AS509 - Biomarkers of lung cancer risk
[This page is intended to provide a study summary, the sections of which are below. Please complete these sections, as applicable. The headings below are suggested headings. You can remove inapplicable sections, or add new ones relevant to your study]
Investigator Names and Contact Information
Mattias Johansson (johanssonm@iarc.fr)
Specific aims of Project 2 in P01(CA203654)
1. To organize the Lung Cancer Cohort Consortium (LC3) and establish a study population with 19 prospective cohorts (including the WHI) with large numbers of pre-diagnostic blood samples available for biomarker analysis.
a. To identify the study population of 2,200 former and current smoking lung cancer cases that were diagnosed within 3-years or less of donating their blood sample, along with 2 subcohort representatives per case (Phase II, including WHI) or 1 matched control and 1 subcohort representative per case (Phase 1).
b. To organize shipping of all plasma samples to Olink Proteomics in Uppsala Sweden where all laboratory analysis of protein markers will be performed. Before shipping to Olink, samples will be plated according to Olink sample preparation instructions. If plating by the cohort necessitates an additional freeze/thaw then samples will be sent to Olink for plating. Plasma is preferred; serum is acceptable. (DNA is on hold as of 11/21/19, pending budget, and shipping of DNA samples to Bristol University for methylation analyses).
c. To gather and harmonize required data from the participating cohorts that are required for risk modeling.
2. Based on a comprehensive panel of promising risk biomarkers, including specifically a large panel of protein biomarkers and methylation markers, identify those that may be useful for risk prediction, and exclude those that are not risk informative (Phase I – does not include WHI).
a. To perform assays on all promising plasma biomarkers at a centralized laboratory Olink in Sweden for 1,200 cases and 2,400 matched controls or subcohort representatives from six prospective cohorts from the LC3 consortium (CPS-II, Australia MCCS, Norwegian HUNT, PLCO, EPIC, and the Asian cohort SCHS). A mixed design will be used. Two control subjects are selected: one that is common with the parallel LC3 case-control studies to allow direct comparison of biomarker performance, and one cohort-representative control sampled in a case-cohort design to facilitate risk modeling.
b. (On hold, pending budget. To conduct methylation analysis at Bristol University targeting 16 specific CpG sites that have been identified by epigenome-wide association studies of lung cancer risk.)
c. Define a panel of replicated risk biomarkers that provide non-redundant information on disease risk by regularized conditional logistic regression (Elastic net) and penalized logistic regression (using matched controls); then quantify the impact of these biomarkers on absolute risk using time-to-event analysis with late entries for non-subcohort cases (using subcohort representatives). At the Olink laboratory, a "custom panel" will be designed including up to 21 of these replicated protein markers.
3. To extensively evaluate the "custom panel" including replicated risk biomarkers in 13 additional LC3 cohorts (including WHI) and evaluate the extent to which they inform risk prediction models (Phase II).
a. To estimate the performance, in terms of calibration and discrimination, of existing lung cancer risk prediction models (e.g. PLCOm2012) in diverse cohorts around the world, without the inclusion of biomarkers. For this aim, data from all participants in the LC3 cohorts (including WHI) will be harmonized at IARC.
b. To perform assays for the custom panel of protein markers, along with any other replicated risk biomarkers from other domains, for the remaining samples from the LC3 consortium, using the same analytical platforms as in Specific aim 2. In order to facilitate risk estimation (e.g., probability of developing lung cancer in 3 years), a case-cohort design will be used. In each of the 13 LC3 cohorts, two subcohort members will be randomly selected for each case stratified by age (above/below the median among cases), sex (if applicable), and smoking status (former/current). For the WHI, all cases diagnosed within 3 years (N) and 2N subcohort members will be selected for Phase II. Selection of subcohort will also be stratified by OS/CT non-intervention arm, in addition to age and smoking status.
c. To identify the minimum number of validated risk biomarkers that provide meaningful information on disease risk by time-to-event analysis with late entries for non-subcohort cases.
d. Based on the complete data generated on 2,200 cases and 4,400 matched controls and subcohort representatives, to evaluate the extent to which using the validated risk biomarkers improve existing risk prediction models. This will involve comparisons of risk prediction models with and without biomarkers using c-statistics, and additional comparisons of the model performance in different ethnicities and minorities, as well as estimation of absolute risks whilst also taking competing risks into account.
