DETECTING EGFR MUTATIONS IN PATIENTS WITH NON-SMALL CELL LUNG CANCER
Hammoudeh ZA, Antonova O, Staneva R, Nikolova D, Kyuchukov Y, Penev A, Mintchev T, Koleva V, Hadjidekova S, Toncheva D
*Corresponding Author: Zora A. Hammoudeh, Molecular Biologist, Department of Medical Genetics, Medical University Sofia, 2 Zdrave Str., 1431 Sofia, Bulgaria. Tel: +359-2-917-2735. Mobile: +359-88-943-0505. E-mail: zorahammoudeh@yahoo.com
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DISCUSSION

In our study, exon 19 deletions and the point mutation L858R in exon 21 constituted 92.7% of all EGFR gene mutations, which confirms the findings of previous studies [11]. Deletions in exon 19 of the EGFR gene were detected in 56.3% (n = 31) of all mutated samples, while L858R was detected in 36.4% (n = 20). All the EGFR gene exon 19 deletions positive patients had stage IV cancer. The L858R mutation was found in 36.4% (n = 20) of EGFR positive cases, with 90.0% (n = 18) having stage IV and 10.0% (n = 2) stage IIIb. Insertions in exon 20 represented 3.6% (n = 2) of all detected mutations. The rarest cases in our cohort, in concordance with previously reported results in the literature, were the double mutants, representing 3.6% (n = 2). A T790M point mutation was detected in only one sample together with a deletion in exon 19. In the other double mutant sample, a combination of a S768I mutation and a deletion in exon 19 was detected. According to smoking status, there was a higher prevalence of the EGFR gene mutation positive cases in smokers. In our cohort, the EGFR gene mutations were found in 15.0% (n = 32) patients who had never smoked and in 6.8% (n = 23) smokers (p <0.003). The prevalence of the EGFR gene mutations was higher in females than in males. Female to male ratio in the EGFR gene mutation positive cases in our cohort was 2.4:1, with 27.1% (n = 39) positive cases in female samples and 3.9% (n = 16) in males (p <0.001). The frequency of the mutations in adenocarcinomas was higher than in other histological types with a statistically different (14.9 vs. 5.1%, p <0.001) frequency. Multiple studies have shown that mutations in the EGFR gene TK domain are used as predictors for the therapeutic response and the progression-free survival benefit of EGFR treatment [12]. Many studies showed that EGFR gene mutations are more common in adenocarcinomas in women and non smokers [13]. Our results are consistent with previous studies. Our results showed that 10.0% of the advanced NSCLC patients in Bulgaria carried mutations in the EGFR gene. The statistical analysis showed the difference in EGFR gene mutation rate between female and male patients to be statistically significant (p <0.001). Likewise, the analysis showed the difference in EGFR gene mutation rate between patients with adenocarcinomas and patients with other histological types (such as squamous cell carcinoma and large cell carcinoma) to be significant (p = 0.0001). Whereas the results showed the difference in EGFR gene mutation rate between non smoking patients and patients who smoked to be statistically significant (p <0.003). In our cohort, exon 19 deletions and the L858R mutation represented 92.7% of the detected mutations conveying sensitivity to TKIs. Deletion in the EGFR gene exon 19 was found in 23 lung adenocarcinomas, eight in other histological types. The L858R EGFR gene mutation was found in 16 lung adenocarcinomas, four in other histological types. The remaining 7.3% of the mutations we detected are insertions in exon 20 and double mutations, exon 19 deletion and T790M, and exon 19 deletion and S768I. The EGFR gene exon 19 deletion and S768I double mutation was detected in lung adenocarcinoma, and the EGFR gene exon 19 deletion and T790M double mutation was found in a squamous cell carcinoma. The EGFR gene exon 20 insertions were found in two samples, one lung adenocarcinoma and one squamous cell carcinoma. Previous studies have shown that NSCLC patients whose tumors have sensitive mutation in the EGFR gene respond better than those with a wild-type tumor variant to drugs that target the TK domain of the gene. Therefore, according to all therapeutic guidelines, it is mandatory to determine the mutational status of the EGFR gene in patients with NSCLC in order to assess their eligibility for TKI treatment [14,15]. The EGFR gene exon 19 deletions and L858R mutation convey sensitivity to first-generation EGFR TKIs [8]. The T790M mutation predicts resistance to first-generation EGFR TKIs.



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