Cumulative Cigarette Tar Exposure, Genetic Polymorphisms, and their Interactions on Susceptibility and Survival of Lung and Upper Aerodigestive Tract Cancers

Author(s): Meyers, Travis James | Advisor(s): Zhang, Zuo-Feng; Sinsheimer, Janet | Abstract: Background: Tobacco smoking is a well-established risk factor for cancer in approximately 20 organ sites, including the lung, head and neck, and esophagus. However, only seven studies to date have evaluated the association between cumulative cigarette ‘tar’ exposure and cancer susceptibility, and no studies have assessed the association with cancer survival. In addition, no studies have addressed potential interactions between cumulative cigarette tar exposure and genetic polymorphisms on cancer susceptibility or survival.Objective and Specific Aims: The overall objective of this dissertation is to examine the associations of cumulative cigarette tar exposure, polymorphisms of candidate genes in two cancer pathways, and their interactions on susceptibility and survival of lung and upper aerodigestive (UADT) tract cancers. The specific aims were: (1) To estimate the associations between cumulative cigarette tar exposure with susceptibility and survival of lung and UADT cancers, across histological subtypes and with additional adjustment for cigarette pack-years; (2) To study the associations between polymorphisms of DNA repair and xenobiotic metabolism genes with susceptibility and survival of lung and UADT cancers, across histological subtypes; and (3) To explore the interactions between cumulative cigarette tar exposure and genetic polymorphisms on susceptibility and survival of lung and UADT cancers. Study Design and Population: The analyses were based on a population-based case-control study conducted in Los Angeles County between 1999 and 2004. The study included 611 incident cases of lung cancer; 601 cases of UADT cancers (oropharyngeal, laryngeal, and esophageal cancers); and 1,040 cancer-free controls. Data sources included responses to a structured interview regarding sociodemographic characteristics; lifetime history of exposure to tobacco, alcohol, marijuana, and other recreational drugs; medical and occupational histories; and family history of cancer. Eighty-eight percent of participants also provided buccal cell samples for genetic analyses.Statistical Methods: For cancer susceptibility analyses, odds ratios (OR’s) and 95% confidence limits (CL’s) were estimated by multivariate unconditional logistic regression models. Covariates included age, sex, race/ethnicity, years of education, smoking pack-years, and alcohol drink-years. For cancer survival analyses, hazard ratios (HR’s) and 95% CL’s were estimated by multivariate Cox proportional hazards models, adjusted for the stated covariates as well as tumor grade. Measures of interaction included the product term to detect departures from multiplicativity, and the relative excess risk due to interaction (RERI) to detect departures from additivity. In addition, semi-Bayes ‘shrinkage’ estimation was employed to reduce the likelihood of false-positive results. Results: (1) Cigarette tar exposure and cancer: Cumulative tar exposure and pack-years were highly correlated. Cumulative tar exposure was associated with increased susceptibility and reduced survival for overall lung and UADT cancers. For susceptibility, stronger associations for small, squamous, and large cell lung cancer were suggested compared to lung adenocarcinoma. After adjusting for pack-years, associations between tar exposure and susceptibility were suggested for small and large cell lung cancer, although discrimination in susceptibility models did not improve over pack-years alone. In addition, associations between tar and reduced survival were suggested for overall lung cancer and squamous cell lung cancer after adjusting for pack-years. (2) Genetic polymorphisms and cancer: A total of 19 SNP’s were associated with susceptibility, and 10 SNP’s were associated with survival for overall lung and UADT cancers. Novel associations were observed between BRCA1 rs1799949, BRCA2 rs543304, BRCA2 rs1799943, CYP2E1 rs2070673, MSH3 rs1805355, POLQ rs1381057, RAD52 rs1833095, and RAD54L rs1048771 with lung cancer susceptibility. In addition, novel associations were identified between BRCA2 rs543304, BRCA2 rs542551, BRCA2 rs144848, PON1 rs662, and RAD54L rs1048771 with UADT cancer susceptibility. Furthermore, novel associations were detected between GSTM3 rs7483 and lung cancer survival, and between MSH3 rs1805355 and UADT cancer survival. Associations between SNP’s with susceptibility and survival of histological subtypes of both cancers were observed. (3) Interactions between tar and genetic polymorphisms: Potential interactions were suggested between six SNP’s with cumulative tar exposure on lung cancer susceptibility: PARP1 rs8679, POLI rs8305, POLQ rs1380157, P53 rs2078486, RAD54L rs1048771, and XRCC1 rs25487. Possible multiplicative interaction was suggested between P53 rs2909430 with cumulative tar exposure on lung cancer survival.Conclusions: These results confirm the associations between tobacco smoking with increased cancer susceptibility and reduced cancer survival. In addition, incorporating the composition of tobacco carcinogens in lifetime smoking exposure may improve estimation of cancer susceptibility and prognosis. Furthermore, associations were observed between SNP’s with cancer susceptibility and survival, with prior evidence ranging from missing, to limited, to extensive. Cumulative tar exposure may modify the association between seven of these SNP’s with lung cancer susceptibility and survival.