It is now widely accepted that classification of tumors based on their genetic markers is an important prerequisite for designing and choosing an appropriate disease-management strategy. Classification of lung cancer, however, still relies on the visual evaluation of the morphology of the tissue. What makes it even more difficult is that each of the major histological types of lung cancer is a heterogeneous collection of tumor subtypes.
The World Health Organization has attempted to describe these subtypes based on morphological appearance, but this classification is of limited usefulness in clinical practice due to high subjectivity of such characterization.
“Other cancers, such as breast cancer, have clearly identifiable genetic characteristics that profoundly influence the choice of therapies,” says D. Neil Hayes, M.D., Lineberger Comprehensive Cancer Center, University of North Carolina. “We were able to lay the background work for clear and reproducible identification of lung cancer subtypes based on DNA microarrays.”
Dr. Hayes’ group supplemented its own studies with the meta-analysis of previously published independent datasets, resulting in a sizable cohort of over 1,000 patients. “Historically, reconciliation of the results of individual gene-expression studies proved to be very difficult. Although tumor subtypes seemed to exist, there was no consensus of their number on nature.
“We realized that if we correct for technical imperfections, we should be able to uncover biological bases characteristic to each subtype.”
The researchers analyzed the studies generated on several different gene-expression platforms and utilized integration correlation statistics to select for the probes that measured the expression reproducibly across the chosen platforms. Out of 3,000–5,000 genes selected by this method, about one-third demonstrated reproducible differential expression of varying degrees.
The analysis placed all adenocarcinoma samples into three subtypes, and squamous cell carcinomas into four subtypes. The subtypes have statistically significant survival differences and patient demographics, independent of disease stage. They are comprised of tumors with differing underlying rates of mutations in key lung cancer genes, including KRAS and EGFR.