Publications by authors named "Kyle Gowen"

21 Publications

  • Page 1 of 1

Testing least cost path (LCP) models for travel time and kilocalorie expenditure: Implications for landscape genomics.

PLoS One 2020 22;15(9):e0239387. Epub 2020 Sep 22.

Department of Anthropology, Binghamton University, Binghamton, NY, United States of America.

Least Cost Path (LCP) analysis allows a user to define a cost parameter through which cost of movement can be assessed using Geographical Information Systems (GIS). These analyses are commonly used to construct theoretical movement through a landscape, which has been useful for creating hypotheses concerning prehistoric archaeology and landscape genomics. However, LCP analysis is commonly employed without testing the generated LCP(s), complicating its usefulness as a methodological tool. This paper proposes a model for analyzing movement in ArcGIS by using topography data to calculate slope. This slope data is then then used to calculate LCPs based on travel time and kilocalorie expenditure. LCPs were constructed in the Nature Preserve at Binghamton University, a 182-acre area that consists of wetland and mountainous terrain, and a Fitbit® Surge activity monitor was used to test the accuracy of the model's predictions. Paired sample t-tests show a lack of significant difference between calculated and walked time in our analysis (p = .953), suggesting that our model can estimate travel time between two points based solely on slope of the region. Paired sample t-tests also show a lack of significant difference between calculated and observed kilocalorie expenditure (p = .930), suggesting that our model is also capable of estimating kilocalorie expenditure associated with movement between two points. Finally, paired sample t-tests confirm that straight line distances do not reflect real movement through a terrain (p = .009), highlighting the need for alternate measures of movement when analyzing the effects of local landscape on movement. Our current model shows strength in its estimations of travel time and kilocalorie expenditure based on topography of a region-future iterations of the model need to establish the statistical similarity between our model's estimations and recorded values for walking time and kilocalorie expenditure.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239387PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508404PMC
November 2020

Recent kuru-induced female gene flow disrupted the coevolution of genes and languages in the Papua New Guinea highlands.

Am J Phys Anthropol 2020 05 9;172(1):87-98. Epub 2020 Mar 9.

Department of Biological Sciences, Binghamton University, Binghamton, New York, USA.

Objectives: The island of New Guinea was settled by modern human over 50,000 years ago, and is currently characterized by a complex landscape and contains one-seventh of the world's languages. The Eastern Highlands of New Guinea were also the home to the devastating prion disease called kuru that primarily affected Fore-speaking populations, with some 68% of cases involving adult females. We characterized the mitochondrial DNA (mtDNA) diversity of highlanders from Papua New Guinea (PNG) to: (a) gain insight into the coevolution of genes and languages in situ over mountainous landscapes; and (b) evaluate the recent influence of kuru mortality on the pattern of female gene flow.

Materials And Methods: We sequenced the mtDNA hypervariable segment 1 of 870 individuals from the Eastern and Southern Highlands of PNG using serums collected in the 1950s to 1960s. These highlanders were selected from villages representing 15 linguistic groups within the Trans-New Guinea phylum. Genetic, linguistic, and geographic distances were calculated separately and correlations among those distance matrices were assessed using the Mantel test.

Results: Geographic, genetic, and linguistic patterns were independently correlated with each other (p < .05). Increased mtDNA diversity in kuru-affected populations and low Fst estimates between kuru-affected linguistic groups were observed.

Discussion: In general, the genetic structure among the Highland populations was shaped by both geography and language, and language is a good predictor of mtDNA affinity in the PNG Highlands. High kuru female mortality increased female gene flow locally, disrupting coevolutionary pattern among genes, languages, and geography.
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http://dx.doi.org/10.1002/ajpa.24047DOI Listing
May 2020

A Novel Next-Generation Sequencing Approach to Detecting Microsatellite Instability and Pan-Tumor Characterization of 1000 Microsatellite Instability-High Cases in 67,000 Patient Samples.

J Mol Diagn 2019 11 22;21(6):1053-1066. Epub 2019 Aug 22.

Department of Research and Development, Foundation Medicine, Inc., Cambridge, Massachusetts.

