EGFR Dinucleotide Repeat Polymorphism as a Prognostic Indicator in Non-small Cell Lung Cancer

Abstract

Background:The epidermal growth factor receptor (EGFR) has been implicated in tumor growth and progression. Intron 1 of the EGFR gene contains a polymorphic simple sequence repeat (SSR) of 14 to 21 CA dinucleotides, the length of which correlates inversely with the level of EGFR transcription. The authors hypothesized that a shorter length of tumor SSR would be associated with poorer survival in patients with non-small cell lung cancer (NSCLC). Methods: Patients enrolled in Eastern Cooperative Oncology Group E3590 (a randomized, prospective trial of adjuvant therapy following resection of stages II and IIIa NSCLC) were randomized to radiation or radiation plus chemotherapy. Genomic DNA extracted from resected tumors was amplified for EGFR intron 1 by polymerase chain reaction and sequenced in a 3730XL DNA analyzer. Results: One hundred fifty-seven primary tumors were sequenced, 106 (68%) of which were heterozygous for intron 1. The most common genotypes were allele lengths of 17/19 dinucleotides (17.8%), 17/18 (11.4%), and 19/19 (11.4%). Allele status (homozygous versus heterozygous) did not correlate with race, gender, weight, performance status, histology, stage, or survival. Shorter allele length (Յ18 versus Ͼ18 CA dinucleotide repeats) was associated with squamous cell histology (p ϭ 0.03). Allele sum of greater than 35 was associated with improved overall survival (log-rank p ϭ 0.03, hazard ratio ϭ 0.66). Conclusion: This is the first study to characterize the EGFR intron 1 SSR polymorphism in NSCLC. Tumors were most commonly heterozygous for SSR length. Squamous histology was associated with a shorter SSR. Longer sequences are associated with improved survival.

Prognostic factors for survival of stage I nonsmall cell lung cancer patients

“…Potential explanations include a greater prevalence of activating epidermal growth factor receptor (EGFR) mutations in Asians, 32 which generally confer a better prognosis, or the greater prevalence of intraallelic EGFR polymorphisms in Asians, 33 which may confer a survival advantage in patients with NSCLC. 34 This report is retrospective in nature and shares many limitations of other population-based studies, including the lack of central pathology review. We could not ascertain the timeline or sequence of the treatment modality rendered.…”

On the pharmacogenetics of non-small cell lung cancer treatment

“…However, more recent studies in Japanese cohorts treated with gefitinib as first-line or adjuvant therapy did not show significant associations [57,58], while lower response rates to gefitinib were observed in Caucasian patients harboring the G/C haplotype [59]. Another EGFR region with relevant polymorphisms is located in the intron-1, characterized by 14 to 21 CA-repeats; with shorter alleles of a CA-dinucleotide repeat polymorphism in intron-1 associated with enhanced EGFR transcription, improved response rates, and longer OS after gefitinib treatment in different ethnicity cohorts [56,[58][59][60][61][62][63][64][65][66][67][68]. Most studies reported a better response to gefitinib, both in Japanese and Caucasian patients.…”

Overview of molecular testing in non-small-cell lung cancer: mutational analysis, gene copy number, protein expression and other biomarkers of EGFR for the prediction of response to tyrosine kinase inhibitors

“…Two Asian studies (Han et al, 2007;Nie et al, 2007) and one American study found associations with lung cancer survival or toxicity with gefitinib, whereas others found no significant association (Ichihara et al, 2007;Gregorc et al, 2008). Shorter CA repeat lengths were associated with poorer survival in the absence of therapy with an EGFR TKI, which is a reversal of expectations in TKI-treated patients (Dubey et al, 2006). The multidrug transporter ABCG2 was shown to be active in removing gefitinib from cells (Elkind et al, 2005).…”