Abstract
BackgroundRole 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.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 in KRAS, BRAF, and PIK3CA genes by automated DNA sequencing.ResultsOverall, 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.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.
Highlights
Colorectal carcinoma (CRC) develops through different pathways, all involving changes at the chromosomal or gene levels
Paraffin-embedded tumour tissues from a total of 478 patients with advanced colorectal carcinoma (CRC) originating from different geographical areas within Sardinia island were screened for mutations in candidate genes
The full coding sequences and intron-exon junctions of the KRAS gene were sequenced in the entire series of 478 CRC patients; KRAS mutations were detected in 145 (30%) primary tumours
Summary
Colorectal carcinoma (CRC) develops through different pathways, all involving changes at the chromosomal or gene levels. KRAS is the member of the RAS gene family mostly mutated in CRC; unlike the BRAF mutations, the KRAS mutations have been found to be distributed in all tumours, regardless of their MSI status [4]. These findings acquire an important role from the pathogenetic point of view since the mutations that hit these two genes are reciprocally exclusive. In this population-based study, we evaluated the incidence rates and distribution of such somatic mutations in genetically isolated population from Sardinia
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