Publications by authors named "William Pao"

198 Publications

Effect of Sand Fines Concentration on the Erosion-Corrosion Mechanism of Carbon Steel 90° Elbow Pipe in Slug Flow.

Materials (Basel) 2020 Oct 16;13(20). Epub 2020 Oct 16.

Department of Mechanical Engineering, Lappeenranta University of Technology, Yliopistonkatu 34, 53850 Lappeenranta, Finland.

Erosion-corrosion of elbow configurations has recently been a momentous concern in hydrocarbon processing and transportation industries. The carbon steel 90° elbows are susceptible to the erosion-corrosion during the multiphase flow, peculiarly for erosive slug flows. This paper studies the erosion-corrosion performance of 90° elbows at slug flow conditions for impact with 2, 5, and 10 wt.% sand fines concentrations on AISI 1018 carbon steel exploiting quantitative and qualitative analyses. The worn surface analyses were effectuated by using laser confocal and scanning electron microscopy. The experiment was conducted under air and water slug flow containing sand fines of 50 µm average size circulated in the closed flow loop. The results manifest that with the increase of concentration level, the erosion-corrosion magnitude increases remarkably. Sand fines instigate the development of perforation sites in the form of circular, elongated, and coalescence pits at the elbow downstream and the corrosion attack is much more obvious with the increase of sand fines concentration. Another congruent finding is that cutting and pitting corrosion as the primitive causes of material degradation, the 10 wt.% sand fines concentration in carrier phase increases the erosion-corrosion rate of carbon steel up to 93% relative to the 2 wt.% sand fines concentration in slug flow.
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http://dx.doi.org/10.3390/ma13204601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602876PMC
October 2020

Erosion-Corrosion of 30°, 60°, and 90° Carbon Steel Elbows in a Multiphase Flow Containing Sand Particles.

Materials (Basel) 2019 Nov 26;12(23). Epub 2019 Nov 26.

Department of Mechanical Engineering, McGill University, Macdonald Engineering Building, 817 Sherbrooke Street West Montreal, Montreal, QC H3A 0C3, Canada.

Erosion-corrosion in flow changing devices as a result of sand transportation is a serious concern in the hydrocarbon and mineral processing industry. In this work, the flow accelerated erosion-corrosion mechanism of 90°, 60°, and 30° long radius horizontal-horizontal (H-H) carbon steel elbows with an inner diameter of 50.8 mm were investigated in an experimental closed-flow loop. For these geometrical configurations, erosion-corrosion was elucidated for erosive slug flow regimes and the extent of material degradation is reported in detail. Qualitative techniques such as multilayer paint modeling and microscopic surface imaging were used to scrutinize the flow accelerated erosion-corrosion mechanism. The 3D roughness characterization of the surface indicates that maximum roughness appears in downstream adjacent to the outlet of the 90° elbow. Microscopic surface imaging of eroded elbow surfaces disseminates the presence of corrosion pits on the exit regions of the 90° and 60° elbows, but erosion scars were formed on the entry regions of the 30° elbow. Surface characterization and mass loss results indicated that changing the elbow geometrical configuration from a small angle to wide angle significantly changed the mechanical wear mechanism of the tested elbows. Moreover, the maximum erosive location was identified at the top of the horizontally-oriented elbow for slug flow.
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http://dx.doi.org/10.3390/ma12233898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6926515PMC
November 2019

Catalyzing the field of precision oncology, one basket at a time.

Nat Med 2018 04;24(4):387-388

Genentech, South San Francisco, California, USA.

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http://dx.doi.org/10.1038/nm.4530DOI Listing
April 2018

Tissue-Specific Immunoregulation: A Call for Better Understanding of the "Immunostat" in the Context of Cancer.

Cancer Discov 2018 04 15;8(4):395-402. Epub 2018 Mar 15.

Roche Innovation Center Basel, F. Hoffmann-La Roche AG, Basel, Switzerland.

Checkpoint inhibitor therapy has been a breakthrough in cancer research, but only some patients with cancer derive substantial benefit. Although mechanisms underlying sensitivity and resistance to checkpoint inhibitors are being elucidated, the importance of organ-specific regulation of immunity is currently underappreciated. Here, we call for a greater understanding of tissue-specific immunoregulation, namely, "tissue-specific immunostats," to make advances in treatments for cancer. A better understanding of how individual organs at baseline regulate the immune system could enable an improved precision medicine approach to cancer immunotherapy. .
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http://dx.doi.org/10.1158/2159-8290.CD-17-1320DOI Listing
April 2018

Continued use of afatinib with the addition of cetuximab after progression on afatinib in patients with EGFR mutation-positive non-small-cell lung cancer and acquired resistance to gefitinib or erlotinib.

Lung Cancer 2017 11 31;113:51-58. Epub 2017 Aug 31.

University of Groningen and University Medical Center Groningen, Hanzeplein 1, Groningen, The Netherlands. Electronic address:

Objectives: In a phase Ib trial, afatinib plus cetuximab demonstrated promising clinical activity (objective response rate [ORR]: 29%; median progression-free survival [PFS]: 4.7 months) in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) with acquired resistance to erlotinib or gefitinib. Here, a separate cohort exploring afatinib plus cetuximab after progression on afatinib is reported.

Materials And Methods: Patients with EGFR mutation-positive NSCLC who progressed on erlotinib or gefitinib received afatinib 40mg daily until progression, followed by afatinib daily plus cetuximab 500mg/m every 2 weeks until progression or intolerable adverse events (AEs). Endpoints included safety, ORR, and PFS.

