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Julian Carretero
Moderator of
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MS12 - Genome Screenings (ID 75)
- Event: WCLC 2019
- Type: Mini Symposium
- Track: Biology
- Presentations: 5
- Now Available
- Moderators:Wan Lam, Julian Carretero
- Coordinates: 9/10/2019, 11:30 - 13:00, Vancouver (2003)
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MS12.01 - Circulating Biomarkers (Now Available) (ID 3506)
11:30 - 13:00 | Presenting Author(s): Caroline Dive, Caroline Dive, Caroline Dive, Caroline Dive
- Abstract
- Presentation
Abstract
I will describe ongoing studies that seek to develop circulating biomarkers for the early detection of lung cancer. We are taking a multi-assay approach to develop a blood test with sufficient sensitivity and specificity. Our efforts are supported with targeted sample collection from a cohort that are typically described as the high risk, hard to reach. Individuals are asked to attend free lung health checks in supermarket car parks in socially deprived areas of North Manchester where many are offered a low dose CT scan. This approach has allowed a paradigm shift from detection of lung cancer at stage 4 to stage 1-2 where surgery can often be offered with curative intent. Individuals are also asked to provide a blood sample for exploratory research. This approach is generating an optimal blood sample set comprising samples from individuals with a CT positive scan (a proportional of which are false positives) or a negative CT scan with full clinical follow up. I will discuss the challenges of early detection with liquid biopsies (ctDNA, CTCs and plasma proteomes) and our strategies to mitigate them.
Information from this presentation has been removed upon request of the author.
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MS12.02 - Genomic and Functional Approaches to Understanding Cancer Aneuploidy (Now Available) (ID 3507)
11:30 - 13:00 | Presenting Author(s): Alison Taylor | Author(s): Juliann Shih, Gavin Ha, Galen Gao, Xiaoyang Zhang, Ashton Berger, Andrew Cherniack, Rameen Beroukhim, Matthew Meyerson
- Abstract
- Presentation
Abstract
Aneuploidy, whole chromosome or chromosome arm copy number imbalance, is a near-universal characteristic of human cancers. We applied methods that define chromosome arm-level aneuploidy and a global cancer aneuploidy score to 10,522 tumors of 33 types in the Cancer Genome Atlas (TCGA). Aneuploidy level was correlated with TP53 mutation, somatic mutation rate, and expression of proliferation genes. Aneuploidy was anti-correlated with expression of immune signaling genes, due to decreased leukocyte infiltrates in high-aneuploidy samples.
Although yeast and mammalian models of whole chromosome aneuploidies have been extensively investigated, chromosome arm-level aneuploidies have rarely been modeled. Cancer subtypes are often characterized by tumor specific patterns of these arm-level copy number alterations; for example, squamous cell carcinomas (SCCs) from different tissues of origin (including lung, esophagus, and bladder) have a pattern of chromosome 3p loss and chromosome 3q gain. Our analysis of 495 lung SCCs found chromosome 3p deletion to be the most frequent genomic alteration, occurring in almost 80% of the tumors and covering the entire length of the chromosome arm. Over two-thirds of chromosome 3p genes showed significantly decreased expression in these samples.
Without models of chromosome arm-level alterations, the phenotypic effects of specific aneuploidies in cancer, such as 3p deletion, remain unknown. However, recent advances in genome engineering and targeting of endonucleases allow new approaches to generate chromosomal alterations. Here, we used the CRISPR-Cas9 system to delete one copy of chromosome 3p in vitro. We successfully isolated almost 90 clones of immortalized lung epithelial cells with deletion of the 3p arm, with 8 validated by whole genome sequencing. Consistent with patient data, expression of 3p genes was also decreased upon deletion, as well as increased expression of interferon response genes. Phenotypic characterization revealed that cells with chromosome 3p deletion initially proliferated more slowly than their siblings. These chromosome 3p deleted cells had increased G1 arrest, but did not undergo increased apoptosis or cell death. Interestingly, after several passages in culture, the proliferation defect was rescued in chromosome 3p deleted cells; genome sequencing and karyotype analyses suggested that this was the result of chromosome 3 duplication. With our cellular model of chromosome arm-level aneuploidy, we uncovered a possible selection mechanism that allows aneuploidy tolerance in vitro. We used genome engineering to model chromosome arm-level deletions, providing a robust model that will address a gap in our understanding of aneuploidy in cancer.
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MS12.03 - LC-SCRM-Japan, a Pan-Japan Genetic Secreening of Lung Cancer (Now Available) (ID 3508)
11:30 - 13:00 | Presenting Author(s): Koichi Goto
- Abstract
- Presentation
Abstract
Precision Medicine Cancer: Development of Asian Cancer Genomic Screening Platform (LC-SCRUM-Asia)
Background: Recently many actionable driver oncogenes such as EGFR, ALK, RET, ROS1, BRAF and MET have been identified in non-small cell lung cancer (NSCLC). However, most of these driver oncogenes are rare and found in only about 1-2% of lung adenocarcinomas. To develop new molecular targeted agents for rare alterations, efficient genomic screening is needed to identify patients.
Methods: A nationwide genomic screening platform (LC-SCRUM-Japan) was established to primarily screen for ALK, RET and ROS1 fusions using RT-PCR and FISH in advanced non-squamous NSCLC without EGFR mutations in February 2013. From March 2015, this project was expanded to an academic-industrial collaboration initiative with broader eligibility criteria and tumor samples were analyzed by next-generation sequencing (NGS multiplex analysis with OncomineTM Cancer Research Panel). In addition, non-squamous NSCLC regardless of EGFR mutation status and other histological type of lung cancer including squamous NSCLC and small cell lung cancer (SCLC) were enrolled. Clinical information of all patients have also been collected to generate a clinical-genomic database that enables detailed outcome analysis of the cohort.
Results: Since its inception, more than 200 Japanese hospitals participated in this project and 7739 patients were enrolled into LC-SCRUM-Japan. 776 squamous NSCLCs and 823 SCLCs were enrolled. Through this platform, many patients with rare driver oncogenes were identified for approved targeted therapies or successfully enrolled into various clinical trials that have helped develop new targeted agents. Based on our project, crizotinib and dabrafenib/trametinib were approved for ROS1 fusions and BRAF mutation positive lung cancers in Japan, respectively. From December 2017, liquid screening with Guardant 360 (LC-SCRUM-Liquid) was initiated and a large concordance study between tissue and liquid NGS analysis was performed in 2000 patients. Additionally, to identify novel biomarkers for immune checkpoint inhibitors, an immuno-oncology biomarker study (LC-SCRUM-IBIS) was conducted with 1017 patients enrolled from February 2017 to May 2018. PD-L1 assessment by IHC and whole exon sequencing was performed. The LC-SCRUM platform was recently expanded to hospitals in Taiwan and we will expand the collaboration to China and other Southeast Asia to establish an integrated Asia cancer clinical genomic database.
Conclusion:. Genomic screening in LC-SCRUM has provided clinical value by identifying patients with actionable mutations and has helped accelerate clinical development of novel agents. To continue to elevate the standard of cancer care and treatment options for patients in Asia, we are establishing a high quality platform of genomic screening technologies and a mechanism of collecting clinical data that will help elevate precision medicine and drug development in Asia.
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MS12.04 - The International Lung Cancer Consortium (ILCCO), an International Study to Identify Risk Factors for Lung Cancer Development (Now Available) (ID 3509)
11:30 - 13:00 | Presenting Author(s): Rayjean J. Hung On Behalf Of The International Lung Cancer Consortium
- Abstract
- Presentation
Abstract
Background: The International Lung Cancer Consortium (ILCCO) was established in 2004 to maximize research efficiency for lung cancer and to share comparable epidemiological and clinical data, and biological samples across studies. Since its establishment, over 70 studies have participated in the ILCCO and shared comparable clinico-epidemiological data and a subset with biological samples and genomic data. The data harmonization was conducted at the Sinai Health System in Toronto, and genomic data is managed at the Dartmouth College of Medicine/Baylor College of Medicine. In total, the ILCCO Data Repository now has epidemiological data for over 1.2 million study participants, including 100,000 lung cancer patients, and genomic data on approximately 50,000 study participants. The large-scale epidemiological and genomic data allow us to extensively study and characterize the etiological factors, including lifestyle risk factors, medical history and genomic architectures for lung cancer development.
