American Association for Cancer Research
Browse
10559965epi160373-sup-165552_1_supp_3553189_596yj4.pptx (104.72 kB)

Supplemental Figure 2 from Rare Variation in TET2 Is Associated with Clinically Relevant Prostate Carcinoma in African Americans

Download (104.72 kB)
figure
posted on 2023-03-31, 13:50 authored by Daniel C. Koboldt, Krishna L. Kanchi, Bin Gui, David E. Larson, Robert S. Fulton, William B. Isaacs, Aldi Kraja, Ingrid B. Borecki, Li Jia, Richard K. Wilson, Elaine R. Mardis, Adam S. Kibel

Analysis of the discovery dataset yielded numerous genes with an excess of rare coding deleterious variants in (A) African-American and (B) European-American samples. Each point represents one gene. Shown are the relative proportions of cases or controls harboring at least one rare deleterious variant in the gene.

Funding

Anthony DeNovi

Donald C. McGraw Foundation

St. Louis Men's Group Against Cancer

Cancer Research Fund

National Human Genome Research Institute

History

ARTICLE ABSTRACT

Background: Common variants have been associated with prostate cancer risk. Unfortunately, few are reproducibly linked to aggressive disease, the phenotype of greatest clinical relevance. One possible explanation is that rare genetic variants underlie a significant proportion of the risk for aggressive disease.Method: To identify such variants, we performed a two-stage approach using whole-exome sequencing followed by targeted sequencing of 800 genes in 652 aggressive prostate cancer patients and 752 disease-free controls in both African and European Americans. In each population, we tested rare variants for association using two gene-based aggregation tests. We established a study-wide significance threshold of 3.125 × 10−5 to correct for multiple testing.Results: TET2 in African Americans was associated with aggressive disease, with 24.4% of cases harboring a rare deleterious variant compared with 9.6% of controls (FET P = 1.84 × 10−5, OR = 3.0; SKAT-O P = 2.74 × 10−5). We report 8 additional genes with suggestive evidence of association, including the DNA repair genes PARP2 and MSH6. Finally, we observed an excess of rare truncation variants in 5 genes, including the DNA repair genes MSH6, BRCA1, and BRCA2. This adds to the growing body of evidence that DNA repair pathway defects may influence susceptibility to aggressive prostate cancer.Conclusions: Our findings suggest that rare variants influence risk of clinically relevant prostate cancer and, if validated, could serve to identify men for screening, prophylaxis, and treatment.Impact: This study provides evidence that rare variants in TET2 may help identify African American men at increased risk for clinically relevant prostate cancer. Cancer Epidemiol Biomarkers Prev; 25(11); 1456–63. ©2016 AACR.