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Published on: May 20, 2020
Genetic and epigenetic analysis of erbB signaling pathway genes in lung cancer
Mohammad Obaidul Hoque1, Mariana Brait, Eli Rosenbaum
1Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Background:
Prognosis for patients with non-small cell lung cancer (NSCLC) is poor. The potential value of modulating epidermal growth factor receptor (EGFR) for treatment is reflected by the recent approval of specific drugs that inhibit its activity. Mutations in EGFR were reported in lung cancer and generated interest, once they enable the identification of lung cancers likely to respond to various targeted small molecules.
Methods:
We tested three key genetic and epigenetic alterations (EGFR, RASSF1A, and BRAF) of this pathway on a series of primary NSCLC (total 111; adenocarcinoma 49, squamous cell carcinoma [SCC] 48, and others 14). The mutational status of KRAS (and p53) was known for these samples. The purpose of this study was to define the pattern of erbB pathway alterations in NSCLC and to test for associations with clinical parameters.
Results:
Five EGFR mutations were identified: three in adenocarcinoma (6%), one in SCC (2%), and one in adenocarcinoma with bronchoalveolar component tumor (7%). EGFR mutations included three in-frame deletions in exon 19 and two point mutations in exon 21. Promoter methylation of RASSF1A was detected in 25 of 45 adenocarcinomas and 18 of 46 SCC. Mutations of EGFR, BRAF, and KRAS in adenocarcinoma were mutually exclusive and inversely correlated with RASSF1A methylation (p = -0.394; p = 0.007).
Discussion:
Overall, genetic and/or epigenetic alterations of erbB pathway genes were detected in 80% (39/49) of adenocarcinomas.Approximately half of primary adenocarcinoma harbor molecular alterations of the erbB pathway. Careful characterization of these alterations and response to anti-EGFR therapies is warranted to determine better and accurate determinants of clinical response.
Insights
Genetic and epigenetic alterations in the erbB pathway are common in non-small cell lung cancer (NSCLC), particularly adenocarcinoma. Identifying these molecular changes can help predict response to targeted therapies like anti-EGFR drugs.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Non-small cell lung cancer (NSCLC) has a poor prognosis.
- Targeted therapies inhibiting epidermal growth factor receptor (EGFR) show promise.
- EGFR mutations identify lung cancers likely to respond to targeted therapies.
Purpose of the Study:
- To define the pattern of erbB pathway alterations in NSCLC.
- To investigate associations between these alterations and clinical parameters.
Main Methods:
- Tested EGFR, RASSF1A, and BRAF alterations in 111 primary NSCLC samples.
- Utilized known KRAS and p53 mutational status.
- Analyzed adenocarcinoma, squamous cell carcinoma, and other NSCLC subtypes.
Main Results:
- Five EGFR mutations found in 6% of adenocarcinomas and 2% of SCCs.
- RASSF1A promoter methylation detected in 56% of adenocarcinomas and 39% of SCCs.
- EGFR, BRAF, and KRAS mutations were mutually exclusive and inversely correlated with RASSF1A methylation in adenocarcinomas.
Conclusions:
- 80% of adenocarcinomas showed genetic and/or epigenetic alterations in the erbB pathway.
- Approximately half of primary adenocarcinomas harbor molecular alterations in the erbB pathway.
- Further characterization of these alterations is needed to guide anti-EGFR therapy response.
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