Case ReportGermline Mutation of T790M and Dual/Multiple EGFR Mutations in Patients With Lung Adenocarcinoma
Introduction
Exon 19 deletions and point mutations in L858R are the most common somatic activating mutations in the epidermal growth factor receptor (EGFR) gene that confer sensitivity to EGFR tyrosine kinase inhibitors (TKIs) in lung cancer.1 However, despite the initial response to EGFR TKIs, all patients will eventually develop resistance. One of the most common mechanisms of resistance is acquisition of a second mutation at exon 20, which causes a T790M substitution.2, 3 Although most of these cases have acquired resistance through somatic mutations, a small number of germline EGFR T790M have been reported and are estimated to occur in 1% of non–small-cell lung cancer (NSCLC) cases.4, 5, 6 These germline EGFR T790M mutations are believed to predispose patients to the development of lung cancer, because preclinical studies have shown the germline T790M mutation to be a weak oncogene that often requires a secondary mutation to potentiate cancer development.5, 6
In Asia, a few cases of dual EGFR mutations containing primary de novo T790M substitution before TKI treatment have been described7, 8; however, none were identified to be germline mutations. In contrast, thus far, germline EGFR T790M mutations have only been described in white patients with lung cancer.5, 6 Several family members of European descent with hereditary bronchoalveolar carcinoma were identified with germline T790M mutations.9 Our group previously reported a case of a 72-year-old patient with a solitary T790M mutation who had a germline T790M mutation in her peripheral blood mononuclear cells (PBMCs).10 Recently, 2 cases of germline T790M mutations were reported in never smoking female white patients in the United States.5, 6 In the present brief report, we describe another case of a white female patient with lung adenocarcinoma who had a germline EGFR T790M mutation and concurrent somatic L858R mutation. We also describe a case series of patient demographics and tumor characteristics associated with primary EGFR T790M mutations in patients with NSCLC.
Section snippets
Patient Selection and Data Collection
After institutional review board approval from the MD Anderson Cancer Center, the clinical and demographic data were collected for all patients with lung adenocarcinoma identified as having ≥ 2 EGFR mutations from May 2005 to August 2009. In 2 patients identified as having a primary de novo T790M mutation, PBMCs were isolated and assessed for germline EGFR mutation status.
Tumor and Germline Genotyping
DNA sequences for EGFR (exons 18-21) extracted from paraffin-embedded tissue (NSCLC tumors) or PBMCs (for germline
Frequency of Primary De Novo Dual or Multiple EGFR Mutations in Patients With Lung Adenocarcinoma
We evaluated 427 patients with lung adenocarcinoma treated from May 2005 to August 2009 at the MD Anderson Cancer Center Thoracic Clinic. Of these 427 NSCLC patients, 55 were identified with de novo EGFR mutations in their tumor tissue. Twelve patients (2.8%) were found to have either dual or multiple EGFR mutations. Five of these patients had primary de novo T790M mutations. The clinical and demographic information of the patients with primary de novo T790M mutations are listed in Table 1. The
Discussion
The occurrence of germline EGFR T790M mutations is rare and has only been reported in case series.5, 6 These cases have been predominantly identified in white women with a history of never smoking and adenocarcinoma histologic features. The findings from our case report are consistent with this clinical presentation. From the published data, about 73% of lung cancers that arise in patients with germline EGFR T790M mutations also appear to carry second EGFR mutations.5 One hypothesis suggests
Conclusion
We report the case of a germline EGFR T790M mutation and a case series of patients with NSCLC and dual/multiple EGFR mutations. A primary de novo EGFR T790M mutation has been found at a greater frequency in patients with dual or multiple EGFR mutations. A sensitive detection method such as next generation sequencing will be helpful in identifying these less-frequent mutations. Although this occurs in a rare population of patients, it is important to identify these patients rapidly and enroll
Disclosure
The authors have stated that they have no conflicts of interest.
Acknowledgments
This study was supported by National Institutes of Health (T32 CA 009666) Research Training in Academic Medical Oncology (to Y.L. and C.V.P).
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2022, Seminars in Cancer BiologyCitation Excerpt :These unmappable reads are typically discarded by the bioinformatics pipeline and can result in VAFs that are lower than their expected frequencies. While EGFR T790M is found predominantly as a somatic variant, it has also been reported as a germline variant in individuals and families affected with lung cancer and has been shown to segregate with disease [75–80]. Notably, a subset of germline EGFR T790 M mutations in plasma can be present at low levels (<50 % VAF) due to somatic copy number changes in EGFR, such that the distinction between somatic and germline origin may not be possible from using VAF alone [81].
Y.L. and C.V.P. contributed equally to this work.
Y. Lou is currently at the Division of Hematology/Oncology, Mayo Clinic, Jacksonville, FL.
C.V. Pecot is currently at Thoracic Medical Oncology, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC.