• Lung Cancer
• Wnt Signalling Pathway
• Bronchioalveolar Carcinoma
• Cancer Stem Cells
• Esophageal Cancer
• Mesothelioma
• Expression Profiling
• Lung Cancer System Genetics
• KRas Pathway
• Other Cancers
• Diagnostics Development

The Thoracic Oncology Lab has, in collaboration with UCSF's Dr. Allan Balmain, Ph.D., FRSE., one of the world's leading molecular geneticists, embarked upon an ambitious project that seeks to make possible an individualized approach to lung cancer therapies.  To do so, the tumor of each patient in the study will be characterized at the molecular level to pinpoint the diagnosis, and consequently the best treatment. The processing of these tumors utilizes state-of-the-art technology from leaders in the analysis of complex genetic information for biomedical purposes.

Discoveries of cancer susceptibility genes have already been made in breast cancer (BRCA genes 1 and 2) and in colon cancer (abnormal Rb gene in HNPCC) but not in lung cancer.  The focus here is the analysis of inherited or germline DNA, DNA present in every cell in the body at birth. The project's goal is to identify small variations in the germline, known as "single nucleotide polymorphisms" or SNPs, by analyzing the normal tissue of lung cancer patients. When SNP analyses are overlaid on clinical data, insights can be gained as to which individuals are at elevated risk for developing the disease.  The Thoracic Oncology Group is performing SNP analysis using Affymetrix Molecular Inversion Probes (MIP).  This work has clear relevance to early detection research because it can help define the population of individuals who should be screened.

As a person ages, the accumulation of "somatic" mutations in cells can reach a tipping point and result in the development of lung cancer. In genetics, "somatic" refers to cells or tissue in the body that reside outside the germline, cells that are constantly being regenerated. Somatic mutations can result from environmental causes, i.e. smoking, air pollution, or radon exposure, or can occur sporadically such as when cells malfunction during gene replication. Known mutations and the pathways within which they reside are logical therapeutic targets for discovery. When paired with clinical outcome data, mutations can serve as diagnostic indicators, predictors of survival, and biomarkers for tumor aggressiveness. Mutations can also predict response to therapy, i.e. presence of EGFR mutations predicts response to the cancer drug Tarceva.   The group is employing Affymetrix Mismatch Repair Detection (MRD) and Affymetrix Mutation Sorters (MS) to better characterize lung cancer tumors.

Extra copies of identical genes and/or missing stretches of DNA in lung cancer tumors may be important even when no mutations are involved. CNVs (copy number variations), like mutations, appear to be useful as prognostic biomarkers and predictors of response to therapy. In non-small cell lung cancer (NSCLC), for example, some scientists believe a patient's EGFR copy number is more clinically significant than the EGFR mutation.  Variation in gene copy numbers is also being explored by microarray-based comparative genomic hybridization (a-CGH) using Affymetrix Molecular Inversion Probe (MIP). 

Another aspect of the project focuses on gene expression-the output of gene products within a cancer cell. A common measure of gene expression is the level of messenger RNA (mRNA) being produced. mRNA is a molecule that carries the blueprint for production of cellular proteins. The amount of mRNA present suggests what genes are active within the cell. The unique pattern of gene activity serves as a "genetic signature" that can be correlated with clinical outcomes and can thereby drive treatment decisions.

Gene or DNA sequencing is the process of defining the contours of a stretch of DNA as a distinct subunit, i.e. a gene, and then mapping its function.  Some of the work above will generate clues as to which regions in the cell might contain genes important in lung cancer. The investigators will then sequence genes already known to be active in the disease as well as any others discovered during the research.

To date, there have been no attempts to link both germline and somatic approaches to lung cancer in a concerted systems approach. Other labs have concentrated on one or two of these platforms at most. This project is unique because it leverages all platforms, combining analysis of germline SNPs with knowledge of somatic mutations, gene copy number abnormalities, and gene expression changes in patients' tumors, all with the goal of developing predictive molecular biomarkers. By using multiple datasets derived from a patient's lung tumor and normal tissue, a more accurate readout of the tumor becomes possible.

The resulting data will be mined using advanced computational methods and mathematical algorithms pioneered at UCSF. These datasets will provide an unprecedented opportunity to develop new diagnostics, biomarkers for risk assessment and prognosis, and novel combinations of therapeutic targets. The ultimate objective is to establish the wiring diagram of the lung cancer cell-the network of genetic variants and their expression patterns that influence individual lung cancer susceptibility, risk of progression, and response to therapy.

Cancer treatment is rapidly proceeding towards the era of personalized medicine where treatment is based on the distinctive molecular characteristics of a patient's tumor. The data from this project will be used to construct networks that will include gene expression profiles of lung tumors. These networks will capture the complexity of somatic events intrinsic to the tumor layered over the genetic background that is inherent to the individual. This knowledge will help to more accurately predict disease outcome so that patients at high risk of relapse will receive the most aggressive treatment. It will also allow patients to receive novel combinations of therapies that will afford maximum treatment.

The research is supported by a generous grant from The  Bonnie J. Addario Lung Cancer Foundation, the nation's largest philanthropy devoted exclusively to eradicating lung cancer, through research, early detection, education, prevention, and treatment.