Microsatellite instability (MSI) is an important biomarker for predicting response to immune checkpoint inhibitor therapy, as emphasized by the recent checkpoint inhibitor approval for MSI-high (MSI-H) solid tumors. Herein, we describe and validate a novel method for determining MSI status from a next-generation sequencing comprehensive genomic profiling assay using formalin-fixed, paraffin-embedded samples. This method is 97% (65/67) concordant with current standards, PCR and immunohistochemistry. We further apply this method to >67,000 patient tumor samples to identify genes and pathways that are enriched in MSI-stable or MSI-H tumor groups. Data show that although rare in tumors other than colorectal and endometrial carcinomas, MSI-H samples are present in many tumor types. Furthermore, the large sample set revealed that MSI-H tumors selectively share alterations in genes across multiple common pathways, including WNT, phosphatidylinositol 3-kinase, and NOTCH. Last, MSI is sufficient, but not necessary, for a tumor to have elevated tumor mutation burden. Therefore, MSI can be determined from comprehensive genomic profiling with high accuracy, allowing for efficient MSI-H detection across all tumor types, especially those in which routine use of immunohistochemistry or PCR-based assays would be impractical because of a rare incidence of MSI. MSI-H tumors are enriched in alterations in specific signaling pathways, providing a rationale for investigating directed immune checkpoint inhibitor therapies in combination with pathway-targeted therapies.
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http://dx.doi.org/10.1016/j.jmoldx.2019.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807551PMC
November 2019

Variable Response to ALK Inhibitors in NSCLC with a Novel MYT1L-ALK Fusion.

J Thorac Oncol 2019 02;14(2):e29-e30

City of Hope Comprehensive Cancer Center, Duarte, California. Electronic address:

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http://dx.doi.org/10.1016/j.jtho.2018.10.169DOI Listing
February 2019

Carving out another slice of the pie: Exceptional response to single agent imatinib in an asian female never-smoker with advanced NSCLC with a de-novo PDGFR-α N848 K mutation.

Lung Cancer 2018 10 31;124:86-89. Epub 2018 Jul 31.

Division of Hematology-Oncology, Department of Medicine, University of California Irvine School of Medicine, Orange, CA 92868, USA; Chao Family Comprehensive Cancer Center, University of California Irvine, Orange, CA 92868, USA. Electronic address:

Non-small cell lung cancer (NSCLC) has emerged as a paradigm for clinical application of precision medicine as optimal therapy is commonly chosen based on genomic biomarkers identified in a patient's tumor sample. Recurrent driver alterations are well described, however, a need to continually identify rare variants remains clinically relevant. We identified an incident case of advanced NSCLC with a PDGFR-α N848 K activation loop mutation with no other concurrent oncogenic drivers. Amino acid sequence alignment confirmed homology to the imatinib-sensitive KIT N822 K activation loop mutation observed in GIST. The patient achieved a 2-year response to single agent imatinib that is ongoing. While PDGFR-α N848 K is rare among public sequencing databases our cases strongly suggests functional relevance and highlights the importance of studying rare variants in NSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2018.07.043DOI Listing
October 2018

Beyond microsatellite testing: assessment of tumor mutational burden identifies subsets of colorectal cancer who may respond to immune checkpoint inhibition.

J Gastrointest Oncol 2018 Aug;9(4):610-617

The Angeles Clinic and Research Institute, Los Angeles, USA.

Background: The clinical application of targeting checkpoint inhibitors in colorectal cancer (CRC) has largely focused on a subset of microsatellite instable (MSI-high) patients. However, the proposed genotype that sensitizes these patients to immunotherapy is not captured by MSI status alone. Estimation of tumor mutational burden (TMB) from comprehensive genomic profiling is validated against whole exome sequencing and linked to checkpoint response in metastatic melanoma, urothelial bladder cancer and non-small cell lung carcinoma. We sought to explore the subset of microsatellite stable (MSS) CRC patients with high TMB, and identify the specific genomic signatures associated with this phenotype. Furthermore, we explore the ability to quantify TMB as a potential predictive biomarker of therapy in CRC.

Methods: Formalin-fixed, paraffin embedded tissue sections from 6,004 cases of CRC were sequenced with a CLIA-approved CGP assay. MSI and TMB statuses were computationally determined using validated methods. The cutoff for TMB-high was defined according to the lower bound value that satisfied the 90% probability interval based on the TMB distribution across all MSI-High patients.

