Functional EGFR Germline Polymorphisms May Confer Risk for EGFR Somatic Mutations in Non–Small Cell Lung Cancer, with a Predominant Effect on Exon 19 Microdeletions

Abstract

Somatic mutations in the EGFR tyrosine kinase domain play a critical role in the development and treatment of non-small cell lung cancer (NSCLC). Strong genetic influence on susceptibility to these mutations has been suggested. To identify the genetic factors conferring risk for the EGFR tyrosine kinase mutations in NSCLC, a case-control study was conducted in 141 Taiwanese NSCLC patients by focusing on three functional polymorphisms in the EGFR gene [À216G/T, intron 1 (CA)n, and R497K]. Allelic imbalance of the EGFR À216G/T polymorphism was also tested in the heterozygous patients and in the NCI-60 cancer cell lines to further verify its function. We found that the frequencies of the alleles À216T and CA-19 are significantly higher in the patients with any mutation (P ¼ 0.032 and 0.01, respectively), in particular in those with exon 19 microdeletions (P ¼ 0.006 and 0.033, respectively), but not in the patients with L858R mutation. The À216T allele is favored to be amplified in both tumor DNA of lung cancer patients and cancer cell lines. We conclude that the local haplotype structures across the EGFR gene may favor the development of cellular malignancies and thus significantly confer risk to the occurrence of EGFR mutations in NSCLC, particularly the exon 19 microdeletions. Cancer Res; 71(7); 2423-7. Ó2011 AACR.

EGFR exon 19 in‐frame deletion and polymorphisms of DNA repair genes in never‐smoking female lung adenocarcinoma patients

“…45 In addition, specific polymorphisms in the EGFR gene have also been suggested to affect the occurrence of EGFR mutations. 9 SNPs in various cytochrome p450 genes and the EGFR gene deserve further comprehensive investigation.…”

“…First, higher frequencies of EGFR mutations have been observed in populations of Asian ethnicity; for example, second-generation Asian immigrants in North America and Europe have a higher EGFR mutation frequency than Caucasian populations in these respective regions. 7 Furthermore, genetic polymorphisms associated with susceptibility to various somatic mutations have been described, [8][9][10][11] including EGFR mutations, implying that EGFR mutations are linked to an individual's genetic background. Moreover, genomic DNA may be continuously damaged by mutagens from both external and internal agents, such as tobacco smoke, chemicals in the environment 12 or estrogen reactive metabolites in internal sources.…”

Common genetic variation in the germline influences where and how tumors develop

“…2,3 Among individuals that develop non-small cell lung cancers, the -216T and CA-19 alleles at the epidermal growth factor receptor (EGFR) locus are associated with the occurrence of EGFR exon 19 microdeletions in the tumor genome. 4 The germline has also been shown to influence gene expression in some tumors. 5,6 These associations, obtained by comparing similar tumors with distinct genomic characteristics, provide a new perspective on cancer risk by tying the germline locus to a specific event in the tumor.…”

Germline pharmacogenomics in oncology: Decoding the patient for targeting therapy

“…The former explains variability in disease, which can usually be associated with differences in natural history and/or etiology, and occasionally in treatment response. On the other hand, germline variation explains variability in the patient, which does affect both pharmacokinetics and pharmacodynamics, as well as potentially disease risk (even risk for specific mutations (Liu et al, 2011)). Some might argue that especially for the latter group of drug-related germline variants, the list of the most extensively studied within oncology (summarized in Table 1) and especially the list of those that has become routinely clinically tested remains relatively small.…”