Methods: Data submitted from all studies are systematically checked for missing values, outliers, inadmissible values, aberrant distributions and internal inconsistencies before harmonization. Common variable definitions were developed. For lifestyle risk factors and medical history, we conducted meta-analysis based on study-specific estimates, when applicable. If heterogeneities were present, random effects models were employed to account for the heterogeneity across studies. For subgroup of interests or when sample size is limited, pooled-analyses based on individual-level data were applied. When applicable, the non-linearity relationship was assessed. For genetic susceptibility of lung cancer, we investigated the genetic loci associated with lung cancer risk using log-additive model adjusted for population ancestry and account for multiple comparisons. To assess the causality of specific exposures and lung cancer risk, we applied Mendelian Randomization and mediation analytical approaches. To estimate 5-year lung cancer absolute risk, we incorporated risk factors, medical history and genetic factors based on age-specific lung cancer incidence and the competing risk.
Results: Based on 17 ILCCO studies (24,000 cases and 81,000 controls), we observed a robust association between lung cancer risk and emphysema and pneumonia, even among never smokers, and after long latency period. Based on 24 ILCCO studies, we quantified the association between family history of lung cancer and its risk by their smoking status and affected relative types. Based on 6 studies in UK, Canada, UK and New Zealand, we assessed the association between cannabis smoking and lung cancer risk by intensity, duration and cumulative exposures and by histological subtypes. We have recently completed a largest lung cancer genetic analysis based over 29,000 lung cancer cases and 56,000 controls. We identified 10 novel lung cancer susceptibility loci, in addition to the known regions, such as TERT/CLPTM1L, CHRNA5, MHC region, RAD52, CHEK2 and found specific associations mediated through mRNA expression. We helped to quantify the effect of specific genetic variant in nicotinic receptor gene on smoking cessation and age of onset. Using genetic instruments and Mendelian Randomization approach, we confirmed the association between lung cancer risk and long telomere length. Most recently, we investigated the association between impaired lung function and lung cancer risk based on UK Biobank and ILCCO OncoArray data, and we found that impaired lung function was associated with lung cancer risk in never smokers and particularly for adenocarcinoma, most likely through immune-mediated pathways. When combining all factors into an integrative risk model, we found that individuals with highly polygenic risk scores reached lung cancer screening threshold at younger age than those with average genetic risk background.
Conclusions and Future Perspectives: ILCCO provides a powerful research platform for research on lung cancer. The collaborative projects based on ILCCO have contributed to the understanding of lung cancer etiology beyond tobacco smoking. As future perspectives, ILCCO has obtained clinical prognosis data for over 50,000 lung cancer patients and will also be able to investigate factors associated with lung cancer prognosis in depth. Finally, ILCCO has built close collaborations with several lung cancer low-dose computed tomography screening programs to jointly investigate the optimal strategy for risk stratification and early detection for lung cancer.
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MS12.05 - Genomic Studies on Small Cell Lung Cancer (Now Available) (ID 3510)
11:30 - 13:00 | Presenting Author(s): Julie George
- Abstract
- Presentation
Abstract
Section not applicable
Information from this presentation has been removed upon request of the author.
Author of
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MA17 - Molecular Mechanisms and Therapies (ID 143)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Biology
- Presentations: 1
- Now Available
- Moderators:Eloisa Jantus-Lewintre, Hongbin Ji
- Coordinates: 9/09/2019, 15:45 - 17:15, Melbourne (1991)
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MA17.04 - Discussant - MA17.01, MA17.02, MA17.03 (Now Available) (ID 3786)
15:45 - 17:15 | Presenting Author(s): Julian Carretero
- Abstract
- Presentation
Abstract not provided
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P1.03 - Biology (ID 161)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.03-26 - Genetic and Molecular Profiling of Non-Smoking Related Lung Adenocarcinomas (ID 1701)
09:45 - 18:00 | Author(s): Julian Carretero
- Abstract
Background
The etiology and many details of the genomic profile and molecular basis of lung adenocarcinomas (LuADs) in nonsmoker patients remain elusive. Further, the scarcity of primary cultures available from non-smoking related lung adenocarcinomas (NSK-LuADs) contributes to hamper our biological understanding of these tumors.
Method
We established patient-derived cancer cell (PDCs) cultures from NSK-LuADs, and performed whole exome sequencing (WES) and RNA sequencing (RNA-seq) analysis to delineate their genomic architecture. For validations, we analyzed independent cohorts of LuADs.