Results: MSS tumors were observed in 5,702 of 6,004 (95.0%) cases and MSI-H tumors were observed in 302 (5.0%) cases. All but one (99.7%) MSI-H cases were TMB-high (range, 6.3-746.9 mut/Mb) and 5,538 of 5,702 (97.0%) MSS cases were TMB-low (range, 0.0-10.8 mut/Mb). Consequently, 164 of 5,702 (2.9%) MSS cases were confirmed as TMB-high (range, 11.7-707.2 mut/Mb), representing an increase in the target population that may respond to checkpoint inhibitor therapy by 54% (466 302, respectively). Response to inhibitor is demonstrated in MSS/TMB-high cases.

Conclusions: Concurrent TMB assessment accurately classifies MSI tumors as TMB-high and simultaneously identifies nearly 3% or CRC as MSS/TMB-high. This subgroup may expand the population of CRC who may benefit from immune checkpoint inhibitor based therapeutic approaches.
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http://dx.doi.org/10.21037/jgo.2018.05.06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087857PMC
August 2018

Impact of EML4-ALK Variant on Resistance Mechanisms and Clinical Outcomes in ALK-Positive Lung Cancer.

J Clin Oncol 2018 04 26;36(12):1199-1206. Epub 2018 Jan 26.

Jessica J. Lin, Satoshi Yoda, Beow Y. Yeap, Ibiayi Dagogo-Jack, Nicholas A. Jessop, Ginger Y. Jiang, Long P. Le, Aaron N. Hata, Justin F. Gainor, Anthony J. Iafrate, and Alice T. Shaw, Massachusetts General Hospital, Boston; Alexa B. Schrock, Kyle Gowen, Philip J. Stephens, Jeffrey S. Ross, Siraj M. Ali, and Vincent A. Miller, Foundation Medicine, Cambridge, MA; Viola W. Zhu and Sai-Hong Ignatius Ou, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA; Melissa L. Johnson, Sarah Cannon Research Institute; and Christine M. Lovly, Vanderbilt-Ingram Cancer Center, Nashville, TN.

Purpose Advanced anaplastic lymphoma kinase ( ALK) fusion-positive non-small-cell lung cancers (NSCLCs) are effectively treated with ALK tyrosine kinase inhibitors (TKIs). However, clinical outcomes in these patients vary, and the benefit of TKIs is limited as a result of acquired resistance. Emerging data suggest that the ALK fusion variant may affect clinical outcome, but the molecular basis for this association is unknown. Patients and Methods We identified 129 patients with ALK-positive NSCLC with known ALK variants. ALK resistance mutations and clinical outcomes on ALK TKIs were retrospectively evaluated according to ALK variant. A Foundation Medicine data set of 577 patients with ALK-positive NSCLC was also examined. Results The most frequent ALK variants were EML4-ALK variant 1 in 55 patients (43%) and variant 3 in 51 patients (40%). We analyzed 77 tumor biopsy specimens from patients with variants 1 and 3 who had progressed on an ALK TKI. ALK resistance mutations were significantly more common in variant 3 than in variant 1 (57% v 30%; P = .023). In particular, ALK G1202R was more common in variant 3 than in variant 1 (32% v 0%; P < .001). Analysis of the Foundation Medicine database revealed similar associations of variant 3 with ALK resistance mutation and with G1202R ( P = .010 and .015, respectively). Among patients treated with the third-generation ALK TKI lorlatinib, variant 3 was associated with a significantly longer progression-free survival than variant 1 (hazard ratio, 0.31; 95% CI, 0.12 to 0.79; P = .011). Conclusion Specific ALK variants may be associated with the development of ALK resistance mutations, particularly G1202R, and provide a molecular link between variant and clinical outcome. ALK variant thus represents a potentially important factor in the selection of next-generation ALK inhibitors.
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http://dx.doi.org/10.1200/JCO.2017.76.2294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5903999PMC
April 2018

Comprehensive Genomic Sequencing of Urothelial Tumors Identifies Rare SMARCB1 (INI-1)-Deficient Carcinomas of the Urinary System.

Clin Genitourin Cancer 2018 04 7;16(2):e373-e382. Epub 2017 Sep 7.

Foundation Medicine Inc, Cambridge, MA.

