Our research group is interested in studying the genetic basis for thoracic and head and neck cancers. For example, the Kaye laboratory previously discovered the role of the retinoblastoma (RB)/p16 cancer gene pathway, which undergoes mutational or epigenetic inactivation in 100% of human lung cancer cases. In addition, the Kaye laboratory has recently identified and characterized recurrent unique RB gene mutations that underlie the phenotype of incomplete penetrance for familial retinoblastoma. This work has allowed the development of a new classification to describe the molecular properties of low-penetrant RB mutant alleles mutations and to develop hypotheses to explain why some affected carriers develop tumors while others do not. In the course of this work we have also recently studied the first case of a low-penetrant RB mutant allele that is naturally expressed in vivo in a small cell carcinoma and discovered that Hsp90 chaperone activity is required for its stability in vivo and in vitro. These data suggest that reversible protein instability and the requirement for a cooperating mutation may provide a stochastic explanation for the molecular basis of incomplete penetrance in kindreds carrying these low-penetrant RB alleles. We also identified a t(11;19) chromosomal translocation and cloned a novel oncogene (Crtc1-Maml2) in a young patient with a lung mucoepidermoid cancer. We have now identified the etiologic Crtc1-Maml2 in 100% of pulmonary mucoepidermoid cancers tested to date and in 70-90% of head and neck salivary gland cancers. In addition, Crtc1-Maml2 has been detected in primary skin, thyroid, and cervical tumors with mucoepidermoid or sweat gland features. While most patients with Crtc1-Maml2 fusion positive tumors show a good outcome following surgical resection, we have recently identified several outlier cases of patients who developed lethal stage 4 metastatic disease. We have now performed high-resolution genomic analyses and have identified the acquisition of a sequential somatic mutation within the CDKN2A locus on chromosome 9p21 as a marker indicating tumors with unfavorable outcome. This work will lead the way to a prospective multi-center trial to genotype and treat patients with salivary gland cancers. This work is also of potential interest to the field of cancer research since fundamental discoveries on isolated cancer syndromes have revealed unexpected insights and potential therapeutic targets for other common adult malignancies as well. For example, we have demonstrated that the Crtc1-Maml2 fusion protein can transform primary epithelial cells by activating a group of cAMP/CREB regulated genes. Some of these CREB-inducible genes are associated with gluconeogenesis and fatty acid metabolic pathways and the normal function of the Crtc gene family activity is now identified as an essential component of glucose control during both feeding and starvation. In addition, the tumor suppressor gene LKB1, which underlies the rare Peutz-Jegher colon cancer syndrome, may serve as a suppressor of Crtc1 function by regulating its phosphorylation and cellular localization. Since the LKB1 is mutated in approximately 20% of common adult lung cancers we are currently studying the implications of deregulated Crtc1 activity in these tumor samples. Further, since Crtc1 activity is tightly correlated with its subcellular localization we have conducted molecular analyses to define the nuclear import and nuclear export mechanisms of the Crtc1 gene family in normal and tumor cells. This work has identified a distinct type of molecular target that may offer new therapeutic strategies for cancer treatment. For example, we have already shown that the sustained expression of Crtc1-Maml2 is essential for the viability and growth of tumors with the reciprocal t(11;19) translocation. Our work has also shown that Crtc1-Maml2 has both important diagnostic and prognostic information for clinicians treating patients with malignant tumors of major and minor salivary glands. Crtc1-Maml2 has also been identified in selected skin, lung, and thyroid tumors, suggesting that this molecular entity will be increasingly recognized in the future. This work continues an important collaboration between the NCI, NIH, the National Naval Medical Center in Bethesda, Maryland, and the extramural research community to study the genetic basis for uncommon human cancers that lack known effective treatments and which are not adequately funded or pursued in the extramural research community. Another research goal within our laboratory is an effort to discover new etiologic somatic mutations in malignant mesothelioma. Malignant mesothelioma currently lacks a diagnostic biomarker and ongoing therapeutic clinical strategies have been disappointing. Therefore, as part of a longstanding collaboration between our laboratory and the Dana-Farber Cancer Institute we have undertaken both high-resolution CGH and SNP analyses using a large collection of both derived tumor cell lines and primary tumors. We have recently identified regions of consistent tumor-specific DNA alterations and are characterizing the functional consequences of these alterations. This work continues a successful effort involving both intramural and extramural collaborations to discover new molecular targets for the diagnosis, early detection, and treatment of thoracic tumors.