DNA polymerase ε and δ variants drive mutagenesis in polypurine tracts in human tumors
Daria Ostroverkhova,
Kathrin Tyryshkin,
Annette K. Beach,
Elizabeth A. Moore,
Yosef Masoudi-Sobhanzadeh,
Stephanie R. Barbari,
Igor B. Rogozin,
Konstantin V. Shaitan,
Anna R. Panchenko,
Polina V. Shcherbakova
Affiliations
Daria Ostroverkhova
Department of Pathology and Molecular Medicine, School of Medicine, Queen’s University, Kingston, ON, Canada
Kathrin Tyryshkin
Department of Pathology and Molecular Medicine, School of Medicine, Queen’s University, Kingston, ON, Canada
Annette K. Beach
Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
Elizabeth A. Moore
Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
Yosef Masoudi-Sobhanzadeh
Department of Pathology and Molecular Medicine, School of Medicine, Queen’s University, Kingston, ON, Canada
Stephanie R. Barbari
Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
Igor B. Rogozin
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, USA
Konstantin V. Shaitan
Lomonosov Moscow State University, Moscow, Russia
Anna R. Panchenko
Department of Pathology and Molecular Medicine, School of Medicine, Queen’s University, Kingston, ON, Canada; Corresponding author
Polina V. Shcherbakova
Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA; Corresponding author
Summary: Alterations in the exonuclease domain of DNA polymerase ε cause ultramutated cancers. These cancers accumulate AGA>ATA transversions; however, their genomic features beyond the trinucleotide motifs are obscure. We analyze the extended DNA context of ultramutation using whole-exome sequencing data from 524 endometrial and 395 colorectal tumors. We find that G>T transversions in POLE-mutant tumors predominantly affect sequences containing at least six consecutive purines, with a striking preference for certain positions within polypurine tracts. Using this signature, we develop a machine-learning classifier to identify tumors with hitherto unknown POLE drivers and validate two drivers, POLE-E978G and POLE-S461L, by functional assays in yeast. Unlike other pathogenic variants, the E978G substitution affects the polymerase domain of Pol ε. We further show that tumors with POLD1 drivers share the extended signature of POLE ultramutation. These findings expand the understanding of ultramutation mechanisms and highlight peculiar mutagenic properties of polypurine tracts in the human genome.