Purpose: Tumor genomic profiling helps direct therapy for advanced urothelial carcinoma (UC). In the course of clinical care, we encountered a patient with a complete loss of SMARCB1 (switch/sucrose nonfermentable-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1), which encodes INI-1 (integrase interactor 1), as the sole detected driver of their urinary tract tumor. Our objective was the identification and genomic characterization of urinary tract neoplasia with complete SMARCB1 loss.

Patients And Methods: Tissue from 1287 patients with UC was assayed by hybrid capture-based comprehensive genomic profiling (CGP) in the course of clinical care to evaluate genomic alterations (GA), such as, base substitutions, insertions/deletions, amplifications, copy number alterations, fusions/rearrangements, and targeted therapy opportunities. A total of 315 genes frequently altered in cancer were assayed.

Results: CGP identified 10 patients with SMARCB1 alterations. Of the 10 patients, 4 (1 each with renal pelvis, ureter, bladder, and unknown primary cancer) had complete loss of SMARCB1, and 6 had loss of heterozygosity with an unknown effect on function or heterozygous loss. Patients with complete SMARCB1 loss had few or no additional alterations. Compared with conventional UC, the tumor mutational burden was significantly lower (P = .004). All 4 patients with complete SMARCB1-loss tumors were < 56 years old and 3 were female.

Conclusion: The genomic profiles of the tumors from patients with UC revealed a population of tumors driven by complete loss of SMARCB1. This previously uncharacterized subset of INI-1-deficient urinary tract tumors might constitute a new tumor category that could be sensitive to targeted therapy, including EZH2 (enhancer of zeste homolog 2) inhibition. Clinical trial testing could be challenging owing to the rarity of the disease.
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http://dx.doi.org/10.1016/j.clgc.2017.09.001DOI Listing
April 2018

De novo ERBB2 amplification causing intrinsic resistance to erlotinib in EGFR-L858R mutated TKI-naïve lung adenocarcinoma.

Lung Cancer 2017 12 24;114:108-110. Epub 2017 Aug 24.

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.

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http://dx.doi.org/10.1016/j.lungcan.2017.08.018DOI Listing
December 2017

A recurrent endometrial stromal sarcoma harbors the novel fusion .

Gynecol Oncol Rep 2017 May 8;20:51-53. Epub 2017 Mar 8.

Department of Obstetrics and Gynecology and the Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United States.

•Genomic alterations may improve diagnostic certainty and subsequent treatment of endometrial stromal sarcoma.•Novel JAZF1-BCORL1 mutation was identified.•Targeted therapeutics to down-stream targets may improve survival benefit in these patients.
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http://dx.doi.org/10.1016/j.gore.2017.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5348601PMC
May 2017

Comprehensive Genomic Profiling Aids in Distinguishing Metastatic Recurrence from Second Primary Cancers.

Oncologist 2017 02 13;22(2):152-157. Epub 2017 Feb 13.

The Angeles Clinic and Research Institute, Los Angeles, California, USA

Background: Metastatic recurrence after treatment for locoregional cancer is a major cause of morbidity and cancer-specific mortality. Distinguishing metastatic recurrence from the development of a second primary cancer has important prognostic and therapeutic value and represents a difficult clinical scenario. Advances beyond histopathological comparison are needed. We sought to interrogate the ability of comprehensive genomic profiling (CGP) to aid in distinguishing between these clinical scenarios.

Materials And Methods: We identified three prospective cases of recurrent tumors in patients previously treated for localized cancers in which histologic analyses suggested subsequent development of a distinct second primary. Paired samples from the original primary and recurrent tumor were subjected to hybrid capture next-generation sequencing-based CGP to identify base pair substitutions, insertions, deletions, copy number alterations (CNA), and chromosomal rearrangements. Genomic profiles between paired samples were compared using previously established statistical clonality assessment software to gauge relatedness beyond global CGP similarities.

Results: A high degree of similarity was observed among genomic profiles from morphologically distinct primary and recurrent tumors. Genomic information suggested reclassification as recurrent metastatic disease, and patients received therapy for metastatic disease based on the molecular determination.

