie Teer, Jingsong Zhang
Journal: Journal of Clinical Oncology (2014)

213 Background: Previous reports on mutations in the isocitrate dehydrogenase 1 (IDH1) gene in prostate cancer focused on the evolutionarily conserved residue R132 located in the substrate binding site of IDH1. One study reported R132 mutations in 2/75 (2.7%) prostate cancers, whereas the other study did not find R132 mutation in 4 prostate cancers. We therefore studied the IDH1 mutations in our prostate cancer targeted exon sequencing database. Methods: Targeted exon sequencing was performed on 52 treatment naïve prostate cancers as part of Moffitt Cancer Center’s Total Cancer Care initiative. The coverage was set to be at least 50 fold. 51/52 samples are primary prostate cancer obtained during radical prostatectomy and 1 sample is a brain metastasis. The 1000 Genomes and the NHLBI Exome Sequencing Project (ESP) were used to exclude likely polymorphisms. The catalogue of somatic mutations in cancer (COSMIC) was used to identify mutations seen in other sequencing projects, and Polyphen2 was used to predict the potential detrimental effect of the amino acid changes predicted from the genetic mutations. Results: 1/51 (2%) primary prostate cancers harbor the R132H mutation, which is known to generate the oncometabolite, (R)-2-hydroxylutarate. Y183C was identified in 1/51 samples. This amino acid change in exon 6 of IDH1 is seen at 1% allele frequency in 1000 Genomes and ESP-euro. It is classified as "probably_damaging" with a PolyPhen2 score of .999. Another "probably_damaging" amino acid change is T325M mutation, which is identified in a different primary prostate cancer. V178I in IDH1 was also identified and is thought to be an inherited variant, given it has an allele frequency of 4% in 1000 Genomes, 5% in ESP-european, and 8% in ESP-African-American. Among the frequent gene mutations in metastatic prostate cancer, only a missense mutation in the androgen receptor (H875Y) was identified in the treatment naïve brain metastasis. This H875Y has been linked to promiscuous androgen receptor. Conclusions: Mutations in IDH1 R132H and other “probably_damaging” amino acid changes are identified in primary prostate cancers. This holds further implications for future studies on prostate cancer, and may point to an interesting target in the disease.
Searching for <i>CDH1</i> gene mutations in early-onset diffuse gastric cancer in Chinese patients.
Authors: Xu Yanjun, Cao Wenming, Xu Qi, Guo Jianmin, Wang Xinbao, Cheng Xiangdong, Ying Jieer
Journal: Journal of Clinical Oncology (2014)

23 Background: CDH1 germline mutations are found to be associated with the development of hereditary diffuse gastric cancer (HDGC) and the early-onset diffuse gastric cancer (EODGC). But the impact of CDH1 gene mutations and large deletions on HDGC and EODGC has not been fully determined in Asians. Although the incidence of gastric cancer is relatively high in China, the detection rate of CDH1 germline mutations in Chinese patients with EODGC is rare compared to that in European patients. Methods: We investigated the mutation status of the CDH1 gene in 57 Chinese EODGC patients younger than 40 years old who met the clinical criteria for HDGC. Polymerase chain reaction-direct sequencing was performed, and multiplex ligation-dependent probe amplification (MLPA) was used to evaluate the patients with negative sequencing results. Associations between mutation, clinicopathologic, and overall survival data were analyzed by SPSS 19. Results: The germline mutations of CDH1gene were identified in 51 (89.5%) of the 57 EODGC patients. The nonsense mutation in exon 13 (c.2200T&gt;C, p.Ala692*) occurred in fourty-six EODGC patients. The missense mutations were detected in twenty patients (Eighteen in exon 5: c.778G&gt;C, p.Glu218Asp; Two in exon 12: c.2012C&gt;G, p.Leu630Val). No deletion or duplication in any patient. Most of the patients carrying the CDH1 mutation in exon 13 had lymph node metastasis when compared with patients lacking CDH1 mutation (87.2% vs 60.0%) ( P &lt; 0.05 ). EODGC patients, lacking germline CDH1 alterations, showed a longer median overall survival (mOS) than patients carrying CDH1 mutation in exon 13 ( P &lt; 0.05 ). Moreover, the presence of CDH1 mutation in exon 13 was associated with the incidence of neural invasion ( P &lt; 0.05 ). Conclusions: This study reveals novel CDH1 mutations in Chinese EODGC patients which had been poorly investigated. The presence of CDH1 mutation in EODGC patients may result in lymph node metastasis and poor prognosis. More research is needed to determine additional genetic targets that trigger EODGC.
Efficient p53 activation and apoptosis induction of MDM2/MDMX inhibitory protein, a recombinant cell-permeable fusion protein, in p53<sup>- </sup>breast cancer cells.
Authors: D. F. Dong, E. X. Li, Y. Y. Wu, M. Dauharry, Q. Q. Geng
Journal: Journal of Clinical Oncology (2011)

