Date of Graduation
8-2014
Document Type
Dissertation (PhD)
Program Affiliation
Biomedical Sciences
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Xifeng Wu
Committee Member
Paul Chiao
Committee Member
Jian Gu
Committee Member
Jonathan M. Kurie
Committee Member
William Plunkett
Abstract
The five-year survival rate for all stages of lung cancer combined is only 17%, which has changed little over the past 40 years. Despite the tremendous efforts made, serum biomarkers with clinical utility for lung cancer early detection and clinical outcome prediction are still lacking. Metabolic alterations have been recognized as an emerging hallmark of cancer. We aimed to investigate the metabolic changes associated with lung cancer and to identify novel clinically applicable serum biomarkers for lung cancer early diagnosis and clinical outcome.
Serum metabolites are potential biomarkers for lung cancer early detection. We first performed global metabolomic profiling followed by targeted validation of individual metabolites in a case-control design of 386 lung cancer cases and 193 matched controls. We then validated the most significant metabolite bilirubin as a risk marker for lung cancer incidence and mortality in a large prospective cohort comprised of 425,660 participants. In this cohort, the inverse association was only seen in male smokers. For every 0.1 mg/dL decrease of bilirubin, the risks for lung cancer incidence and mortality increased by 5% and 6%, respectively (both P < 0.001).
We next investigated pre-treatment laboratory tests indicative of a patient’s overall metabolic status, as biomarkers for non-small cell lung cancer (NSCLC) clinical outcome. We assessed seven pre-treatment serum laboratory test levels in 2,675 NSCLC patients, including 623 early stage and 2,052 advanced stage patients. Among 978 advanced stage NSCLC patients we studied who were treated with platinum-based chemotherapy, lower than normal levels of albumin, higher than normal levels of alkaline phosphatase and lactate dehydrogenase were all associated with worse 2-year overall survival, after adjusting for other variables. In addition, there was a cumulative effect among these three adverse laboratory test levels.
In conclusion, low serum bilirubin levels are associated with higher risks of lung cancer incidence and mortality in male smokers and may be used to identify higher risk smokers for lung cancer. In addition, pre-treatment laboratory test levels indicative of metabolic status could be utilized to enhance predictions of survival among advanced stage NSCLC patients treated with platinum-based chemotherapy. Taken together, our results suggested that metabolic alterations associated with lung cancer could serve as novel serum biomarkers with clinical significance for lung cancer early detection and clinical outcome.
Keywords
Lung cancer, serum biomarker, metabolism