Results: Thirty-seven patients received afatinib monotherapy. Two (5%) patients responded; median PFS was 2.7 months. Thirty-six patients transitioned to afatinib plus cetuximab. Four (11%) patients responded; median PFS was 2.9 months. Median PFS with afatinib plus cetuximab for patients who received afatinib monotherapy for ≥12 versus <12 weeks was 4.9 versus 1.8 months (p=0.0354), and for patients with T790M-positive versus T790M-negative tumors was 4.8 versus 1.8 months (p=0.1306). Fifty percent of patients receiving afatinib plus cetuximab experienced drug-related grade 3/4 AEs. The most frequent drug-related AEs (any grade) were diarrhea (70%), rash (49%), and fatigue (35%) with afatinib monotherapy and rash (69%), paronychia (39%), and dry skin (36%) with afatinib plus cetuximab.

Conclusion: Sequential EGFR blockade with afatinib followed by afatinib plus cetuximab had a predictable safety profile and demonstrated modest activity in patients with EGFR mutation-positive NSCLC with resistance to erlotinib or gefitinib. CLINICALTRIALS.

Gov Identifier: NCT01090011.
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http://dx.doi.org/10.1016/j.lungcan.2017.08.014DOI Listing
November 2017

Twice weekly pulse and daily continuous-dose erlotinib as initial treatment for patients with epidermal growth factor receptor-mutant lung cancers and brain metastases.

Cancer 2018 Jan 21;124(1):105-109. Epub 2017 Sep 21.

Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: In a phase 1 study of pulse/continuous-dose erlotinib, no patient had disease progression in the central nervous system (CNS). This expansion cohort of the phase 1 study tested the same regimen in a cohort of individuals with epidermal growth factor receptor (EGFR)-mutant lung cancers with untreated brain metastases.

Methods: Patients had not received EGFR tyrosine kinase inhibitors or radiation for brain metastases. All received 1200 mg of erlotinib on days 1 and 2 and 50 mg on days 3 to 7 weekly. The primary endpoints were the overall and CNS response rates (according to version 1.1 of the Response Evaluation Criteria in Solid Tumors).

Results: Between May 2015 and August 2016, 19 patients were enrolled. Forty-two percent of the patients had target brain lesions, and the median size of the target brain lesions was 13 mm. Overall, 14 patients (74%; 95% confidence interval [CI], 51%-89%) had partial responses. The response rate in brain metastases was 75%. The overall median progression-free survival was 10 months (95% CI, 7 months to not reached). Only 3 patients (16%) had CNS progression. To date, 4 patients required CNS radiation at some time during their course. The adverse events (any grade) seen in 10% or more of the patients were rash, diarrhea, nausea, an increase in alanine aminotransferase, and fatigue.

Conclusions: Pulse/continuous-dose erlotinib produced a 74% overall response rate and a 75% response rate in brain metastases in patients with EGFR-mutant lung cancers and untreated brain metastases. CNS control persisted even after progression elsewhere. Although this regimen did not improve progression-free survival or delay the emergence of EGFR T790M, it prevented progression in the brain and could be useful in situations in which CNS control is critical. Cancer 2018;124:105-9. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5735028PMC
January 2018

SFK/FAK Signaling Attenuates Osimertinib Efficacy in Both Drug-Sensitive and Drug-Resistant Models of EGFR-Mutant Lung Cancer.

Cancer Res 2017 06 17;77(11):2990-3000. Epub 2017 Apr 17.

Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.

Mutant-selective EGFR tyrosine kinase inhibitors (TKI), such as osimertinib, are active agents for the treatment of -mutant lung cancer. Specifically, these agents can overcome the effects of the T790M mutation, which mediates resistance to first- and second-generation EGFR TKI, and recent clinical trials have documented their efficacy in patients with -mutant lung cancer. Despite promising results, therapeutic efficacy is limited by the development of acquired resistance. Here we report that Src family kinases (SFK) and focal adhesion kinase (FAK) sustain AKT and MAPK pathway signaling under continuous EGFR inhibition in osimertinib-sensitive cells. Inhibiting either the MAPK pathway or the AKT pathway enhanced the effects of osimertinib. Combined SFK/FAK inhibition exhibited the most potent effects on growth inhibition, induction of apoptosis, and delay of acquired resistance. SFK family member was amplified in osimertinib-resistant -mutant tumor cells, the effects of which were overcome by combined treatment with osimertinib and SFK inhibitors. In conclusion, our data suggest that the concomitant inhibition of both SFK/FAK and EGFR may be a promising therapeutic strategy for -mutant lung cancer. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-2300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5467531PMC
June 2017

Genomic analysis of 63,220 tumors reveals insights into tumor uniqueness and targeted cancer immunotherapy strategies.

Genome Med 2017 02 24;9(1):16. Epub 2017 Feb 24.

Foundation Medicine, Inc, 150 2nd St, Cambridge, MA, 02141, USA.

Background: The integration of genomics with immunotherapy has potential value for cancer vaccine development. Given the clinical successes of immune checkpoint modulators, interest in cancer vaccines as therapeutic options has been revived. Current data suggest that each tumor contains a unique set of mutations (mutanome), thus requiring the creation of individualized cancer vaccines. However, rigorous analysis of non-individualized cancer immunotherapy approaches across multiple cancer types and in the context of known driver alterations has yet to be reported. We therefore set out to determine the feasibility of a generalizable cancer vaccine strategy based on targeting multiple neoantigens in an HLA-A/B subtype-directed manner.

Methods: A cancer gene-focused, hybrid capture-based genomic analysis was performed on 63,220 unique tumors. Neoantigens were predicted using a combined peptide processing and MHC-I binding prediction tool (IEDB) for all recurrent (>10 tumors) missense alterations and non-frameshift indels for the two most common HLA-A/B subtypes in North American/European populations.

Results: Despite being overwhelmingly unique overall, many mutanomes (~45%) contain at least one mutation from a set of ten mutations chosen to maximize the number of unique tumors. This held true for tumors driven by KRAS G12C (n = 1799), PIK3CA E545K (n = 1713), or EGFR L858R (n = 478) alterations, which define distinct sample subsets. We therefore hypothesized that sets of carefully selected mutations/neoantigens may allow the development of broadly applicable semi-universal cancer vaccines. To test the feasibility of such an approach, antigen processing and MHC-I binding prediction was applied for HLA subtypes A*01:01/B*08:01 and A*02:01/B*44:02. In tumors with a specific HLA type, 0.7 and 2.5% harbored at least one of a set of ten neoantigens predicted to bind to each subtype, respectively. In comparison, KRAS G12C-driven tumors produced similar results (0.8 and 2.6% for each HLA subtype, respectively), indicating that neoantigen targets still remain highly diverse even within the context of major driver mutations.

