Author

FANG YU LIN

Date of Award

12-2019

Degree Name

Doctor of Philosophy (PhD)

Advisor(s)

KAI ZHANG

Second Advisor

XIFENG WU

Third Advisor

YUANQING YE

Abstract

Higher dietary fat intake and alterations in fatty acid metabolism may affect cancer development and progression. This dissertation conducted a series of studies examining whether dietary fat intake and genetic variants in fatty acid metabolism genes have an impact on clinical outcomes among non-Hispanic whites newly diagnosed with non-small cell lung cancer (NSCLC). First, a cohort of 2,262 NSCLC patients was prospectively examined for intakes of total, saturated, monounsaturated, and polyunsaturated fat in relation to overall survival and recurrence. Dietary fat intake at diagnosis was assessed with a previously validated food frequency questionnaire and categorized by Dietary Reference Intakes. Multivariable Cox proportional hazard models were used to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). Neither high intake of total, nor any subtype of fat, was associated with overall survival or recurrence for NSCLC. Analysis of stage-specific overall survival revealed that early-stage patients with high intake of saturated fat were at increased risk of poor survival compared to those who had intake less than the recommended amount (HR: 1.27; 95% CI: 1.02, 1.59). However, a protective effect was observed in advanced-stage patients who received primary chemotherapy (HR: 0.84; 95% CI: 0.71, 0.99). This protective effect was also evident for high intake of monounsaturated fat in this same group of patients (HR: 0.64; 95% CI: 0.43, 0.96). In the second aim, the associations between single nucleotide polymorphisms (SNPs) in genes related to fatty acid metabolism and overall survival and recurrence among NSCLC patients were examined by using two-stage design, and further evaluated for differences by dietary fat intake. Among 1,593 NSCLC patients in the discovery set, candidate SNPs associated with overall survival or recurrence were identified, and were further validated in the replication set of 746 NSCLC patients. Four SNPs were associated with overall survival and one SNP was associated with recurrence in both datasets. Functional assessment identified three variants ACSL1:rs4862417, CYP2C8:rs1934953, and FADS2:rs174611 to be putatively functional. Early-stage patients with a G variant rs174611 were associated with 28% and 47% increased risk of death in the discovery (95% CI: 1.03, 1.59) and replication sets (95% CI: 1.03, 2.08), respectively. Monounsaturated fat intake was found to interact with rs174611 genotype in relation to overall survival (multiplicative Pinteraction = 0.03). In summary, dietary fat intake and genetic variants in fatty acid metabolism genes play roles in survival among NSCLC patients. The association of dietary fat and overall survival is dependent on disease stage and treatment for NSCLC. Genetic variants and dietary fat intake may have multiplicative effect on overall survival in NSCLC. These findings provide evidence for potential genetically-targeted nutritional consultation on dietary fat intake for NSCLC patients.

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