KRAS Amplification in Non-Small Cell Lung Carcinoma
AC Stiedl, PL Wagner, T Wilbertz, NK Altorki, SR Perner. Universtiy Hospital of Tuebingen, Tuebingen, Germany; New York Hospital/Weill Cornell Medical Center, New York
Background: Amplification of 12p12.1, containing the KRAS gene, is one of the commonest amplification events in lung adenocarcinoma. Although activating KRAS mutations are well characterized, KRAS amplification as an oncogenic mechanism is relatively unexplored. We have previously demonstrated that KRAS amplification is associated with increased p21 expression in NSCLCs, and that amplification is often associated with an activating KRAS mutation. In the current study, we sought to determine the frequency of KRAS amplification in NSCLC and to identify associated clinicopathologic features.
Design: Fluorescence in situ hybridization, utilizing a probe for the KRAS gene, was applied to a series of 385 NSCLSs, including 300 tumors consecutively resected with curative intent. KRAS amplification was compared with clinicopathologic features derived from a prospectively collected patient database. Statistics: categorical variables, Fisher's exact test; continuous variables, student's t test; overall survival, Kaplan-Meier method and log-rank test; p<0.05.
Results: Among 385 NSCLCs, 58 (15%) exhibited KRAS amplification. Amplification was significantly associated with larger mean tumor size (p=0.003), poor differentiation (p=0.004) and pleural invasion (p=0.046). KRAS amplification was not associated with patient age, gender, race, or smoking history; angiolymphatic invasion; or node status. Although the rate of KRAS amplification did not differ between squamous cell and adenocarcinomas, among adenocarcinomas KRAS amplification was far less common in tumors consisting of pure bronchioloalveolar subtype versus those of mixed or invasive subtypes (p=0.004). At a median followup of 2.3 years, no difference in overall survival based on KRAS amplification status was noted.
Conclusions: KRAS amplification is seen in a substantial minority of NSCLCs, and is often but not always associated with an activating KRAS mutation. KRAS amplification is associated with increased p21 protein levels, as well as poor prognostic indicators including larger tumor size, poor differentiation and pleural invasion. Further studies will be necessary to characterize the ocogenic mechanisms of KRAS amplification, its relationship with activating KRAS mutation, and its prognostic significance.
Tuesday, March 23, 2010 9:30 AM
Poster Session III # 257, Tuesday Morning