e13524 Background: P53 is the most important tumor suppressor and it plays a key role in protection against malignant transformation. MDM2 and MDMX are important regulators of the transcriptional activity and stability of p53 by binding to its NH2 terminus. Recent studies suggest that inhibition of both MDM2 and MDMX is necessary for robust activation of p53 in certain tumor cells. The p53 activation effect of MDM2/MDMX inhibition is more when combined than MDM2 inhibition or MDMX inhibition alone. So searching for a new MDM2/MDMX inhibitor is a promising approach for cancer therapy. Methods: A cell-permeable MDM2/MDMX inhibitory fusion protein, containing TAT peptide for transduction across membranes and the scaffold protein (thioredoxin) displaying the MDM2/MDMX inhibitory peptide pDI, was constructed and expressed by molecular cloning and prokaryotic expression technology. ELISA and co-immunoprecipitation were used to evaluate the feasibility and biological effects of simultaneously disrupting p53 binding to MDM2 and MDMX. MTT, annexin V-FITC, cell cycle detection, Western-Blot were used to identify the activity and mechanism of MDM2/MDMX inhibitory protein in vitro. Results: The MDM2/MDMX inhibitory fusion protein was successfully constructed and expressed. The fusion protein is effectively delivered into tumor cells and disrupts both MDM2 and MDMX interaction with p53 resulting in efficient p53 activation, cell cycle arrest, and cell apoptosis in p53- breast cancer cells. Conclusions: These results show that the fusion protein can be a novel protein drug for antitumor therapies, and also show the therapeutic potential of targeting both MDM2 and MDMX in cancer.
Stage I lung cancer survivorship: Incidence of secondary malignancies and need for individualized care plan.
Authors: R. Surapaneni, K. Rajagopalan, A. Hageboutros
Journal: Journal of Clinical Oncology (2011)

9074 Background: There is paucity of published data addressing long term survivorship of patients treated with curative intent for stage I Lung cancer. Using a population based approach we planned to study the trends in incidence and survival of Stage I lung cancer as well as the incidence of secondary malignancies. Methods: We conducted analysis of the data from the Surveillance Epidemiology and End results data base of patients diagnosed with Stage I lung cancer. Survival analysis was done by calculating the observed 5 year survival from 1988 to 2003, so that it gives us at least 5 years of follow up. Using multiple outcome analysis we calculated the Observed/ Expected ratio of all secondary malignancies in the survivors diagnosed from 1988-2003. Results: The age adjusted incidence rate of stage I lung cancer shows only slight increase from 1988 (18.5, CI: 17.6- 19.4) to 2003 (21.4, CI: 20.6- 22.3) but shows a steady increase from 2003 to 2007 (26, CI: 24.8- 27.3). In the SEER database there were 44,960 patients with newly diagnosed stage 1 Lung cancer during 1988-2003. That gave us 181,158.59 patient years of follow up. The observed 5 year survival has not changed since 1988 (45.5%, CI: 42.80%- 48%) to 2003 (45.4%, CI: 42.9%- 47.9%). Risk of second lung cancer is highest in the 1st year with Observed /Expected ratio (O/E) 6.78 (CI: 6.29-7.31; N= 695) and continues to be high at 10 years O/E 4.12 (CI: 4.44- 4.80; N=276). Laryngeal cancer has the highest risk is in the first year (O/E 9.78 CI: 7.51- 12.51; N= 63) and continues to be high at 10 years. For GI there is increased risk of colon (O/E 1.33 CI: 1.22-1.44; N=568), esophagus (O/E 2.29; CI: 1.85-2.89; N=91) and stomach (O/E1.43 CI: 1.15-1.75; N=94). In the genitourinary system there is increased risk of bladder cancer (O/E 1.83 CI: 1.65- 2.03; N= 363) that stays high even at 10 years. Conclusions: Using a large population based data base we show increasing incidence of stage I lung cancer. There was no change in observed 5 year survival for the time period selected. We also show higher incidence of second malignancies persisting many years after their initial diagnosis of lung cancer. This information might help evaluate various risk modification and screening strategies to improve survival.
Increases in IgE, Eosinophils, and Mast Cells Can be Used in Diagnosis and to Predict Relapse of IgG4-Related Disease
Authors: Emma L. Culver, Ross Sadler, Adrian C. Bateman, Mateusz Makuch, Tamsin Cargill, Berne Ferry, Rob Aalberse, Eleanor Barnes, Theo Rispens
Journal: Clinical Gastroenterology and Hepatology (2017)

