Virtual Library
Start Your Search
R. Thomas
Author of
-
+
MO10 - Molecular Pathology II (ID 127)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Pathology
- Presentations: 1
- Moderators:W.A. Franklin, A. Mahar
- Coordinates: 10/28/2013, 16:15 - 17:45, Bayside 104, Level 1
-
+
MO10.13 - DISCUSSANT (ID 3986)
17:25 - 17:35 | Author(s): R. Thomas
- Abstract
- Presentation
Abstract not provided
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
MS03 - The Cutting Edge of Molecularly Targeted Therapy (ID 20)
- Event: WCLC 2013
- Type: Mini Symposia
- Track: Medical Oncology
- Presentations: 1
- Moderators:N. Saijo, H.A. Wakelee
- Coordinates: 10/28/2013, 14:00 - 15:30, Plenary Hall, Ground Level
-
+
MS03.1 - Novel Targets in Small Cell Cancer (ID 467)
14:05 - 14:30 | Author(s): R. Thomas
- Abstract
- Presentation
Abstract
I will discuss recent results from genomic sequencing studies on small cell lung cancer. In particular, results related to possible therapeutic opportunities will be a focus of my talk.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
MTE21 - Genomics in Lung Cancer (FULL) (ID 65)
- Event: WCLC 2013
- Type: Meet the Expert (ticketed session)
- Track: Pathology
- Presentations: 1
- Moderators:N. n/a
- Coordinates: 10/30/2013, 07:00 - 08:00, Bayside 104, Level 1
-
+
MTE21a.1 - Genomics in Lung Cancer (ID 618)
07:00 - 08:00 | Author(s): R. Thomas
- Abstract
- Presentation
Abstract
Novel therapeutic targets have been revealed in lung cancer through the use of systematic large-scale sequencing approaches. While some of these are already part of routine clinical care, others still await confirmation in clinical trials. I will discuss basics of lung cancer genomics, differences in targets and target candidates in lung adenocarcinoma, squamous cell lung cancer and small cell lung cancer and problems arising during the path of translating basic discoveries into clinical practice.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
O04 - Molecular Pathology I (ID 126)
- Event: WCLC 2013
- Type: Oral Abstract Session
- Track: Pathology
- Presentations: 1
- Moderators:I.I. Wistuba, W.A. Cooper
- Coordinates: 10/28/2013, 10:30 - 12:00, Parkside Ballroom A, Level 1
-
+
O04.01 - Identification of CD74-NRG1, a new recurrent fusion gene in invasive mucinous lung adenocarcinomas of never smokers (ID 4022)
10:30 - 10:40 | Author(s): R. Thomas
- Abstract
- Presentation
Background
Lung adenocarcinoma (AD) of patients who have never smoked frequently bear targetable genome kinase alterations, such as EGFR mutations and translocations affecting ALK, ROS1, and RET genes. These mutations correlate with kinase inhibitor sensitivity in mouse models or in patients. Unfortunately, therapeutically relevant kinase alterations are not present in all lung cancer specimens. Thus, additional genome alterations need to be discovered in order to provide a therapeutic opportunity for the remaining patients.Methods
We collected a cohort of 25 AD specimens of never smokers lacking mutations in KRAS or EGFR, in which we performed transcriptome sequencing with the aim of identifying new oncogenic driver genes.Results
We were able to identify known kinase fusions affecting ALK, ROS1 and RET genes in 3 cases each. Moreover, we detected one sample carrying a novel chimeric transcript fusing the first six exons of CD74 to the EGF-like domain of the NRG1 III-β3 isoform, leading to the expression of its EGF-like domain in an otherwise NRG1-negative tumor tissue. The fusion gene was further detected in four additional cases out of 94 pan-negative* ADs of never smokers. In total, all 5 cases were identified in stage I invasive mucinous lung adenocarcinomas (IMA) of never smoker females. This tumor type frequently presents with multifocal unresectable disease, for which no effective treatment has been yet established. IMA is highly associated with KRAS mutations; indeed, out of 15 IMA analysed, 6 carried a KRAS mutation (40%), and 4 the CD74-NRG1 fusion (27%). Given the fact that NRG1 signals through ERBB3 and ERBB4 receptors, we aimed to determine which receptor CD74-NRG1 provides the ligand for. We observed that ERBB4 was not expressed in the index case, while ERBB3 was relatively highly expressed and this expression also correlated with a positive phospho-ERBB3 (p-ERBB3) signal in the tumoral tissue of all 5 CD74-NRG1 positive cases. In order to test if this phosphorylation of ERBB3 was statistically significant, we stained a cohort of 241 ADs and found that p-ERBB3 was only positive in 6 of them (p-value<0.0001). Additionally, although both EGFR and ERBB2 were expressed in the index case, only ERBB2 expression correlated with a p-ERBB2 positive signal. These data suggest that CD74-NRG1 might provide the ligand for ERBB3, which may form heterodimers with ERBB2, since ERBB3 is devoid of intrinsic kinase activity and cannot support linear signaling in isolation. This is in line with previous studies showing that NRG1 induces an oncogenic signal through ERBB2-ERBB3 heterodimers engaging the PI3K-AKT pathway. This was further supported by the activation of the PI3K-AKT, but not the MAPK pathway, in CD74-NRG1 transduced H2052 lung cells, after 24h starvation. *pan-negative: EGFR, KRAS, ALK, HER2, BRAF, ROS1 and RET wild-typeConclusion
Altogether, these data shows that CD74-NRG1 is a new recurrent oncogenic fusion gene, highly associated with IMA of never smokers. It also suggests that CD74-NRG1 fusion protein signals through the ERBB2-ERBB3 receptors complex leading to the activation of the PI3K-AKT pathway, providing a therapeutic opportunity for a tumor type with, so far, no effective treatment.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