Conclusions: Our cases demonstrate an important adjunct role for CGP technologies in separating metastatic recurrence from development of a second primary cancer. Larger series are needed to confirm our observations, but comparative CGP may be considered in patients for whom distinguishing metastatic recurrence from a second primary would alter the therapeutic approach. 2017;22:152-157 Distinguishing a metastatic recurrence from a second primary cancer can represent a difficult clinicopathologic problem but has important prognostic and therapeutic implications. Approaches to aid histologic analysis may improve clinician and pathologist confidence in this increasingly common clinical scenario. Our series provides early support for incorporating paired comprehensive genomic profiling in clinical situations in which determination of metastatic recurrence versus a distinct second primary cancer would influence patient management.
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http://dx.doi.org/10.1634/theoncologist.2015-0511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5330711PMC
February 2017

Inactivation of Capicua drives cancer metastasis.

Nat Genet 2017 01 21;49(1):87-96. Epub 2016 Nov 21.

Department of Medicine, University of California, San Francisco, San Francisco, California, USA.

Metastasis is the leading cause of death in people with lung cancer, yet the molecular effectors underlying tumor dissemination remain poorly defined. Through the development of an in vivo spontaneous lung cancer metastasis model, we show that the developmentally regulated transcriptional repressor Capicua (CIC) suppresses invasion and metastasis. Inactivation of CIC relieves repression of its effector ETV4, driving ETV4-mediated upregulation of MMP24, which is necessary and sufficient for metastasis. Loss of CIC, or an increase in levels of its effectors ETV4 and MMP24, is a biomarker of tumor progression and worse outcomes in people with lung and/or gastric cancer. Our findings reveal CIC as a conserved metastasis suppressor, highlighting new anti-metastatic strategies that could potentially improve patient outcomes.
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http://dx.doi.org/10.1038/ng.3728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5195898PMC
January 2017

Activity of c-Met/ALK Inhibitor Crizotinib and Multi-Kinase VEGF Inhibitor Pazopanib in Metastatic Gastrointestinal Neuroectodermal Tumor Harboring EWSR1-CREB1 Fusion.

Oncology 2016 21;91(6):348-353. Epub 2016 Oct 21.

The University of Texas MD Anderson Cancer Center, Houston, Tex., USA.

Malignant gastrointestinal neuroectodermal tumor (GNET) is an aggressive rare tumor, primarily occurring in young adults with frequent local-regional metastases and recurrence after local control. The tumor is characterized by the presence of EWSR1-ATF1 or EWSR1-CREB1 and immunohistochemical positivity for S-100 protein without melanocytic marker positivity. Due to poor responses to standard sarcoma regimens, GNET has a poor prognosis, and development of effective systemic therapy is desperately needed to treat these patients. Herein, we present a patient with a small bowel GNET who experienced recurrent hepatic and skeletal metastases after a primary resection. Comprehensive genomic profiling (CGP) in the course of clinical care with DNA and RNA sequencing demonstrated the presence of an exon 7 to exon 6 EWSR1-CREB1 fusion in the context of a diploid genome with no other genomic alterations. In a clinical trial, the patient received a combination of 250 mg crizotinib with 600 mg pazopanib quaque die and achieved partial response and durable clinical benefit for over 2.8 years, and with minimal toxicity from therapy. Using a CGP database of over 50,000 samples, we identified 11 additional cases that harbor EWSR1-CREB1 and report clinicopathologic characteristics, as these patients may also benefit from such a regimen.
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http://dx.doi.org/10.1159/000449204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5130597PMC
January 2017

Comprehensive Genomic Profiling Identifies a Subset of Crizotinib-Responsive ALK-Rearranged Non-Small Cell Lung Cancer Not Detected by Fluorescence In Situ Hybridization.

Oncologist 2016 06 31;21(6):762-70. Epub 2016 May 31.

Department of Medicine, The University of Chicago, Chicago, Illinois, USA

Introduction: For patients with non-small cell lung cancer (NSCLC) to benefit from ALK inhibitors, sensitive and specific detection of ALK genomic rearrangements is needed. ALK break-apart fluorescence in situ hybridization (FISH) is the U.S. Food and Drug Administration approved and standard-of-care diagnostic assay, but identification of ALK rearrangements by other methods reported in NSCLC cases that tested negative for ALK rearrangements by FISH suggests a significant false-negative rate. We report here a large series of NSCLC cases assayed by hybrid-capture-based comprehensive genomic profiling (CGP) in the course of clinical care.

Materials And Methods: Hybrid-capture-based CGP using next-generation sequencing was performed in the course of clinical care of 1,070 patients with advanced lung cancer. Each tumor sample was evaluated for all classes of genomic alterations, including base-pair substitutions, insertions/deletions, copy number alterations and rearrangements, as well as fusions/rearrangements.