Result
The analysis revealed non-smoker related alterations such as those at the growth factor receptors RET, ALK, EGFR and ERBB2. There were also mutations affecting signal transduction molecules such as AKT1, BRAF and KRAS, and mutations in tumor suppressor genes, including TP53, CDKN2A, RB1, ARID1A, ATM and STK11. We also identified new fusions and recurrent mutations in some genes, one of them, a possible regulator of gene expression, affecting ten percent of the LuADs, thus constituting a potentially relevant tumor suppressor gene. We also report a predominance of RB1-inactivation, mostly complex intragenic rearrangements (homozygous deletions or duplications) in EGFR-mutant tumors. Three EGFR-/RB1-mutant tumors, treated with EGFR-TKIs, and one EGFR-wild type tumor, treated with standard chemotherapy, developed small cell lung cancer and/or squamous cell carcinoma transformation, evident in the re-biopsies and/or PDCs. Finally, we found pathogenic germ-line mutations at genes associated to familiar-cancer syndromes, especially the TP53-associated Li Fraumeni syndrome, affecting ten percent of EGFR-mutant LuADs patients, underscoring a genetic predisposition origin for a subset of NSK-LuADs.
Conclusion
The recurrent gene inactivation found in candidate gene in LuADs heralds a tumor suppressor role which deserves further exploration. The pre-existent inactivation of RB1 predominates in EGFR-mutant tumors and may underlie an extremely ductile nature, albeit additional gene alterations are required to overcome sensitivity to the TKIs. Given their potential clinical and therapeutic implications, testing for RB1-alterations and for the Li-Fraumeni syndrome in EGFR-mutant LuADs patients may need to be incorporated in the clinical settings.
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P2.03 - Biology (ID 162)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.03-31 - Chemokine Receptor CXCR7 Reactivates ERK Signaling to Promote Resistance to EGFR Kinase Inhibitors in NSCLC (ID 2817)
10:15 - 18:15 | Author(s): Julian Carretero
- Abstract
Background
Activating EGFR mutations in NSCLC confer sensitivity to reversible EGFR TKIs, including gefitinib and erlotinib. Despite promising initial response, acquired resistance develops mediated by the emergence of the secondary T790M mutation or by focal amplification of MET. An epithelialtomesenchymal transition (EMT) is clinically linked to NSCLCs with acquired EGFR TKI resistance. The exact mechanisms of EGFR TKI resistance with EMT phenotype remain elusive.
Method
We have engineered EGFRmutated NSCLC cell lines with a mesenchymal phenotype by stably depleting ECadherin, overexpressing Snail, or chronically exposing the cells to TGFβ1. The resulting mesenchymal cells are resistant to EGFR TKIs. We employed genomic analyses to identify commonly activated oncogenic drivers that maintain signaling pathways upon EGFR inhibition. We also used EGFRmutated HCC4006 NSCLC cells grown resistant to gefitinib that developed a mesenchymal phenotype (HCC4006GeR). To extend our findings to in vivo, we have utilized matched pre- and post-EGFR TKI treatment samples from NSCLC patient and mouse models of acquired EGFR TKI resistance to test if our approach using these cell lines is instructive.
Result
We discovered that an atypical GPCR, CXC chemokine receptor type 7 (CXCR7), is commonly overexpressed in the cell line models of EGFR TKI resistance with a mesenchymal phenotype. The murine tumors driven by human EGFR exon19 deletion/T790M (TD) with acquired resistance to WZ4002 present mesenchymal phenotype and overexpress CXCR7. 50% of NSCLC patients harboring an EGFR kinase domain mutation who progressed on EGFR inhibitors showed an increase in CXCR7 expression. Using the cell line model of EGFR TKI acquired resistance with a mesenchymal phenotype, we find that CXCR7 activates the MAPK-ERK pathway via b-arrestin. Depletion of CXCR7 abrogates the MAPK pathway and significantly attenuated EGFR TKI resistance in the cells with a mesenchymal phenotype. In the long term, the depletion of CXCR7 resulted in mesenchymal to epithelial transition. Ectopic overexpression of CXCR7 in HCC4006 cells was sufficient in activation of ERK1/2 for the generation of EGFR TKI resistant cells. Furthermore, CXCL12 stimulation resulted in an increase in ERK phosphorylation while EGFR was inhibited in HCC4006Ge-R cells. Similarly, we found we found CXCL12 expression is elevated in patient samples with increased CXCR7 expression.
Conclusion
Taken together, we discovered that the CXCR7-CXCL12 signaling axis is necessary and sufficient for the maintenance of EGFR TKI resistance with mesenchymal phenotype and CXCR7 inhibition could significantly delay and prevent the emergence of acquired EGFR TKI resistance in EGFR mutant NSCLC.
