Related Experiment Video
Updated: Nov 18, 2025
Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
Published on: July 17, 2019
Whole-genome characterization of lung adenocarcinomas lacking the RTK/RAS/RAF pathway
Jian Carrot-Zhang1, Xiaotong Yao2, Siddhartha Devarakonda3
1Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA.
Abstract:
RTK/RAS/RAF pathway alterations (RPAs) are a hallmark of lung adenocarcinoma (LUAD). In this study, we use whole-genome sequencing (WGS) of 85 cases found to be RPA(-) by previous studies from The Cancer Genome Atlas (TCGA) to characterize the minority of LUADs lacking apparent alterations in this pathway. We show that WGS analysis uncovers RPA(+) in 28 (33%) of the 85 samples. Among the remaining 57 cases, we observe focal deletions targeting the promoter or transcription start site of STK11 (n = 7) or KEAP1 (n = 3), and promoter mutations associated with the increased expression of ILF2 (n = 6). We also identify complex structural variations associated with high-level copy number amplifications. Moreover, an enrichment of focal deletions is found in TP53 mutant cases. Our results indicate that RPA(-) cases demonstrate tumor suppressor deletions and genome instability, but lack unique or recurrent genetic lesions compensating for the lack of RPAs. Larger WGS studies of RPA(-) cases are required to understand this important LUAD subset.
Insights
Whole-genome sequencing revealed that some lung adenocarcinomas lacking RTK/RAS/RAF pathway alterations (RPAs) actually have them. Other cases show tumor suppressor gene deletions and genome instability, but no clear alternative drivers.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Lung adenocarcinoma (LUAD) is frequently characterized by alterations in the RTK/RAS/RAF pathway (RPAs).
- A subset of LUADs lacks apparent RPAs, necessitating further investigation into their underlying genetic landscape.
Purpose of the Study:
- To characterize the genomic features of LUAD cases initially classified as lacking RPAs using whole-genome sequencing (WGS).
- To identify potential genetic drivers or mechanisms contributing to tumorigenesis in this specific LUAD subset.
Main Methods:
- Whole-genome sequencing (WGS) was performed on 85 LUAD samples previously identified as RPA-negative.
- Analysis focused on identifying genetic alterations including pathway mutations, gene deletions, promoter mutations, and structural variations.
Main Results:
- WGS identified RPA-positive cases in 33% (28/85) of the initially RPA-negative samples.
- Among the remaining cases, focal deletions in STK11 or KEAP1 promoters and increased ILF2 expression due to promoter mutations were observed.
- TP53 mutant cases showed an enrichment of focal deletions, and complex structural variations were linked to copy number amplifications.
Conclusions:
- LUADs lacking apparent RPAs can harbor occult RPA alterations or exhibit tumor suppressor gene deletions and genome instability.
- This subset of LUADs does not present unique or recurrent genetic lesions that compensate for the absence of RPAs.
- Larger WGS studies are crucial to fully understand the genetic basis of RPA-negative LUAD.
More Related Videos
Related Concept Videos
02:38The Ras Gene
Ras is a...
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...