Results: A total of 47 patients (4.4%) were found to harbor ALK rearrangements, of whom 41 had an EML4-ALK fusion, and 6 had other fusion partners, including 3 previously unreported rearrangement events: EIF2AK-ALK, PPM1B-ALK, and PRKAR1A-ALK. Of 41 patients harboring ALK rearrangements, 31 had prior FISH testing results available. Of these, 20 were ALK FISH positive, and 11 (35%) were ALK FISH negative. Of the latter 11 patients, 9 received crizotinib based on the CGP results, and 7 achieved a response with median duration of 17 months.

Conclusion: Comprehensive genomic profiling detected canonical ALK rearrangements and ALK rearrangements with noncanonical fusion partners in a subset of patients with NSCLC with previously negative ALK FISH results. In this series, such patients had durable responses to ALK inhibitors, comparable to historical response rates for ALK FISH-positive cases.

Implications For Practice: Comprehensive genomic profiling (CGP) that includes hybrid capture and specific baiting of intron 19 of ALK is a highly sensitive, alternative method for identification of drug-sensitive ALK fusions in patients with non-small cell lung cancer (NSCLC) who had previously tested negative using standard ALK fluorescence in situ hybridization (FISH) diagnostic assays. Given the proven benefit of treatment with crizotinib and second-generation ALK inhibitors in patients with ALK fusions, CGP should be considered in patients with NSCLC, including those who have tested negative for other alterations, including negative results using ALK FISH testing.
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http://dx.doi.org/10.1634/theoncologist.2015-0497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912370PMC
June 2016

TPD52L1-ROS1, a new ROS1 fusion variant in lung adenosquamous cell carcinoma identified by comprehensive genomic profiling.

Lung Cancer 2016 07 22;97:48-50. Epub 2016 Apr 22.

Chao Family Comprehensive Cancer Center, Department of Medicine, Division of Hematology-Oncology, University of California, Irvine School of Medicine, Orange, CA 92868, United States.

Crizotinib was approved for the treatment of ROS1-rearranged non-small cell lung cancer (NSCLC) patients in the US on 11 March, 2016. Interestingly no one companion diagnostic test (CDx) has been approved simultaneously with this approval of crizotinib. Hence, an ideal and adequate CDx will have to be able to identify ROS1 fusions without the knowledge of the fusion partners to ROS1, and as to date there are 13 fusion partners reported for ROS1 in NSCLC. Here we report a novel TPD52L1-ROS1 fusion variant in NSCLC. This novel TPD52L1-ROS1 fusion variant is generated by the fusion of exons 1-3 of TPD52L1 on chromosome 6q22-23 to the exons 33-43 of ROS1 on chromosome 6q22, likely from an intra-chromosomal deletion and subsequent fusion event similar to the generation of EML4-ALK. The predicted TPD52L1-ROS1 protein product contains 655 amino acids comprising of the N-terminal amino acids 1-95 of TPD52L1 and C-terminal amino acids of 1789-2348 of ROS1. In summary, TPD52L1-ROS1 is a novel ROS1 fusion variant in NSCLC identified by comprehensive genomic profiling and should be included in any ROS1 detecting assays that depend on identifying the corresponding fusion partners, such as reverse transcriptase-polymerase chain reaction (RT-PCR).
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http://dx.doi.org/10.1016/j.lungcan.2016.04.013DOI Listing
July 2016

EGFR Fusions as Novel Therapeutic Targets in Lung Cancer.

Cancer Discov 2016 06 21;6(6):601-11. Epub 2016 Apr 21.

Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee. Addario Lung Cancer Medical Institute, Cambridge, Massachusetts. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.

Unlabelled: Here, we report that novel epidermal growth factor receptor (EGFR) gene fusions comprising the N-terminal of EGFR linked to various fusion partners, most commonly RAD51, are recurrent in lung cancer. We describe five patients with metastatic lung cancer whose tumors harbored EGFR fusions, four of whom were treated with EGFR tyrosine kinase inhibitors (TKI) with documented antitumor responses. In vitro, EGFR-RAD51 fusions are oncogenic and can be therapeutically targeted with available EGFR TKIs and therapeutic antibodies. These results support the dependence of EGFR-rearranged tumors on EGFR-mediated signaling and suggest several therapeutic strategies for patients whose tumors harbor this novel alteration.

