Genetic Epidemiology of Lung Cancer

Lung cancer is the leading cause of cancer death in the US, and represents a significant burden on health care resources. Accumulated evidence suggests that there are genetic susceptibility components in lung cancer, and that gene-environment interactions are important. While major breakthroughs have been made in understanding the genetic susceptibility basis of other cancers, studies to identify specific major loci affection lung cancer risk are notably lacking. The high case fatality rate (14 percent 5-year survival rate) and low resection rate (25 percent) makes the study of lung cancer families particularly challenging because it is difficult to collect adequate numbers of biospecimens for DNA analysis. Only a collaborative effort to identify, accrue, and genotype familial lung cancer (FLC) families will be successful in characterizing the genetic basis of familial lung cancer.

This project is part of a multi-center, multi-investigator, interdisciplinary team highly experienced in genetic epidemiology, gene mapping, lung biology, and cancer molecular genetics, known as the Genetic Epidemiology of Lung Cancer Consortium (GELCC) formed to identify a lung cancer susceptibility gene(s) and to estimate gene-environment interaction in the etiology of this neoplasm in order to elucidate a strategy for the prevention, control and clinical management of this disease through identification of genetically high-risk individuals.

Confirmation of a genetic predisposition for lung cancer may be possible by using linkage analysis to localize the putative susceptibility gene to a specific chromosomal region. The strength of linkage analysis is dependent upon the recruitment of multiple large kindreds for which tissue samples are available and the history of tumor incidence exists for two, preferably more, generations. Our strategy is to combine the most informative pedigrees but preferably eventually up to 500 pedigrees. This strategy yields a substantial increase in power and cost-effectiveness over the usual strategy of each site working independently and genotyping many marginally informative families. To date this strategy appears successful, in that results from our first 52 genotyped families resulted in significant evidence in favor of linkage to a region on chromosome 6q and suggestive evidence for several other regions. We believe that ongoing data collection and analysis of these preliminary results will also be fruitful. Recently, the National Cancer Institute funded this ongoing project in a competitive renewal (5 years) of our multi-center R01 that supports data collection and work at all sites besides NHGRI and NCI.

All data collection is under the direction of each P.I. at the data collection sites and funded by their respective grants and contracts. NHGRI investigators do not have any contact with study subjects and no NHGRI employees receive any funds from these grants. Because this disorder is complex and has a high likelihood of being caused by multiple loci, multiple parametric and non-parametric methods of analysis will be employed. Heterogeneity will be taken into account during these analyses, as will environmental covariates, such as the effect of smoking. Only statistical analyses are performed at the NHGRI site, but laboratory work ranging from genotyping, sequencing, array CGH, model organism experiments and other methods occurs at other sites as part of this collaboration.