Heterogeneous prevalence of somatic mutations in KRAS, BRAF, and PIK3CA genes among patients with colorectal carcinoma: Clues from Sardinia.

e14094 Background: Role of KRAS, BRAF and PIK3CA mutations in pathogenesis of colorectal cancer (CRC) has been mostly clarified. In this population-based study, we investigated the incidence rates and roles for such somatic mutations in genetically isolated population of 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 tumor mutation rate was 30% (145/478 positive cases). Distribution of mutation carriers was however different within the island: 87/204 (43%) in North Sardinia vs. 58/274 (21%) in Middle-South Sardinia (p=0.023). Among 384 CRC cases whose DNA was available, only one (0.3%) mutation in BRAF gene was observed; conversely, PIK3CA was found mutated in 158/384 (41%) patients. An inverse distribution of PIK3CA mutation rates was observed within Sardinian population: 60/181 (33%) cases from northern vs. 98/203 (48%) cases from central-southern island. 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 in our series. Conclusions: Our findings further support the hypothesis that patients’ origin and genetic background may contribute to even determine the incidence rate of somatic mutations in candidate cancer genes.