PLoS ONE (Jan 2016)

A Germline Variant on Chromosome 4q31.1 Associates with Susceptibility to Developing Colon Cancer Metastasis.

  • Sanford D Markowitz,
  • Nora L Nock,
  • Stephanie L Schmit,
  • Zsofia K Stadler,
  • Vijai Joseph,
  • Lu Zhang,
  • Joseph E Willis,
  • Peter Scacheri,
  • Martina Veigl,
  • Mark D Adams,
  • Leon Raskin,
  • John F Sullivan,
  • Kelly Stratton,
  • Jinru Shia,
  • Nathan Ellis,
  • Hedy S Rennert,
  • Christopher Manschreck,
  • Li Li,
  • Kenneth Offit,
  • Robert C Elston,
  • Gadi Rennert,
  • Stephen B Gruber

DOI
https://doi.org/10.1371/journal.pone.0146435
Journal volume & issue
Vol. 11, no. 1
p. e0146435

Abstract

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We tested for germline variants showing association to colon cancer metastasis using a genome-wide association study that compared Ashkenazi Jewish individuals with stage IV metastatic colon cancers versus those with stage I or II non-metastatic colon cancers. In a two-stage study design, we demonstrated significant association to developing metastatic disease for rs60745952, that in Ashkenazi discovery and validation cohorts, respectively, showed an odds ratio (OR) = 2.3 (P = 2.73E-06) and OR = 1.89 (P = 8.05E-04) (exceeding validation threshold of 0.0044). Significant association to metastatic colon cancer was further confirmed by a meta-analysis of rs60745952 in these datasets plus an additional Ashkenazi validation cohort (OR = 1.92; 95% CI: 1.28-2.87), and by a permutation test that demonstrated a significantly longer haplotype surrounding rs60745952 in the stage IV samples. rs60745952, located in an intergenic region on chromosome 4q31.1, and not previously associated with cancer, is, thus, a germline genetic marker for susceptibility to developing colon cancer metastases among Ashkenazi Jews.