Prevalence ofKRAS,BRAF, andPIK3CAsomatic mutations in patients with colorectal carcinoma may vary in the same population: clues from Sardinia

BackgroundRole ofKRAS,BRAFandPIK3CAmutations in pathogenesis of colorectal cancer (CRC) has been recently investigated worldwide. In this population-based study, we evaluated the incidence rates and distribution of such somatic mutations in genetically isolated population from Sardinia.MethodsFrom April 2009 to July 2011, formalin-fixed paraffin-embedded tissues (N = 478) were prospectively collected from Sardinian CRC patients at clinics across the entire island. Genomic DNA was isolated from tissue sections and screened for mutations inKRAS,BRAF, andPIK3CAgenes by automated DNA sequencing.ResultsOverall,KRAStumour mutation rate was 30% (145/478 positive cases). Distribution of mutation carriers was surprisingly different within the island: 87/204 (43%) in North Sardiniavs. 58/274 (21%) in Middle-South Sardinia (p<0.001). Among 384 CRC cases whose DNA was available, only one (0.3%) patient carried a mutation inBRAFgene;PIK3CAwas found mutated in 67 (17%) patients. A significant inverse distribution ofPIK3CAmutation rates was observed within Sardinian population: 19/183 (10%) cases from northernvs. 48/201 (24%) cases from central-southern island (p<0.001). This heterogeneity in frequencies ofKRAS/PIK3CAsomatic mutations is consistent with already-reported discrepancies in distribution of germline mutations for other malignancies within Sardinian population. Preliminary clinical evaluation of 118 KRAS wild-type patients undergoing anti-EGFR-based treatment indicated lack of role forPIK3CAin predicting response to therapy.ConclusionsOur findings support the hypothesis that differences in patients’ origins and related genetic backgrounds may contribute to even determine the incidence rate of somatic mutations in candidate cancer genes.