AS294 - Investigation of one-carbon metabolism pathway and lung cancer within the cohort consortium

Investigator Names and Contact Information

Mattias Johansson

Introduction/Intent

We recently conducted a study of circulating B-vitamins and lung cancer within the EPIC cohort based on 900 cases and 1,800 controls. The study strongly implicated important protective effects of vitamin B6 and methionine independent of tobacco smoking. Combined analysis resulted in an approximate 3-fold risk difference between the top and bottom 25% of the population for concentrations of vitamin B6 and methionine.

Aims

The overall aim of this expanded study is to elucidate the role of one-carbon metabolism in lung cancer etiology in a study population large enough to allow stratified robust analyses by smoking status, histology and socio-economic status. We will assess risk profiles for groups stratified on B-vitamin levels and smoking status, and correct risk estimates for regression dilution. In addition we will investigate if these associations for B-vitamins also translate to Asian populations with important differences in dietary and genetic background.

Project overall

The specific aims of the whole project are the following:

1. To accurately measure the association between circulating levels of vitamin B6, methionine and folate, as well as other B-vitamins and related compounds (including homocysteine, vitamin B2 and vitamin B12) and subsequent lung cancer risk
2. To provide accurate risk estimates for groups stratified by B-vitamin levels and smoking status (in particular in never and ex-smokers)
3. To analyze the effect of having low levels of multiple B-vitamins and related compounds, and test the hypothesis that their effects are, at least partially, independent
4. To calculate the within-person variation of B-vitamins and adjust results for regression dilution that occurs because of this variation
5. To analyze SNPs known to be associated with B-vitamin levels based on recent genome-wide studies, including additional case-control studies from the ILCCO consortium, in order to obtain independent and robust evidence of a causal effect of these B-vitamins

Participating cohorts

The specific aims for participating cohorts are the following:

1. To provide 500 µL plasma or serum for prospectively collected lung cancer cases and controls (individually matched 1:1)
2. To provide repeated plasma or serum samples for a subset of included controls
3. To provide detailed questionnaire data on risk factors including smoking variables, demographic, and dietary variables
4. To provide DNA (500 ng) in order to analyze specific single nucleotide polymorphisms known to influence factors of one-carbon metabolism
5. To provide follow-up data on vital status and cause of death

Methods

To robustly measure relative risks in subgroups, including never- and ex-smokers, we aim to gather serum or plasma from prospectively collected case-control pairs of lung cancer from 23 individual cohorts participating in the NCI cohort consortium. This will include 5,000 cases from US/European cohorts and 1,500 cases from Asian cohorts. We will adjust for regression dilution by estimating the within person variation in B-vitamins based on an additional 1,000 repeat samples from a subgroup of the controls, resulting in a total of 14,000 serum/plasma samples. In addition, we will analyze SNPs known to be associated with B-vitamin levels based on recent genome-wide studies, including an additional 10,000 case-control pairs from studies participating in the ILCCO consortium.