Mutations in main candidate genes (egfr, kras, braf) among patients with non-small-cell lung cancer from Sardinia

Background: Assessment of the mutational status in EGFR, KRAS, BRAF has become crucial in recent years for the molecular classification of patients with non small cell lung cancer (NSCLC). In this population-based study, we evaluated the incidence rates and distribution of such somatic mutations among NSCLC patients in genetically isolated population from Sardinia. Material and methods: From July 2010, a total of 1,047 formalin-fixed paraffin-embedded tumor tissues from patients with NSCLC and ascertained Sardinian origin was prospectively collected at clinics across the entire island. Genomic DNA was isolated from tissue sections and screened for somatic mutations in EGFR, KRAS, and BRAF genes by automated DNA sequencing. Results: Overall, 112 (10.7%) analyzed patients carried an EGFR mutation. Somatic mutations in EGFR gene were quite equally distributed between exon 19 (57/112; 51%) and exon 21 (52/112; 46%), with few mutations (3/112; 3%) in exon 18 of EGFR. No significant difference in distribution of EGFR mutations according to the age at diagnosis was observed [EGFR mutant: median age, 67 (range, 37-85); EGFR wild-type: median age, 65 (range, 35-89)]. Females presented a significantly higher frequency of EGFR mutations in comparison to males (23.6% vs. 5.7%, respectively] (p = 0.003). According to the smoking history, a significant preponderance of EGFR mutations were observed in never smokers (43.2%) as compared to former smokers (5.8%) and smokers (3.6%) (p < 0.001). Among 634 patients whose somatic DNA was available for further analyses [71 (11.2%) cases carried EGFR mutations], we detected 138 cases (21.8%) with KRAS mutations and 3 (0.5%) with BRAF mutation (V600E). KRAS and BRAF mutations were significantly more prevalent in males than females (22.4% vs. 10.3%, respectively; p = 0.012) as well as in smokers (31.8%) than in former smokers (17.6%) or never smokers (4.5%) (p = 0.023). In this series, no concomitant mutations in EGFR, KRAS, and BRAF genes were detected. Therefore, two thirds (422/ 634; 66.6%) of such patients lacked somatic mutations in all three analyzed genes. Conclusions: Although the prevalence of mutations in the three main candidate gens among NSCLC patients from Sardinia was consistent with that reported in literature for Western populations, their distribution varied into the different clinical subgroups