Conclusions: This "best case scenario" analysis of a large tumor set across multiple cancer types and in the context of driver alterations reveals that semi-universal, HLA-specific cancer vaccine strategies will be relevant to only a small subset of the general population. Similar analysis of whole exome/genome sequencing, although not currently feasible at scale in a clinical setting, will likely uncover further diversity.
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http://dx.doi.org/10.1186/s13073-017-0408-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5324279PMC
February 2017

Functional KRAS mutations and a potential role for PI3K/AKT activation in Wilms tumors.

Mol Oncol 2017 04 15;11(4):405-421. Epub 2017 Mar 15.

Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.

Wilms tumor (WT) is the most common renal neoplasm of childhood and affects 1 in 10 000 children aged less than 15 years. These embryonal tumors are thought to arise from primitive nephrogenic rests that derive from the metanephric mesenchyme during kidney development and are characterized partly by increased Wnt/β-catenin signaling. We previously showed that coordinate activation of Ras and β-catenin accelerates the growth and metastatic progression of a murine WT model. Here, we show that activating KRAS mutations can be found in human WT. In addition, high levels of phosphorylated AKT are present in the majority of WT. We further show in a mouse model and in renal epithelial cells that Ras cooperates with β-catenin to drive metastatic disease progression and promotes in vitro tumor cell growth, migration, and colony formation in soft agar. Cellular transformation and metastatic disease progression of WT cells are in part dependent on PI3K/AKT activation and are inhibited via pharmacological inhibition of this pathway. Our studies suggest both KRAS mutations and AKT activation are present in WT and may represent novel therapeutic targets for this disease.
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http://dx.doi.org/10.1002/1878-0261.12044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5378659PMC
April 2017

Design of Helical Capacitance Sensor for Holdup Measurement in Two-Phase Stratified Flow: A Sinusoidal Function Approach.

Sensors (Basel) 2016 Jul 4;16(7). Epub 2016 Jul 4.

Department of Electrical and Electronic Engineering, Universiti Teknologi PETRONAS, Bandar Seri Iskandar 32610, Malaysia.

A 360° twisted helical capacitance sensor was developed for holdup measurement in horizontal two-phase stratified flow. Instead of suppressing nonlinear response, the sensor was optimized in such a way that a 'sine-like' function was displayed on top of the linear function. This concept of design had been implemented and verified in both software and hardware. A good agreement was achieved between the finite element model of proposed design and the approximation model (pure sinusoidal function), with a maximum difference of ±1.2%. In addition, the design parameters of the sensor were analysed and investigated. It was found that the error in symmetry of the sinusoidal function could be minimized by adjusting the pitch of helix. The experiments of air-water and oil-water stratified flows were carried out and validated the sinusoidal relationship with a maximum difference of ±1.2% and ±1.3% for the range of water holdup from 0.15 to 0.85. The proposed design concept therefore may pose a promising alternative for the optimization of capacitance sensor design.
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http://dx.doi.org/10.3390/s16071032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970081PMC
July 2016

Heterogeneous Mechanisms of Primary and Acquired Resistance to Third-Generation EGFR Inhibitors.

Clin Cancer Res 2016 Oct 1;22(19):4837-4847. Epub 2016 Jun 1.

Institute for Theoretical Physics. University of Cologne, Cologne, Germany.

Purpose: To identify novel mechanisms of resistance to third-generation EGFR inhibitors in patients with lung adenocarcinoma that progressed under therapy with either AZD9291 or rociletinib (CO-1686).

Experimental Design: We analyzed tumor biopsies from seven patients obtained before, during, and/or after treatment with AZD9291 or rociletinib (CO-1686). Targeted sequencing and FISH analyses were performed, and the relevance of candidate genes was functionally assessed in in vitro models.

Results: We found recurrent amplification of either MET or ERBB2 in tumors that were resistant or developed resistance to third-generation EGFR inhibitors and show that ERBB2 and MET activation can confer resistance to these compounds. Furthermore, we identified a KRAS mutation in a patient with acquired resistance to AZD9291 as a potential driver of acquired resistance. Finally, we show that dual inhibition of EGFR/MEK might be a viable strategy to overcome resistance in EGFR-mutant cells expressing mutant KRAS CONCLUSIONS: Our data suggest that heterogeneous mechanisms of resistance can drive primary and acquired resistance to third-generation EGFR inhibitors and provide a rationale for potential combination strategies. Clin Cancer Res; 22(19); 4837-47. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-1915DOI Listing
October 2016

Facilitating a culture of responsible and effective sharing of cancer genome data.

Nat Med 2016 05;22(5):464-71

The Netherlands Cancer Institute, Amsterdam, the Netherlands.

Rapid and affordable tumor molecular profiling has led to an explosion of clinical and genomic data poised to enhance the diagnosis, prognostication and treatment of cancer. A critical point has now been reached at which the analysis and storage of annotated clinical and genomic information in unconnected silos will stall the advancement of precision cancer care. Information systems must be harmonized to overcome the multiple technical and logistical barriers to data sharing. Against this backdrop, the Global Alliance for Genomic Health (GA4GH) was established in 2013 to create a common framework that enables responsible, voluntary and secure sharing of clinical and genomic data. This Perspective from the GA4GH Clinical Working Group Cancer Task Team highlights the data-aggregation challenges faced by the field, suggests potential collaborative solutions and describes how GA4GH can catalyze a harmonized data-sharing culture.
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http://dx.doi.org/10.1038/nm.4089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995884PMC
May 2016

JAK2 inhibition sensitizes resistant EGFR-mutant lung adenocarcinoma to tyrosine kinase inhibitors.