IgG subclass 4-related disease (IgG4-RD) is characterized by increased serum levels of IgG4 and infiltration of biliary, pancreatic, and other tissues by IgG4-positive plasma cells. We assessed the prevalence of allergy and/or atopy, serum, and tissue IgE antibodies, and blood and tissue eosinophils in patients with IgG4-RD. We investigated the association between serum IgE and diagnosis and relapse of this disease.We performed a prospective study of 48 patients with IgG4-RD, 42 patients with an increased serum level of IgG4 with other inflammatory and autoimmune conditions (disease control subjects), and 51 healthy individuals (healthy control subjects) recruited from Oxford, United Kingdom from March 2010 through March 2014, and followed for a median of 41 months (range, 3-73 months). Serum levels of immunoglobulin were measured at diagnosis, during steroid treatment, and at disease relapse for patients with IgG4-RD; levels at diagnosis were compared with baseline levels of control subjects. Allergen-specific IgEs were measured using the IgE ImmunoCAP. Levels and distribution of IgG4 and IgE antibodies in lymphoid, biliary, and pancreatic tissues from patients with IgG4-RD and disease control subjects were measured by immunohistochemistry. We analyzed data using the Spearman rank correlation and receiver operating characteristic curves.Serum levels of IgG4 increased to 1.4 g/L or more, and IgE increased to 125 kIU/L or more, in 81% and 54% of patients with IgG4-RD, respectively, compared with 6% and 16% of healthy control subjects (P < .0001). Peripheral blood eosinophilia was detected in 38% of patients with IgG4-RD versus 9% of healthy control subjects (P = .004). Of patients with IgG4-RD, 63% had a history of allergy and 40% had a history of atopy with an IgE-specific response; these values were 60% and 53% in patients with increased serum levels of IgE (P < .05). Level of IgE at diagnosis >480 kIU/L distinguished patients with IgG4-RD from disease control subjects with 86% specificity, 36% sensitivity, and a likelihood ratio of 3.2. Level of IgE at diagnosis >380 kIU/L identified patients with disease relapse with 88% specificity, 64% sensitivity, and a likelihood ratio of 5.4. IgE-positive mast cells and eosinophilia were observed in lymphoid, biliary, and pancreatic tissue samples from 50% and 86% of patients with IgG4-RD, respectively.In a prospective study, we associated IgG4-RD with allergy, atopy, eosinophilia, increased serum levels of IgE, and IgE-positive mast cells in lymphoid, biliary, and pancreatic tissue. An IgE-mediated allergic response therefore seems to develop in most patients with IgG4-RD; levels of IgE might be used in diagnosis and predicting relapse.
Molecular tumor grading of non muscle invasive bladder cancer based on whole transcriptome analysis.
Authors: Jess Shen, Aidan Noon, Yu LIU, Cynthia Kuk, C Ilczynski, R Ni, B Sukhu, K Chan, Adrian Gunaratne, Annette Erlich, Chris Cremer, Quaid Morris, Nuno L Barbosa-Morais, Neil Eric Fleshner, Girish S. Kulkarni, Ben Blencowe, Azar Azad, Theodorus van der Kwast, Alexandre Zlotta, Jeff L Wrana
Journal: Journal of Clinical Oncology (2016)

