Common and Rare Sequence Variants Influencing Tumor Biomarkers in Blood

Cancer Epidemiol Biomarkers Prev. 2020 Jan;29(1):225-235. doi: 10.1158/1055-9965.EPI-18-1060. Epub 2019 Oct 30.


Background: Alpha-fetoprotein (AFP), cancer antigens 15.3, 19.9, and 125, carcinoembryonic antigen, and alkaline phosphatase (ALP) are widely measured in attempts to detect cancer and to monitor treatment response. However, due to lack of sensitivity and specificity, their utility is debated. The serum levels of these markers are affected by a number of nonmalignant factors, including genotype. Thus, it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects.

Methods: We performed genome-wide association studies of serum levels of AFP (N = 22,686), carcinoembryonic antigen (N = 22,309), cancer antigens 15.3 (N = 7,107), 19.9 (N = 9,945), and 125 (N = 9,824), and ALP (N = 162,774). We also examined the correlations between levels of these biomarkers and the presence of cancer, using data from a nationwide cancer registry.

Results: We report a total of 84 associations of 79 sequence variants with levels of the six biomarkers, explaining between 2.3% and 42.3% of the phenotypic variance. Among the 79 variants, 22 are cis (in- or near the gene encoding the biomarker), 18 have minor allele frequency less than 1%, 31 are coding variants, and 7 are associated with gene expression in whole blood. We also find multiple conditions associated with higher biomarker levels.

Conclusions: Our results provide insights into the genetic contribution to diversity in concentration of tumor biomarkers in blood.

Impact: Genetic correction of biomarker values could improve prediction algorithms and decision-making based on these biomarkers.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / blood*
  • Biomarkers, Tumor / genetics
  • Child
  • Child, Preschool
  • Female
  • Gene Frequency
  • Genome-Wide Association Study
  • Humans
  • Iceland / epidemiology
  • Infant
  • Infant, Newborn
  • Male
  • Middle Aged
  • Neoplasms / blood
  • Neoplasms / diagnosis
  • Neoplasms / epidemiology*
  • Neoplasms / genetics
  • Polymorphism, Single Nucleotide
  • Predictive Value of Tests
  • Reference Values
  • Registries / statistics & numerical data
  • Sequence Analysis, RNA
  • Whole Genome Sequencing
  • Young Adult


  • Biomarkers, Tumor