Significance: We report for the first time the identification and therapeutic targeting of EGFR C-terminal fusions in patients with lung cancer and document responses to the EGFR inhibitor erlotinib in 4 patients whose tumors harbored EGFR fusions. Findings from these studies will be immediately translatable to the clinic, as there are already several approved EGFR inhibitors. Cancer Discov; 6(6); 601-11. ©2016 AACR.See related commentary by Paik, p. 574This article is highlighted in the In This Issue feature, p. 561.
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http://dx.doi.org/10.1158/2159-8290.CD-16-0075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4893907PMC
June 2016

BRAFV600E Mutations in High-Grade Colorectal Neuroendocrine Tumors May Predict Responsiveness to BRAF-MEK Combination Therapy.

Cancer Discov 2016 06 5;6(6):594-600. Epub 2016 Apr 5.

Foundation Medicine, Inc., Cambridge, Massachusetts.

Unlabelled: Neuroendocrine tumors comprise a heterogeneous group of malignancies with a broad spectrum of clinical behavior. Poorly differentiated tumors follow an aggressive course with limited treatment options, and new approaches are needed. Oncogenic BRAF V600E (BRAF(V600E)) substitutions are observed primarily in melanoma, colon cancer, and non-small cell lung cancer, but have been identified in multiple tumor types. Here, we describe the first reported recurrent BRAF(V600E) mutations in advanced high-grade colorectal neuroendocrine tumors and identify a BRAF alteration frequency of 9% in 108 cases. Among these BRAF alterations, 80% were BRAF(V600E) Dramatic response to BRAF-MEK combination therapy occurred in two cases of metastatic high-grade rectal neuroendocrine carcinoma refractory to standard therapy. Urinary BRAF(V600E) circulating tumor DNA monitoring paralleled disease response. Our series represents the largest study of genomic profiling in colorectal neuroendocrine tumors and provides strong evidence that BRAF(V600E) is an oncogenic driver responsive to BRAF-MEK combination therapy in this molecular subset.

Significance: BRAF(V600E) is an established oncogenic driver, but significant disparities in response exist among tumor types. Two patients with treatment-refractory high-grade colorectal neuroendocrine tumors harboring BRAF(V600E) exhibited rapid and durable response to combined BRAF-MEK inhibition, providing the first clinical evidence of efficacy in this aggressive tumor type. Cancer Discov; 6(6); 594-600. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 561.
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http://dx.doi.org/10.1158/2159-8290.CD-15-1192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008024PMC
June 2016

Oncogenic ALK Fusion in Rare and Aggressive Subtype of Colorectal Adenocarcinoma as a Potential Therapeutic Target.

Clin Cancer Res 2016 08 1;22(15):3831-40. Epub 2016 Mar 1.

Oncology Division, Department of Internal Medicine, Rhode Island Hospital, and Alpert Medical School at Brown University, Providence, Rhode Island.

Purpose: Chromosomal translocations in the anaplastic lymphoma kinase (ALK) gene have been identified as oncogenic drivers in lung adenocarcinomas and other tumors, recently including rare cases of colorectal carcinoma. We identified a patient with refractory metastatic colorectal carcinoma harboring a STRN-ALK gene fusion who achieved an exceptional clinical benefit to the ALK inhibitor ceritinib. Our goal was to further define the clinicopathologic features of ALK-rearranged colorectal carcinoma in a large cohort.

Experimental Design: Clinical cases of colorectal carcinoma evaluated by comprehensive genomic profiling (CGP) or by ALK immunohistochemistry (IHC) were reviewed retrospectively. FISH and microsatellite instability (MSI) analyses were performed.

Results: Nine colorectal carcinoma cases harbored ALK gene fusions. Six cases were identified by CGP of 3,157 colorectal carcinoma (0.2%) and three by IHC of 2,980 colorectal carcinoma (0.1%). The ALK fusions involved known ALK partners EML4, C2orf44, CAD, and the novel STRN, PPP1R21, SENPF, MAPRE3, and PRKAP1B partners. These advanced-stage colorectal carcinomas lacked mutations in other oncogenic drivers, predominantly involved the proximal colon, and often exhibited MSI and mucinous phenotype. The index patient was treated with the ALK inhibitor ceritinib, resulting in a marked decrease in size of a skin metastasis, and resolution by computerized tomography of all contrast enhancing tumor. After 9 months of treatment, biopsy of progressive disease demonstrated a KRAS mutation, consistent with acquired resistance to ceritinib.

