Oncogene mutations and translocations as molecular biomarkers and targets in advanced lung adenocarcinomas
Authors: Bunn Paul A. , Kris Mark , Johnson Bruce , Minna John , Kwiatkovski David , Iafrate John , Wistuba Ignacio , Wistuba Wilbur , Varella-Garcia Marileila 
Published: May 2015

Abstract
Activation of at least one oncogene by mutation, translocation or fusion has been shown to be relatively frequent in adenocarcinomas of the lung. The types and frequency of these mutations is often related to clinical features including smoking status, ethnicity, gender, age and to histology. For example, KRAS mutations are more frequent in smokers, whereas EGFR mutations and EML4/ALK fusions are more common in never-smokers. EGFR mutations are more frequent in Asians than Caucasians, Africans or African-Americans whereas EML4/ALK fusions have a similar frequency in Asians and Caucasians. Females may have more of several types of mutations but it is not clear if this is independent of smoking status. KRAS mutations are associated with an inferior prognosis while EGFR mutations and EML4/ALK fusions associate with a superior outcome. In North America, KRAS mutations are the most frequent of these mutations occurring in about 20% of cases. EGFR mutations are next most frequent occurring in about 12-15% of cases. Mutations in NRAS, BRAF, Her2, PIK3CA, MEK1 and AKT1 are less frequent occurring in 1-5% of cases. Mutations in other tyrosine kinase receptors such as FGFR have been reported but are infrequent (&lt;1%) and widely scattered in several receptor genes. In some cases oncogenes such as ALK are activated by fusion with other genes, most frequently with EML4. These cases may be detected by FISH analyses. KRAS mutations, EGFR mutations and ALK fusions appear to be mutually exclusive. Small molecule receptor tyrosine kinase inhibitors (TKIs) have been developed targeting all of these mutated receptors. The EGFR TKIs erlotinib and gefitinib have been shown to produce high response rates, long progression free survival and improved quality of life in patients with activating EGFR mutations. These TKIs have been shown to be superior to chemotherapy in the initial treatment of patients with such mutations. An ALK TKI termed crizotinib was shown to produce a response rate of approximately 60% and progression-free survival of longer than 9 months in NSCLC patients with EML4/ALK fusions. Thus, the new paradigm for treatment of advanced NSCLC requires molecular testing of patient biopsies to select the optimal treatment. It is likely that the other oncogene mutations will be mutually exclusive with these oncogene mutations and will be predictive biomarkers for the TKIs selective for these receptors. To determine if these predictions are true and to develop sufficient numbers of cases, the Lung Cancer Mutation Consortium (LCMC) was formed and supported by an NCI “GO” grant. The LCMC will analyze 1000 cases of stage IIIB or IV adenocarcinoma of the lung for specific hot spot mutations in 8 genes (KRAS, BRAF, EGFR, Her2, PIK3CA, AKT1, MEK1, NRAS using either the sequenome or snapshot platforms. EML4/ALK fusions and MEK amplification will be tested by FISH analysis. All analyses will be done in CLIA certified labs. Correlations between the molecular abnormalities with one another, with clinical features and with survival outcome will be done. The LCMC will attempt to put as may of these patients on therapeutic trials with oncogene directed molecularly targeted drugs.