467 Background: There is an unmet need for a comprehensive genomic characterization of non muscle invasive bladder cancer (NMIBC). NMIBC comprise over 70% of all bladder cancers at presentation. They have highly variable clinical behavior that is not always adequately predicted on the basis of their histological grade (2004 World Health Organization low and high grade, LG-HG). The discrepancy between phenotype and genotype is compounded further by interobserver variability in pathological grading. We have previously established methods for whole transcriptome RNAseq from formalin fixed paraffin embedded tissues (FFPE). Methods: Whole transcriptomic analysis of 110 NMI FFPE BC both LG and HG was performed incorporating messenger RNA expression, splice variants, gene fusion, and pathway perturbation. We used a discovery (n = 40) and a validation cohort (n = 70). These data were integrated and tested for correlation with both pathological grading and clinical outcomes. Grade Risk Index (GRI) score quantifying how closely a patient's transcriptome is related to a reference set of LG NMIBC samples was established. Conventional pathological grading was reviewed by 3 different expert uro-pathologists and interobserver variability calculated. Results: Unsupervised clustering of data from RNA sequencing uncovered classification of three robust - - nonoverlapping, prognostically significant subtypes of NMIBC with distinct GRIs and signatures. When applied by expert pathologists, interobserver variability in histological grading was observed in 17.5%. In the intermediate group (GRI 0.13 to 0.19), pathologists disagreed in 37.5% whether BC was LG or HG. HG NMIBC clustered with MIBC. LG NMIBC in the intermediate GRI group included either very bulky tumors or extremely rare metastatic LG BC (n = 4). HG disease was associated with a shift in BMP signaling and a germ stem cell-like phenotype. Multiple components of the centromere complex and APOBEC3B were upregulated in HG BC. FGFR3::TACC3 fusion events were observed in LG NMIBC only (11.5%). Conclusions: Whole transcriptomic sequencing data delineated three molecular classes of NMIBC.
Detection of prostate cancer with the [<sup>68</sup>Ga]-labeled bombesin antagonist RM2 in patients undergoing radical prostatectomy.
Authors: Andrew Stephens, Wolfgang C. Loidl, Mohsen Beheshti, Ivan Jambor, Jukka Kemppainen, Peter Bostrom, Esa Kahkonen, Mathias Berndt, Andre Mueller, Heikki Minn, Werner Langsteger
Journal: Journal of Clinical Oncology (2016)

80 Background: Gastrin-releasing-peptide receptor (GRPr) is overexpressed in prostate carcinoma (PCa) and offer new means to detect prostate cancer. The bombesin derivative RM2 (DOTA-4-amino-1-carboxymethylpiperidine-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2) is a GRPr antagonist with high binding affinity (Kd 3 nM). A first-in-man study was performed to assess tumor targeting potential of [ 68 Ga]RM2 in patients with local PCa using PET/CT. Based on promising results a Phase I/II study in local PCa was initiated. Methods: In the initial study eleven men with biopsy-proven PCa scheduled for radical prostatectomy were enrolled. The patients (pt) received an i.v. dose of 140 MBq of [ 68 Ga]RM2 followed by dynamic imaging for at least 60 min p.i. The PET assessment included visual evaluation of [ 68 Ga]RM2 intra-prostatic and nodal uptake as well as quantification. An ongoing Phase I/II study is designed to enroll 30+50 biopsy-positive PCa patients. The initial 30 pt have been enrolled, stratified into high, intermediate and low risk of prostate Ca recurrence as defined by NCCN criteria. Results: High uptake of [ 68 Ga]RM2 is seen in pancreas and the urinary system with low background in the rest of the body. Despite of high bladder activity focal or multifocal intraprostatic uptake was detectable. In the first study 10 of 11 pt had positive scans. Subsector analysis of PET positivity vs. pathology yielded a sensitivity, specificity and accuracy of 89, 81, and 83%, respectively. SUVmax was measured in 14 lesions from 9 pts, classified in two groups according to postoperative Gleason score (GS). The higher GS group showed a trend toward higher SUV-values, 10.0 ± 6.7 vs. 6.2 ± 2.5 (t-test: t = -1.21, p-value = 0.28). Both of which were elevated compared to normal tissue 1.2 ± 0.8 The ongoing study is designed with a power of 95% to discriminate between the two GS groups with statistical significance (p = 0.05). Conclusions: [ 68 Ga]RM2 is a promising new tracer with a high detection rate for PCa. Preliminary data indicates higher uptake in more aggressive cancers. The current study is assessing the diagnostic accuracy and impact of presurgical risk assessment on tumor detection in newly diagnosed PCa patients. Clinical trial information: NCT02483884.
MST1R, a receptor tyrosine kinase expressed in malignant pleural mesothelioma.
Authors: D. Easty, S. G. Gray, A. Soltermann, D. Nonaka, D. A. Fennell, I. Opitz, H. I. Pass, L. Mutti, D. M. O'Donnell, K. J. O'Byrne
Journal: Journal of Clinical Oncology (2010)