Sci Signal 2016 Mar 29;9(421):ra33. Epub 2016 Mar 29.

Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA. WCMC, New York, NY 10021, USA.

Lung adenocarcinomas with mutant epidermal growth factor receptor (EGFR) respond to EGFR-targeted tyrosine kinase inhibitors (TKIs), but resistance invariably occurs. We found that the Janus kinase (JAK)/signal transduction and activator of transcription 3 (STAT3) signaling pathway was aberrantly increased in TKI-resistant EGFR-mutant non-small cell lung cancer (NSCLC) cells. JAK2 inhibition restored sensitivity to the EGFR inhibitor erlotinib in TKI-resistant cell lines and xenograft models of EGFR-mutant TKI-resistant lung cancer. JAK2 inhibition uncoupled EGFR from its negative regulator, suppressor of cytokine signaling 5 (SOCS5), consequently increasing EGFR abundance and restoring the tumor cells' dependence on EGFR signaling. Furthermore, JAK2 inhibition led to heterodimerization of mutant and wild-type EGFR subunits, the activity of which was then blocked by TKIs. Our results reveal a mechanism whereby JAK2 inhibition overcomes acquired resistance to EGFR inhibitors and support the use of combination therapy with JAK and EGFR inhibitors for the treatment of EGFR-dependent NSCLC.
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http://dx.doi.org/10.1126/scisignal.aac8460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4950506PMC
March 2016

MET Exon 14 Skipping in Non-Small Cell Lung Cancer.

Oncologist 2016 Apr 28;21(4):481-6. Epub 2016 Mar 28.

Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.

Background: Non-small cell lung cancers (NSCLCs) harboring specific genetic alterations can be highly sensitive to targeted therapies.

Materials And Methods: We performed a targeted rearrangement assay on 54 NSCLCs across all stages that were from patients who were never smokers and did not have driver mutations. Because MET exon 14 skipping was the most frequent alteration found, we surveyed the results for MET exon 14 skipping at Massachusetts General Hospital (MGH) since the inclusion of this alteration into our current molecular profiling panel.

Results: In a cohort of 54 never-smokers with lung cancers that were wild-type for known driver mutations, MET exon 14 skipping was the most frequently recurring alteration, occurring in 10 cancers (19%). Clinical testing at MGH via our next-generation sequencing (NGS) and NGS-rearrangement panels showed an additional 16 cases of MET exon 14 skipping, for an overall estimated frequency of 5.6%. A clinical case of a patient with MET exon 14 skipping treated with the MET inhibitor crizotinib is also described.

Conclusion: MET exon 14 skipping is a targetable gene alteration found in NSCLC. Patients with these alterations may respond well to MET inhibition.

Implications For Practice: MET exon 14 skipping occurs with an approximately 5% frequency in NSCLC and is seen in both squamous and adenocarcinoma histology. Patients whose cancers have MET exon 14 skipping can respond well to MET inhibitors. Molecular testing for MET exon 14 skipping should be performed on all lung cancers because this is a targetable alteration.
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http://dx.doi.org/10.1634/theoncologist.2015-0510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4828128PMC
April 2016

CUSTOM-SEQ: a prototype for oncology rapid learning in a comprehensive EHR environment.

J Am Med Inform Assoc 2016 07 23;23(4):692-700. Epub 2016 Mar 23.

Department of Medicine, Division of Hematology/Oncology, Vanderbilt University, Nashville, TN, USA. Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, USA. Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA.

Background: As targeted cancer therapies and molecular profiling become widespread, the era of "precision oncology" is at hand. However, cancer genomes are complex, making mutation-specific outcomes difficult to track. We created a proof-of-principle, CUSTOM-SEQ: Continuously Updating System for Tracking Outcome by Mutation, to Support Evidence-based Querying, to automatically calculate and display mutation-specific survival statistics from electronic health record data.

Methods: Patients with cancer genotyping were included, and clinical data was extracted through a variety of algorithms. Results were refreshed regularly and injected into a standard reporting platform. Significant results were highlighted for visual cueing. A subset was additionally stratified by stage, smoking status, and treatment exposure.

Results: By August 2015, 4310 patients with a median follow-up of 17 months had sufficient data for survival calculation. As expected, epidermal growth factor receptor (EGFR) mutations in lung cancer were associated with superior overall survival, hazard ratio (HR) = 0.53 (P < .001), validating the approach. Guanine nucleotide binding protein (G protein), q polypeptide (GNAQ) mutations in melanoma were associated with inferior overall survival, a novel finding (HR = 3.42, P < .001). Smoking status was not prognostic for epidermal growth factor receptor-mutated lung cancer patients, who also lived significantly longer than their counterparts, even with advanced disease (HR = 0.54, P = .001).

Interpretation: CUSTOM-SEQ represents a novel rapid learning system for a precision oncology environment. Retrospective studies are often limited by study of specific time periods and can lead to incomplete conclusions. Because data is continuously updated in CUSTOM-SEQ, the evidence base is constantly growing. Future work will allow users to interactively explore populations by demographics and treatment exposure, in order to further investigate significant mutation-specific signals.
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http://dx.doi.org/10.1093/jamia/ocw008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4926743PMC
July 2016

EPHA2 Blockade Overcomes Acquired Resistance to EGFR Kinase Inhibitors in Lung Cancer.

Cancer Res 2016 Jan 7;76(2):305-18. Epub 2016 Jan 7.

Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee. Division of Rheumatology and Immunology, Vanderbilt University, Nashville, Tennessee. Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee. Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee. Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, Tennessee.

Despite the success of treating EGFR-mutant lung cancer patients with EGFR tyrosine kinase inhibitors (TKI), all patients eventually acquire resistance to these therapies. Although various resistance mechanisms have been described, there are currently no FDA-approved therapies that target alternative mechanisms to treat lung tumors with acquired resistance to first-line EGFR TKI agents. Here we found that EPHA2 is overexpressed in EGFR TKI-resistant tumor cells. Loss of EPHA2 reduced the viability of erlotinib-resistant tumor cells harboring EGFR(T790M) mutations in vitro and inhibited tumor growth and progression in an inducible EGFR(L858R+T790M)-mutant lung cancer model in vivo. Targeting EPHA2 in erlotinib-resistant cells decreased S6K1-mediated phosphorylation of cell death agonist BAD, resulting in reduced tumor cell proliferation and increased apoptosis. Furthermore, pharmacologic inhibition of EPHA2 by the small-molecule inhibitor ALW-II-41-27 decreased both survival and proliferation of erlotinib-resistant tumor cells and inhibited tumor growth in vivo. ALW-II-41-27 was also effective in decreasing viability of cells with acquired resistance to the third-generation EGFR TKI AZD9291. Collectively, these data define a role for EPHA2 in the maintenance of cell survival of TKI-resistant, EGFR-mutant lung cancer and indicate that EPHA2 may serve as a useful therapeutic target in TKI-resistant tumors.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-0717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4715957PMC
January 2016

Meta-analysis of genome-wide association studies identifies multiple lung cancer susceptibility loci in never-smoking Asian women.

Hum Mol Genet 2016 Feb 4;25(3):620-9. Epub 2016 Jan 4.

Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.

Genome-wide association studies (GWAS) of lung cancer in Asian never-smoking women have previously identified six susceptibility loci associated with lung cancer risk. To further discover new susceptibility loci, we imputed data from four GWAS of Asian non-smoking female lung cancer (6877 cases and 6277 controls) using the 1000 Genomes Project (Phase 1 Release 3) data as the reference and genotyped additional samples (5878 cases and 7046 controls) for possible replication. In our meta-analysis, three new loci achieved genome-wide significance, marked by single nucleotide polymorphism (SNP) rs7741164 at 6p21.1 (per-allele odds ratio (OR) = 1.17; P = 5.8 × 10(-13)), rs72658409 at 9p21.3 (per-allele OR = 0.77; P = 1.41 × 10(-10)) and rs11610143 at 12q13.13 (per-allele OR = 0.89; P = 4.96 × 10(-9)). These findings identified new genetic susceptibility alleles for lung cancer in never-smoking women in Asia and merit follow-up to understand their biological underpinnings.
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http://dx.doi.org/10.1093/hmg/ddv494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4731021PMC
February 2016

Dose-Dependent Mutation Rates Determine Optimum Erlotinib Dosing Strategies for EGFR Mutant Non-Small Cell Lung Cancer Patients.

PLoS One 2015 4;10(11):e0141665. Epub 2015 Nov 4.

Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, United States of America.

Background: The advent of targeted therapy for cancer treatment has brought about a paradigm shift in the clinical management of human malignancies. Agents such as erlotinib used for EGFR-mutant non-small cell lung cancer or imatinib for chronic myeloid leukemia, for instance, lead to rapid tumor responses. Unfortunately, however, resistance often emerges and renders these agents ineffective after a variable amount of time. The FDA-approved dosing schedules for these drugs were not designed to optimally prevent the emergence of resistance. To this end, we have previously utilized evolutionary mathematical modeling of treatment responses to elucidate the dosing schedules best able to prevent or delay the onset of resistance. Here we expand on our approaches by taking into account dose-dependent mutation rates at which resistant cells emerge. The relationship between the serum drug concentration and the rate at which resistance mutations arise can lead to non-intuitive results about the best dose administration strategies to prevent or delay the emergence of resistance.

Methods: We used mathematical modeling, available clinical trial data, and different considerations of the relationship between mutation rate and drug concentration to predict the effectiveness of different dosing strategies.

Results: We designed several distinct measures to interrogate the effects of different treatment dosing strategies and found that a low-dose continuous strategy coupled with high-dose pulses leads to the maximal delay until clinically observable resistance. Furthermore, the response to treatment is robust against different assumptions of the mutation rate as a function of drug concentration.

Conclusions: For new and existing targeted drugs, our methodology can be employed to compare the effectiveness of different dose administration schedules and investigate the influence of changing mutation rates on outcomes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0141665PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4633116PMC
June 2016

Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for Thirteen Cancer Types.

J Natl Cancer Inst 2015 Dec 12;107(12):djv279. Epub 2015 Oct 12.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD (JNS, OP, SIB, QL, CCA, LTA, JDF, MTL, LM, SAS, PRT, KAM, PR, DA, DB, BAB, AB, LBr, WHC, CCC, JSC, JFFJr, NDF, LEBF, MGC, AMG, RNH, NH, WH, PDI, BTJ, CK, CMK, LML, MSL, LEM, LPO, RSSS, WeiT, MT, CWa, SW, NW, KY, PH, LMM, NEC, NR, DTS, SJC, NC); Information Management Services, Silver Spring, MD (WAW, CG); Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Gaithersburg, MD (MY, ZW, LBu, AH, CLi); Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (IDV, KAB, BMB, CoC, MCB, CF, EG, SL, JP, MSt, DJH); Department of Epidemiology, Harvard School of Public Health, Boston, MA (IDV, OA, KAB, CoC, MCB, EG, RSK, SL, JP, HDS, MSt, DTr, DJH, PK); Ontario Health Study, Toronto, Ontario, Canada (MPP); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (HOA, EWe); Unit of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (AA, MF); UCL Cancer Institute, London, UK (MFA, AMF, DH); Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, UK (MFA, AMF, DH, RT); Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China (SJA, JS, YLW, XCZ); Department of Radiation Sciences, Oncology, Umea University, Umea, Sweden (UA, RH, BSM); Division of Urologic Surgery, Washington University School of Medicine, Saint Louis, MO (GAJr, RGIII); Litwin Centre for Cancer Genetics, University of Toronto, Ontario, Canada (ILA, NG, JSW); Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (ILA, SG, NG, JSW); Hematology Unit, Ospedale Oncologico di Riferimento Regionale A. Businco, Cagliari, Italy (EA); Department of Medicin

Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites.

Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers.

Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl (2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures.

Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
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http://dx.doi.org/10.1093/jnci/djv279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4806328PMC
December 2015

Afatinib plus Cetuximab Delays Resistance Compared to Single-Agent Erlotinib or Afatinib in Mouse Models of TKI-Naïve EGFR L858R-Induced Lung Adenocarcinoma.

Clin Cancer Res 2016 Jan 4;22(2):426-35. Epub 2015 Sep 4.

Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut. Department of Pathology, Yale University School of Medicine, New Haven, Connecticut. Department of Medicine, Section of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut.

Purpose: The EGFR tyrosine kinase inhibitors (TKIs), erlotinib and afatinib, have transformed the treatment of advanced EGFR-mutant lung adenocarcinoma. However, almost all patients who respond develop acquired resistance on average approximately 1 year after starting therapy. Resistance is commonly due to a secondary mutation in EGFR (EGFR(T790M)). We previously found that the combination of the EGFR TKI afatinib and the EGFR antibody cetuximab could overcome EGFR(T790M)-mediated resistance in preclinical models. This combination has shown a 29% response rate in a clinical trial in patients with acquired resistance to first-generation TKIs. An outstanding question is whether this regimen is beneficial when used as first-line therapy.

Experimental Design: Using mouse models of EGFR-mutant lung cancer, we tested whether the combination of afatinib plus cetuximab delivered upfront to mice with TKI-naïve EGFR(L858R)-induced lung adenocarcinomas delayed tumor relapse and drug-resistance compared with single-agent TKIs.

Results: Afatinib plus cetuximab markedly delayed the time to relapse and incidence of drug-resistant tumors, which occurred in only 63.6% of the mice, in contrast to erlotinib or afatinib treatment where 100% of mice developed resistance. Mechanisms of tumor escape observed in afatinib plus cetuximab resistant tumors include the EGFR(T790M) mutation and Kras mutations. Experiments in cell lines and xenografts confirmed that the afatinib plus cetuximab combination does not suppress the emergence of EGFR(T790M).

Conclusions: These results highlight the potential of afatinib plus cetuximab as an effective treatment strategy for patients with TKI-naïve EGFR-mutant lung cancer and indicate that clinical trial development in this area is warranted.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-0620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4715986PMC
January 2016

The Impact of Microenvironmental Heterogeneity on the Evolution of Drug Resistance in Cancer Cells.

Cancer Inform 2015 15;14(Suppl 4):19-31. Epub 2015 Jul 15.

Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University, Palo Alto, CA, USA.

Therapeutic resistance arises as a result of evolutionary processes driven by dynamic feedback between a heterogeneous cell population and environmental selective pressures. Previous studies have suggested that mutations conferring resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in non-small-cell lung cancer (NSCLC) cells lower the fitness of resistant cells relative to drug-sensitive cells in a drug-free environment. Here, we hypothesize that the local tumor microenvironment could influence the magnitude and directionality of the selective effect, both in the presence and absence of a drug. Using a combined experimental and computational approach, we developed a mathematical model of preexisting drug resistance describing multiple cellular compartments, each representing a specific tumor environmental niche. This model was parameterized using a novel experimental dataset derived from the HCC827 erlotinib-sensitive and -resistant NSCLC cell lines. We found that, in contrast to in the drug-free environment, resistant cells may hold a fitness advantage compared to parental cells in microenvironments deficient in oxygen and nutrients. We then utilized the model to predict the impact of drug and nutrient gradients on tumor composition and recurrence times, demonstrating that these endpoints are strongly dependent on the microenvironment. Our interdisciplinary approach provides a model system to quantitatively investigate the impact of microenvironmental effects on the evolutionary dynamics of tumor cells.
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http://dx.doi.org/10.4137/CIN.S19338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504404PMC
August 2015

Disparities by Race, Age, and Sex in the Improvement of Survival for Major Cancers: Results From the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Program in the United States, 1990 to 2010.

JAMA Oncol 2015 Apr;1(1):88-96

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.

Importance: Substantial progress has been made in cancer diagnosis and treatment, resulting in a steady improvement in cancer survival. The degree of improvement by age, race, and sex remains unclear.

Objective: To quantify the degree of survival improvement over time by age, race, and sex in the United States.

Design, Setting, And Participants: Longitudinal analyses of cancer follow-up data from 1990 to 2010, from 1.02 million patients who had been diagnosed as having cancer of the colon or rectum, breast, prostate, lung, liver, pancreas, or ovary from 1990 to 2009 and who were included in 1 of 9 population-based registries of the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program.

Main Outcomes And Measures: Hazard ratios (HRs) and 95% CIs for cancer-specific death were estimated for patients diagnosed as having any of these cancers during 1995 to 1999, 2000 to 2004, and 2005 to 2009, compared with those diagnosed in 1990 to 1994.

Results: Significant improvements in survival were found for cancers of the colon or rectum, breast, prostate, lung, and liver. Improvements were more pronounced for younger patients. For patients aged 50 to 64 years and diagnosed from 2005 to 2009, adjusted HRs (95% CIs) were 0.57 (95% CI, 0.55-0.60), 0.48 (95% CI, 0.45-0.51), 0.61 (95% CI, 0.57-0.69), and 0.32 (95% CI, 0.30-0.36), for cancer of the colon or rectum, breast, liver, and prostate, respectively, compared with the same age groups of patients diagnosed during 1990 to 1994. However, the corresponding HRs (95% CIs) for elderly patients (those 75-85 years old) were only 0.88 (95% CI, 0.84-0.92), 0.88 (95% CI, 0.82-0.95), 0.76 (95% CI, 0.69-0.84), and 0.65 (95% CI, 0.61-0.70), for the same 4 cancer sites, respectively. A similar, although weaker, age-related period effect was observed for lung and pancreatic cancers. The adjusted HRs (95% CIs) for lung cancer were 0.75 (95% CI, 0.73-0.77) and 0.84 (95% CI, 0.81-0.86), respectively, for patients aged 50 to 64 years and 75 to 85 years diagnosed between 2005 and 2009, compared with the same age groups of patients diagnosed between 1990 and 1994 (0.73 [95% CI, 0.69-0.77] and 0.90 [95% CI, 0.85-0.95], respectively. Compared with whites or Asians, African Americans experienced greater improvement in prostate cancer survival. From 1990 to 2009, ovarian cancer survival declined among African Americans but improved among whites. No apparent sex difference in the degree of improvement for any non-sex-specific cancer was noted.

