Molecular alterations in key-regulator genes among patients with T4 breast carcinoma

Background: Prognostic factors in patients who are diagnosed with T4 breast carcinomas are widely awaited. We here evaluated the clinical role of some molecular alterations involved in tumorigenesis in a well-characterized cohort of T4 breast cancer patients with a long follow-up period. Methods: A consecutive series of 53 patients with T4 breast carcinoma was enrolled between 1992 and 2001 in Sardinia, and observed up for a median of 125 months. Archival paraffin-embedded tissue sections were used for immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analyses, in order to assess alterations in expression levels of survivin, p53, and pERK1-2 proteins as well as in amplification of CyclinD1 and h-prune genes. The Kaplan-Meier and Cox regression methods were used for survival assessment and statistical analysis. Results: Overall, patients carrying increased expression of pERK1-2 (p = 0.027) and survivin (p = 0.008) proteins as well as amplification of h-prune gene (p = 0.045) presented a statistically-significant poorer overall survival in comparison with cases found negative for such alterations. After multivariate analysis, the pathological response to primary chemotherapy and the survivin overexpression in primary carcinoma represented the main parameters with a role as independent prognostic factors in our series. Conclusions: Although retrospective, our study identified some molecular parameters with a significant impact on prediction of the response to therapy or prognosis among T4 breast cancer patients. Further large prospective studies are needed in order to validate the use of such markers for the management of these patients

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

<p>Abstract</p> <p>Background</p> <p>Role of <it>KRAS</it>, <it>BRAF</it> and <it>PIK3CA</it> 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.</p> <p>Methods</p> <p>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 <it>KRAS</it>, <it>BRAF</it>, and <it>PIK3CA</it> genes by automated DNA sequencing.</p> <p>Results</p> <p>Overall, <it>KRAS</it> 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 <it>vs.</it> 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 <it>BRAF</it> gene; <it>PIK3CA</it> was found mutated in 67 (17%) patients. A significant inverse distribution of <it>PIK3CA</it> mutation rates was observed within Sardinian population: 19/183 (10%) cases from northern <it>vs.</it> 48/201 (24%) cases from central-southern island (p<0.001). This heterogeneity in frequencies of <it>KRAS</it>/<it>PIK3CA</it> somatic mutations is consistent with already-reported discrepancies in distribution of germline mutations for other malignancies within Sardinian population. Preliminary clinical evaluation of 118 <it>KRAS</it> wild-type patients undergoing anti-EGFR-based treatment indicated lack of role for <it>PIK3CA</it> in predicting response to therapy.</p> <p>Conclusions</p> <p>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.</p