10583 Background: Receptor tyrosine kinases (RTK) represent novel therapeutic targets for the treatment of malignancy. Using a phospho-RTK array strategy we identified macrophage stimulating 1 receptor (MST1R/RON) as being frequently expressed in malignant pleural mesothelioma (MPM). Methods: We investigated the expression and function of RON in 4 MPM cell lines, 1 transformed mesothelial cell line, and 16 MPM and 5 benign mesothelial surgically resected specimens. Western Blot analysis in fresh frozen samples, immunohistochemistry (IHC) on fixed formalin paraffin embedded (FFPE) specimens, and cellular migration assays in cell lines were performed. Results: Western blot analysis detected RON in the fresh frozen tumour and benign pleural specimens and the 4 MPM cell lines but not in the SV-40 transformed normal mesothelial MET-5A cells. MPM expressed different isoforms of RON compared to benign pleural plaques: both benign pleural plaques and MPM expressed the shortform of RON (sf-RON) whereas the larger RON variants, Δ160 and Δ165, were seen in MPM samples only. The presence of RON message was confirmed by RT-PCR in the MPM cell lines. IHC was performed on a TMA array of FFPE samples resected from 352 patients. 94% showed expression as follows – weak (26%), moderate (37%), strong (31%). The correlation of the IHC scores with clinico-pathological and outcomes variables is ongoing. Using a pre-clinical anti-RON monoclonal antibody, migration assays demonstrate that targeting MST1R/RON prevents cellular migration but not proliferation. Conclusions: Based on the phospho-RTK assays and protein expression studies MST1R/RON is frequently expressed in MPM. The migration inhibition assays suggest that RON may be a novel target for therapy in mesothelioma. Previously, MST1R/RON was shown to mediate epithelial mesenchymal transition (EMT). Therefore RON may play a role in the epithelioid to sarcomatoid spectrum of disease seen with mesothelioma. No significant financial relationships to disclose.
Zap-70 EXPRESSION and Igvh Mutational Status as Markers for Gene EXPRESSION Signature IN B-CLL PATIENTS for Prognostic Classification.
Authors: Alessandra Trojani, Barbara Di Camillo, Alessandra Tedeschi, Milena Lodola, Chiara Colombo, Francesca Ricci, Silvio Veronese, Barbara Scarpati, Enrica Morra, Marco Montillo
Journal: Blood (2009)
Epithelial–mesenchymal transition in circulating tumor cells during and after chemoradiation treatment.
Authors: S. H. Lin, H. Gao, U. Giri, W. Malit, L. Wang, L. Hamblin, I. Beketaev, Z. X. Liao, J. M. Reuben
Journal: Journal of Clinical Oncology (2011)

e21167 Background: Circulating Tumor Cells (CTCs) in peripheral blood (PB) are associated with poor prognosis. We have shown that CTCs in Epithelial-to-Mesenchymal Transition (CTC-EMT) downregulate EpCAM/CD326 and are not detectable by conventional methods but are detectable in PB depleted of CD326 and CD45+ leukocytes. To determine the clinical relevance of CTC-EMT, we assessed epithelial (CD326+) and non-epithelial CD326- cells in PB of stage II-III non-small cell lung cancer (NSCLC; n=8) and esophageal cancer (EC; n=5) patients (pts) undergoing chemoradiation (Tx). Methods: Five mL of PB were collected at baseline (BL), during Tx, and at follow-up (FU). CTC-EMT in CD326+ cells was measured by AdnaTest EMT (AdnaEMT) that measured Twist, Akt, PI3Ka, and ALDH1 by RT-PCR. To determine CTC-EMT in non-epithelial cells, we depleted PB of CD326+ cells and enriched for CD45- cells prior to measuring EMT markers Twist1, Snail1, Transglutaminase-2 (TG2) and Zeb1 by qRT-PCR. A two-fold increase in the expression of any EMT gene transcripts in CD45- cells relative to that of CD45+ cells is positive for CTC-EMT. Results: A total of 38 samples were analyzed (range 2-4 samples per pt). By AdnaEMT, only 1/13 pt expressed Twist+ in epithelial cells at BL and became negative at FU. For non-epithelial CD45- cells, EMT marker gene transcripts were present at BL and at FU in all EC (Twist1: 2/5; TG2: 3/5; Zeb1: 4/5). For NSCLC pts, 2 were negative at BL and became positive at FU. Six NSCLC pts expressed a combination of EMT gene transcripts at BL and FU. No PB contained Snail1. To date, 2/8 pts with at least one FU have developed distant metastasis. Conclusions: This ongoing study shows that CTC-EMT can be detected in epithelial and non-epithelial cells from PB of NSCLC and EC pts. AdnaEMT test was able to detect EMT-related gene transcripts in CD326+ epithelial cells from only 1/13 pts whereas EMT-inducing transcription factors by qRT-PCR were detected in CD45- cells in all pts, with some alterations during Tx. Additional analyses will be performed to determine the prognostic value of these assays and the role(s) of EMT-inducing transcription factors in pts with NSCLC and esophageal cancer receiving chemoradiation.