Análisis molecular del cáncer de colon esporádico / Molecular analysis of sporadic colon cancer

Background: In Chile, colorectal cancer (CRC) is often diagnosed in late stages. Thus, surgical treatment must be complemented with chemotherapy. KRAS mutations and microsatellite instability have been detected in these tumors. However, the response to treatment in patients without KRAS mutations varies and requires a better understanding. Aim: To determine the frequency and distribution of somatic point mutations in KRAS, BRAF and PIK3CA genes and microsatellite instability status (MSI) in patients with colon cancer (CC). Material and Methods: A prospective observational study of patients undergoing surgery for colon cancer. Tumor-derived DNA was analyzed by polymerase chain reaction (PCR) for the most frequent mutations of KRAS, BRAF and PIK3CA. PCR was also used to analyze MSI. Results: Fifty-eight patients with sporadic CC were analyzed, 16 showed KRAS mutations (G12R, G12D, G12V, G13D) and out of the 42 patients that did not show any mutation, 10 had mutations in BRAF (V600E) and PIK3CA (E542K, E545D, E545K, Q546E, H1047R). BRAF mutations alone or in combination with PIK3CA mutations were observed in 27% of high MSI tumors and in 2% of tumors without instability (p < 0.049). A higher percentage of high MSI tumors were located in the right colon (p < 0.001), and showed BRAF mutation (p < 0.020). Conclusions: The highest percentage of high MSI and BRAF mutations was observed in the right colon. Therefore, this study suggests the presence of different molecular features between right and left colon tumors that should be considered when defining the therapeutic management.

Prevalencia y características de mutaciones somáticas del gen KRAS en pacientes chilenos con cáncer colorrectal / KRAS gene somatic mutations in Chilean patients with colorectal cancer

Background: The molecular testing of KRAS mutation status in metastatic colorectal cancer patients is mandatory to identify patients eligible for anti-epidermal growth factor receptor monoclonal antibody therapy. Aim: To report the frequency of KRAS gene mutations in Chilean patients with colorectal cancer (CRC). Material and Methods: A cohort of 262 Chilean patients with CRC aged 26 to 90 years (53% males), was studied. KRAS mutation status was analyzed by real-time polymerase chain reaction and correlated with clinicopathological data. Results: Ninety-eight patients (37%) were positive for KRAS mutations. G12D was the most common mutation with a frequency of 36.7%, followed by G12V (25.5%), G13D (17.3%), G12A (7.1%), G12C (6.1%), G12S (5.1%) and G12R (2%). The frequency of the mutation in left, right colon and rectal tumors was 37.8, 32.6 and 44.9%, respectively. Among tumors with mutations, 86.7% were well or moderately differentiated tumors and the rest were poorly differentiated. No significant associations between KRAS gene mutations and other clinicopathological features of the tumor were observed. Conclusions: The frequencies of KRAS mutations reported in this study are similar to frequencies reported for European and North-American populations, lower than in a Spanish study and higher than in a Peruvian study.

LIN28B confers radio-resistance through the posttranscriptional control of KRAS

To screen the differentially expressed microRNAs related to radio-resistance, we compared the microRNA profiles of lung cancer cells with different responses to ionizing radiation (IR). Of 328 microRNAs in microarray, 27 microRNAs were differentially expressed in NCI-H460 (H460) and NCI-H1299 (H1299) cells. Among them, let-7g was down-regulated in radio-resistant H1299 cells, and the level of let-7g was higher in radio-sensitive cells like Caski, H460, and ME180 in qRT-PCR analysis than in radio-resistant cells like A549, H1299, DLD1, and HeLa. Over-expression of let-7g in H1299 cells could suppress the translation of KRAS, and increase the sensitivity to IR. When we knockdown the expression of LIN28B, an upstream regulator of let-7g, the level of mature let-7g was increased in H1299 cells and the sensitivity to IR was also enhanced in LIN28B knockdown cells. From these data, we suggest that LIN28B plays an important role in radiation responses of lung cancer cells through inhibiting let-7g processing and increasing translation of KRAS.

Predictive Significance of KRAS and Tau for Chemoresponse in Advanced Non-Small-Cell Lung Cancer

BACKGROUND: Taxane-platinum combinations are often used as first-line treatments for patients with advanced non-small cell lung cancer (NSCLC). Response to chemotherapy for these patients is still poor. The aim of our study was to investigate, for this disease, whether KRAS and Tau proteins affect responses to taxane-platinum combinations. METHODS: Expression of KRAS and Tau was examined immunohistochemically in 71 tumor samples obtained from patients with stage IIIB or IV NSCLC prior to combination therapy. Expression was correlated with tumor responses. RESULTS: The response rate was 55% (39 of 71). KRAS and Tau were expressed in seven (10%) and 31 (44%) patients, respectively. All seven KRAS-positive patients were non-responders (p=0.014). Among Tau-positive patients, 35% (11 of 31) responded to therapy, whereas a partial response was observed in 70% (28 of 40) of Tau-negatives (p=0.045). Two were positive for both, and they were non-responders. In patients negative for both, the response rate was 71% (25 of 35) (p=0.012). CONCLUSIONS: Expression of KRAS and Tau are significantly correlated with poor responses to this combination therapy in advanced NSCLC patients, and may be a useful marker for chemoresistance.