Lung Cancer SPORE

Projects

PROJECT 4: NUCLEOTIDE EXCISION REPAIR/CELL CYCLE CONTROL HAPLOTYPES AND LUNG CANCER RISK AND PROGNOSIS
PROGRESS REPORT

Co-Project Leaders: Marjorie Romkes, PhD, Joel Weissfeld, MD, MPH, Emanuela Taioli, MD, PhD

Specific Aims

Project 4 of the UPCI Lung Cancer SPORE is investigating the hypothesis that nucleotide excision repair and cell cycle control gene haplotypes may not only predict lung cancer risk, but also drug resistance and survival. The ability to identify individuals with the highest risk of developing tobacco-related cancers, most importantly lung cancer, has important public health and clinical implications for screening, early detection, prevention and treatment. In addition to variability in activation and detoxification pathways of mutagenic agents, there is a very strong biologic rationale to also study the variability in the capacity to repair smoking induced DNA damage as another major family of susceptibility biomarkers. The nucleotide excision repair (NER) pathway is important in the repair of chemical carcinogen induced genotoxic damage. The XPD protein is a key member of this pathway and mutations in the XPD gene, including the common A35931C (Lys751Gln) variant allele, result in reduced repair capacity. Furthermore, regulation of the cell cycle control mechanism can influence the potential for increased cell proliferation and the promotion of genetic instability. Cyclin D1 (CCND1) is an essential cell cycle regulatory protein and is involved in the regulation of proliferation and differentiation. The CCND1 G870A single nucleotide polymorphism (SNP) has been reported to enhance alternate splicing and increase cyclin D1 protein half-life. Our initial case/control studies, partially supported by the previous SPORE Genomics Core, of which Dr. Romkes was the Director, have demonstrated a significant association between elevated risk of upper aerodigestive tract cancer among individuals who carried both the CCND1 G870A variant allele and XPD Gln allele (OR=7.1, 95%CI 4.0-12.5).

We proposed to further investigate these preliminary results and to conduct a genetic epidemiological haplotype association study by evaluating polymorphisms of genes in the NER and cell cycle control pathways in a series of NSCLC cases and controls. The following Specific Aims are designed to validate these initial observations in a larger patient population and to also extend the model to a prospective study to evaluate the prognostic significance of the “at risk” haplotypes.

Specific Aim 1. To select tagSNPs identifying haplotypes for genes of the NER and cell cycle control pathways.

Specific Aim 2. To develop a model relating NER and cell cycle control pathway gene haplotypes to lung cancer risk.

Specific Aim 3. To test the prognostic significance of the NER and cell cycle control pathway gene haplotypes by genotyping the PLuSS and Moffitt Cancer Center High-Risk sub-cohorts.

Specific Aim 4. To develop a final predictive model by combining the datasets from Specific Aims 2 and 3 for purposes of external validation.

Specific Aim 5. To evaluate whether the NER pathway haplotypes are associated with platinum drug resistance and survival.