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Background  Role of  KRAS ,  BRAF  and  PIK3CA  mutations 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.    Methods  From 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 in  KRAS ,  BRAF , and  PIK3CA  genes by automated DNA sequencing.    Results  Overall,  KRAS  tumour mutation rate was 30% (145/478 positive cases). Distribution of mutation carriers was surprisingly different within the island: 87/204 (43%) in North Sardinia  vs.  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 in  BRAF  gene;  PIK3CA  was found mutated in 67 (17%) patients. A significant inverse distribution of  PIK3CA  mutation rates was observed within Sardinian population: 19/183 (10%) cases from northern  vs.  48/201 (24%) cases from central-southern island (p<0.001). This heterogeneity in frequencies of  KRAS / PIK3CA  somatic 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 for  PIK3CA  in predicting response to therapy.    Conclusions  Our 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.

Prevalence of KRAS, BRAF, and PIK3CA somatic mutations in patients with colorectal carcinoma may vary in the same population: clues from Sardinia