Virtual Library
Start Your Search
C. Chow
Author of
-
+
P2.02 - Biology/Pathology (ID 616)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
-
+
P2.02-013 - Investigation of Genomic and TCR Repertoire Evolution of AAH, AIS, MIA to Invasive Lung Adenocarcinoma by Multiregion Exome and TCR Sequencing (ID 9192)
09:30 - 09:30 | Author(s): C. Chow
- Abstract
Background:
Carcinogenesis may result from accumulation of molecular aberrations (molecular evolution) and escaping from host immune surveillance (immunoediting). It has been postulated that atypical adenomatous hyperplasia (AAH) represents preneoplastic lesion that may progress to adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and further to frankly invasive adenocarcinoma (ADC). However, due to lack of appropriate study materials, the molecular and immune landscape of AAH, AIS or MIA have not been well studied and the definition and management of these lesions remain controversial.
Method:
With the intent to delineate the pivotal molecular and immune events during early carcinogenesis of lung adenocarcinoma, we have collected 119 resected pre- and early neoplastic lung lesions including AAH (N=24), AIS (N=27), MIA (N=54) and ADC (N=14) from 53 patients including 41 patients presenting with multifocal lesions and 25 patients carrying more than one type of pathology. Two to five spatially separated regions from each lesion were subjected to whole exome sequencing and T cell receptor sequencing.
Result:
Mutation burden (average SNVs) was found to progressively increase from 1.32/Mb in AAH to 2.55/MB in AIS, 5.42/MB in MIA and 15.38/MB in ADC. Genomic heterogeneity has also become more complex with neoplastic progression with mean Shannon index of 1.53 in AAH, 1.78 in AIS, 1.56 in MIA and 1.79 in ADC. An increase in C>A transversions coincident with a decrease in A>G transitions and progressively increasing APOBEC enrichment scores (4.13 in AAH, 5.63 in AIS, 6.02 in MIA and 6.59 in ADC) were observed with neoplastic disease progression. Furthermore, phylogenetic analysis revealed varying evolutional processes in AAH, AIS, MIA and ADC with canonical cancer gene mutations in KRAS, ATM, TP53 and EGFR etc. as key drivers in a subset of patients. TCR sequencing demonstrated a progressive decrease in T cell density (average percent T cells among all nuclear cells: 12% in AAH, 8% in AIS, 7% in MIA and 4% in ADC) and a progressive decrease in productive TCR clonality (average productive TCR clonality: 0.0434 in AAH, 0.0427 in AIS, 0.0399 in MIA and 0.0395 in ADC) suggesting suppressive T cell repertoire in more advanced diseases.
Conclusion:
Our results provide molecular evidence supporting the model of early lung carcinogenesis from AAH, to AIS, MIA and ADC and demonstrated that with disease progression, genomic landscape of lung neoplastic lesions has become progressively more complex along with progressive immunosuppressive TCR repertoire.