Conclusions And Relevance: Younger patients experienced greater benefit from recent oncology advances than elderly patients. African Americans experienced poorer survival than whites for all cancers, and the racial difference decreased for prostate cancer but increased for ovarian cancer. Identifying factors associated with varied improvement in cancer survival can inform future improvements in cancer care for all.
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http://dx.doi.org/10.1001/jamaoncol.2014.161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4523124PMC
April 2015

ERBB activation modulates sensitivity to MEK1/2 inhibition in a subset of driver-negative melanoma.

Oncotarget 2015 Sep;6(26):22348-60

Department of Medicine/Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Melanomas are characterized by activating "driver" mutations in BRAF, NRAS, KIT, GNAQ, and GNA11. Resultant mitogen-activated protein kinase (MAPK) pathway signaling makes some melanomas susceptible to BRAF (BRAF V600 mutations), MEK1/2 (BRAF V600, L597, fusions; NRAS mutations), or other kinase inhibitors (KIT), respectively. Among driver-negative ("pan-negative") patients, an unexplained heterogeneity of response to MEK1/2 inhibitors has been observed. Analysis of 16 pan-negative melanoma cell lines revealed that 8 (50%; termed Class I) are sensitive to the MEK1/2 inhibitor, trametinib, similar to BRAF V600E melanomas. A second set (termed Class II) display reduced trametinib sensitivity, paradoxical activation of MEK1/2 and basal activation of ERBBs 1, 2, and 3 (4 lines, 25%). In 3 of these lines, PI3K/AKT and MAPK pathway signaling is abrogated using the ERBB inhibitor, afatinib, and proliferation is even further reduced upon the addition of trametinib. A potential mechanism of ERBB activation in Class II melanomas is minimal expression of the ERK1/2 phosphatase, DUSP4, as ectopic restoration of DUSP4 attenuated ERBB signaling through potential modulation of the ERBB ligand, amphiregulin (AREG). Consistent with these data, immunohistochemical analysis of patient melanomas revealed a trend towards lower overall DUSP4 expression in pan-negative versus BRAF- and NRAS-mutant tumors. This study is the first to demonstrate that differential ERBB activity in pan-negative melanoma may modulate sensitivity to clinically-available MEK1/2 inhibitors and provides rationale for the use of ERBB inhibitors, potentially in combination with MEK1/2 inhibitors, in subsets of this disease.
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http://dx.doi.org/10.18632/oncotarget.4255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4673168PMC
September 2015

Epidermal growth factor receptor as a novel molecular target for aggressive papillary tumors in the middle ear and temporal bone.

Oncotarget 2015 May;6(13):11357-68

Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Adenomatous tumors in the middle ear and temporal bone are rare but highly morbid because they are difficult to detect prior to the development of audiovestibular dysfunction. Complete resection is often disfiguring and difficult because of location and the late stage at diagnosis, so identification of molecular targets and effective therapies is needed. Here, we describe a new mouse model of aggressive papillary ear tumor that was serendipitously discovered during the generation of a mouse model for mutant EGFR-driven lung cancer. Although these mice did not develop lung tumors, 43% developed head tilt and circling behavior. Magnetic resonance imaging (MRI) scans showed bilateral ear tumors located in the tympanic cavity. These tumors expressed mutant EGFR as well as active downstream targets such as Akt, mTOR and ERK1/2. EGFR-directed therapies were highly effective in eradicating the tumors and correcting the vestibular defects, suggesting these tumors are addicted to EGFR. EGFR activation was also observed in human ear neoplasms, which provides clinical relevance for this mouse model and rationale to test EGFR-targeted therapies in these rare neoplasms.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4484461PMC
http://dx.doi.org/10.18632/oncotarget.3605DOI Listing
May 2015

NF-κB drives acquired resistance to a novel mutant-selective EGFR inhibitor.

Oncotarget 2015 Dec;6(40):42717-32

Department Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.

The clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) harbouring activating EGFR mutations is limited by the emergence of acquired resistance, mostly ascribed to the secondary EGFR-T790M mutation. Selective EGFR-T790M inhibitors have been proposed as a new, extremely relevant therapeutic approach. Here, we demonstrate that the novel irreversible EGFR-TKI CNX-2006, a structural analog of CO-1686, currently tested in a phase-1/2 trial, is active against in vitro and in vivo NSCLC models expressing mutant EGFR, with minimal effect on the wild-type receptor. By integration of genetic and functional analyses in isogenic cell pairs we provide evidence of the crucial role played by NF-κB1 in driving CNX-2006 acquired resistance and show that NF-κB activation may replace the oncogenic EGFR signaling in NSCLC when effective and persistent inhibition of the target is achieved in the presence of the T790M mutation. In this context, we demonstrate that the sole, either genetic or pharmacologic, inhibition of NF-κB is sufficient to reduce the viability of cells that adapted to EGFR-TKIs. Overall, our findings support the rational inhibition of members of the NF-κB pathway as a promising therapeutic option for patients who progress after treatment with novel mutant-selective EGFR-TKIs.
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http://dx.doi.org/10.18632/oncotarget.3956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767465PMC
December 2015

Inconsistency and features of single nucleotide variants detected in whole exome sequencing versus transcriptome sequencing: A case study in lung cancer.

Methods 2015 Jul 23;83:118-27. Epub 2015 Apr 23.

Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN 37203, United States; Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37232, United States; Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States. Electronic address:

Whole exome sequencing (WES) and RNA sequencing (RNA-Seq) are two main platforms used for next-generation sequencing (NGS). While WES is primarily for DNA variant discovery and RNA-Seq is mainly for measurement of gene expression, both can be used for detection of genetic variants, especially single nucleotide variants (SNVs). How consistently variants can be detected from WES and RNA-Seq has not been systematically evaluated. In this study, we examined the technical and biological inconsistencies in SNV detection using WES and RNA-Seq data from 27 pairs of tumor and matched normal samples. We analyzed SNVs in three categories: WES unique - those only detected in WES, RNA-Seq unique - those only detected in RNA-Seq, and shared - those detected in both. We found a small overlap (average ∼14%) between the SNVs called in WES and RNA-Seq. The WES unique SNVs were mainly due to low coverage, low expression, or their location on the non-transcribed strand in RNA-Seq data, while the RNA-Seq unique SNVs were primarily due to their location out of the WES-capture boundary regions (accounting ∼71%), as well as low coverage of the regions, low coverage of the mutant alleles or RNA-editing. The shared SNVs had high locus-specific coverage in both WES and RNA-Seq and high gene expression levels. Additionally, WES unique and RNA-Seq unique SNVs showed different nucleotide substitution patterns, e.g., ∼55% of RNA-Seq unique variants were A:T→G:C, a hallmark of RNA editing. This study provides an important evaluation on the inconsistencies of somatic SNVs called in WES and RNA-Seq data.
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http://dx.doi.org/10.1016/j.ymeth.2015.04.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4509831PMC
July 2015

Acquired Resistance to the Mutant-Selective EGFR Inhibitor AZD9291 Is Associated with Increased Dependence on RAS Signaling in Preclinical Models.

Cancer Res 2015 Jun 13;75(12):2489-500. Epub 2015 Apr 13.

AstraZeneca Oncology Innovative Medicines, Alderley Park, Macclesfield, Cheshire, United Kingdom.

Resistance to targeted EGFR inhibitors is likely to develop in EGFR-mutant lung cancers. Early identification of innate or acquired resistance mechanisms to these agents is essential to direct development of future therapies. We describe the detection of heterogeneous mechanisms of resistance within populations of EGFR-mutant cells (PC9 and/or NCI-H1975) with acquired resistance to current and newly developed EGFR tyrosine kinase inhibitors, including AZD9291. We report the detection of NRAS mutations, including a novel E63K mutation, and a gain of copy number of WT NRAS or WT KRAS in cell populations resistant to gefitinib, afatinib, WZ4002, or AZD9291. Compared with parental cells, a number of resistant cell populations were more sensitive to inhibition by the MEK inhibitor selumetinib (AZD6244; ARRY-142886) when treated in combination with the originating EGFR inhibitor. In vitro, a combination of AZD9291 with selumetinib prevented emergence of resistance in PC9 cells and delayed resistance in NCI-H1975 cells. In vivo, concomitant dosing of AZD9291 with selumetinib caused regression of AZD9291-resistant tumors in an EGFRm/T790M transgenic model. Our data support the use of a combination of AZD9291 with a MEK inhibitor to delay or prevent resistance to AZD9291 in EGFRm and/or EGFRm/T790M tumors. Furthermore, these findings suggest that NRAS modifications in tumor samples from patients who have progressed on current or EGFR inhibitors in development may support subsequent treatment with a combination of EGFR and MEK inhibition.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-3167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4605607PMC
June 2015

Old Habits Die Hard: Addiction of BRAF-Mutant Cancer Cells to MAP Kinase Signaling.

Cancer Discov 2015 Apr;5(4):348-50

Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee. Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.

Dual and triple combination therapies with RAF inhibitors plus other targeted agents have demonstrated promising clinical utility in BRAFV600-mutant solid tumors. However, despite vertical inhibition at multiple nodes on the MAPK signaling pathway, resistant tumors emerge. Ahronian and colleagues show that in BRAF-mutant colorectal cancer, resistance involves reactivation of RAS/RAF/MEK/ERK signaling and may be overcome by newly emerging ERK inhibitors.
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http://dx.doi.org/10.1158/2159-8290.CD-15-0221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4507433PMC
April 2015

Genetic variants associated with longer telomere length are associated with increased lung cancer risk among never-smoking women in Asia: a report from the female lung cancer consortium in Asia.

Int J Cancer 2015 Jul 29;137(2):311-9. Epub 2014 Dec 29.

Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.

Recent evidence from several relatively small nested case-control studies in prospective cohorts shows an association between longer telomere length measured phenotypically in peripheral white blood cell (WBC) DNA and increased lung cancer risk. We sought to further explore this relationship by examining a panel of seven telomere-length associated genetic variants in a large study of 5,457 never-smoking female Asian lung cancer cases and 4,493 never-smoking female Asian controls using data from a previously reported genome-wide association study. Using a group of 1,536 individuals with phenotypically measured telomere length in WBCs in the prospective Shanghai Women's Health study, we demonstrated the utility of a genetic risk score (GRS) of seven telomere-length associated variants to predict telomere length in an Asian population. We then found that GRSs used as instrumental variables to predict longer telomere length were associated with increased lung cancer risk (OR = 1.51 (95% CI = 1.34-1.69) for upper vs. lower quartile of the weighted GRS, p value = 4.54 × 10(-14) ) even after removing rs2736100 (p value = 4.81 × 10(-3) ), a SNP in the TERT locus robustly associated with lung cancer risk in prior association studies. Stratified analyses suggested the effect of the telomere-associated GRS is strongest among younger individuals. We found no difference in GRS effect between adenocarcinoma and squamous cell subtypes. Our results indicate that a genetic background that favors longer telomere length may increase lung cancer risk, which is consistent with earlier prospective studies relating longer telomere length with increased lung cancer risk.
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http://dx.doi.org/10.1002/ijc.29393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4733320PMC
July 2015
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