Conclusions: Colorectal carcinoma harboring ALK fusions represent a rare aggressive subtype of colorectal carcinoma with distinct clinicopathologic features. This report provides the first clinical evidence that such patients may benefit from targeted monotherapy with ALK inhibitors. Clin Cancer Res; 22(15); 3831-40. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-3000DOI Listing
August 2016

Emergence of RET rearrangement co-existing with activated EGFR mutation in EGFR-mutated NSCLC patients who had progressed on first- or second-generation EGFR TKI.

Lung Cancer 2015 Sep 29;89(3):357-9. Epub 2015 Jun 29.

Division of Hematology-Oncology, Department of Medicine, Chao Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA 92868, USA. Electronic address:

Objectives: The gatekeeper mutation T790M mutation is the responsible for the majority of the resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with EGFR-mutated non-small cell lung cancer (NSCLC). Other previously described resistance mechanisms include HER2 amplification, MET amplification, PIK3CA mutation, epithelial-mesenchymal transition (EMT), small cell transformation have also been identified. However other resistance mechanisms remains to be discovered.

Materials And Methods: Hybrid-capture based comprehensive genomic profiling (CGP) was performed on pre- and post-EGFR TKI progression EGFR-mutated NSCLC tumor samples during routine clinical care. We identify two paired pre- and post-EGFR TKI progression EGFR-mutated NSCLC patient tumor samples where both post EGFR TKI samples harbored in-frame CCDC6-RET rearrangements but not in the pre-EGFR TKI tumor samples. Furthermore analysis of the clinical database revealed one additional NCOA4-RET rearrangement co-existing with activated EGFR mutation in an EGFR-mutated NSCLC patient who had progressed on afatinib. None of the known resistance mechanisms to EGFR TKI including EGFR T790M, EGFR amplification, HER2 amplification, MET amplification, PIK3CA mutation, BRAF mutation, EMT or small cell transformation was identified in the three post progression samples that now harbored RET rearrangements.

Results And Conclusions: This is the first report of RET rearrangement co-existing with activated EGFR mutations in EGFR-mutated patients who had progressed on either first- or second generation EGFR TKI. As such, RET rearrangement may serve as a potential resistance mechanism to EGFR TKI in EGFR-mutated NSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2015.06.021DOI Listing
September 2015

Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors.

Cancer Discov 2015 Aug 13;5(8):850-9. Epub 2015 May 13.

Foundation Medicine Inc., Cambridge, Massachusetts.

Unlabelled: Focal amplification and activating point mutation of the MET gene are well-characterized oncogenic drivers that confer susceptibility to targeted MET inhibitors. Recurrent somatic splice site alterations at MET exon 14 (METex14) that result in exon skipping and MET activation have been characterized, but their full diversity and prevalence across tumor types are unknown. Here, we report analysis of tumor genomic profiles from 38,028 patients to identify 221 cases with METex14 mutations (0.6%), including 126 distinct sequence variants. METex14 mutations are detected most frequently in lung adenocarcinoma (3%), but also frequently in other lung neoplasms (2.3%), brain glioma (0.4%), and tumors of unknown primary origin (0.4%). Further in vitro studies demonstrate sensitivity to MET inhibitors in cells harboring METex14 alterations. We also report three new patient cases with METex14 alterations in lung or histiocytic sarcoma tumors that showed durable response to two different MET-targeted therapies. The diversity of METex14 mutations indicates that diagnostic testing via comprehensive genomic profiling is necessary for detection in a clinical setting.

Significance: Here we report the identification of diverse exon 14 splice site alterations in MET that result in constitutive activity of this receptor and oncogenic transformation in vitro. Patients whose tumors harbored these alterations derived meaningful clinical benefit from MET inhibitors. Collectively, these data support the role of METex14 alterations as drivers of tumorigenesis, and identify a unique subset of patients likely to derive benefit from MET inhibitors.
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http://dx.doi.org/10.1158/2159-8290.CD-15-0285DOI Listing
August 2015