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Identification of RASAL1 as a major tumor suppressor gene in thyroid cancer
Dingxie Liu1, Chongfei Yang, Ermal Bojdani
1Affiliation of authors: Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes, and Metabolism, Johns Hopkins University School of Medicine, Baltimore, MD (DL, CY, EB, AKM, MX).
Background:
RAS-coupled MAPK and PI3K pathways play a fundamental role in thyroid tumorigenesis, and classical genetic alterations upregulating these pathways are well characterized. We hypothesized that gene abnormality of negative modulators of these signaling pathways might be an important alternative genetic background for thyroid cancer.
Methods:
By examining gene expression patterns of negative modulators of RAS signaling, we attempted to identify potential tumor suppressor genes. We then analyzed the methylation and mutation patterns of the identified gene in 101 thyroid tumors and tested its functions in vitro and in vivo to establish the tumor suppressor role in thyroid cancer.
Results:
Among 13 negative modulators of the RAS pathway screened, RASAL1, encoding a RAS GTPase-activating protein, was frequently hypermethylated in thyroid cancers, which was coupled to its silencing in thyroid cancer cells. We also, for the first time, identified the presence of RASAL1 mutations, with a prevalence of 4.88% (n = 2 of 41) in follicular thyroid cancer (FTC) and 16.67% (n = 5 of 30) in anaplastic thyroid cancer (ATC). RASAL1 displayed MAPK- and PI3K-suppressing and thyroid tumor-suppressing activities, which were all impaired by the mutations. Hypermethylation and mutations of RASAL1 were mutually exclusive and collectively found in zero of 20 benign thyroid tumors, 3.22% (n = 1 of 31) of papillary thyroid cancers, 31.70% (n = 13 of 41) of FTCs, and 33.33% (n = 10 of 30) of ATCs. A rate of 20.83% (n = 5 of 24) of tumors carrying RASAL1 mutation or methylation at high levels (>50%) vs 44.16% (n = 34 of 77) of tumors carrying no RASAL1 mutation or methylation at low levels (< 50%) harbored any of the classical mutations (two-sided P = .02, Fisher exact test) in RAS, BRAF, PTEN, and PIK3CA genes in the MAPK and PI3K pathways, revealing a largely mutually exclusive relationship.
Conclusions:
We identified RASAL1 as a major tumor suppressor gene that is frequently inactivated by hypermethylation and mutations, providing a new alternative genetic background for thyroid cancer, particularly FTC and ATC.
Insights
RASAL1 is a tumor suppressor gene frequently inactivated in thyroid cancers through hypermethylation and mutations. This finding reveals a new genetic pathway contributing to thyroid tumor development, especially in follicular and anaplastic types.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- RAS-coupled MAPK and PI3K pathways are crucial in thyroid cancer development.
- Classical genetic alterations in these pathways are well-documented.
- Gene abnormalities in negative modulators of these pathways may represent alternative genetic drivers.
Purpose of the Study:
- To identify potential tumor suppressor genes among negative modulators of RAS signaling.
- To analyze the methylation and mutation patterns of identified genes in thyroid tumors.
- To investigate the in vitro and in vivo functions of candidate genes to confirm their tumor suppressor role.
Main Methods:
- Screening of 13 negative modulators of the RAS pathway for gene expression patterns.
- Analysis of methylation and mutation status of RASAL1 in 101 thyroid tumors.
- Functional assays (in vitro and in vivo) to assess tumor suppressor activities.
Main Results:
- RASAL1, a RAS GTPase-activating protein gene, was frequently hypermethylated and silenced in thyroid cancers.
- RASAL1 mutations were identified in 4.88% of follicular thyroid cancer (FTC) and 16.67% of anaplastic thyroid cancer (ATC).
- RASAL1 inactivation (methylation or mutation) was significantly associated with the absence of classical MAPK/PI3K pathway mutations, indicating mutual exclusivity.
Conclusions:
- RASAL1 is identified as a key tumor suppressor gene in thyroid cancer.
- Frequent inactivation via hypermethylation and mutations provides a new genetic mechanism for thyroid tumorigenesis.
- This finding is particularly relevant for follicular thyroid cancer (FTC) and anaplastic thyroid cancer (ATC).
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