{
  "abstract": "Background The heritability of urinary tract cancer (UTC) remains unexplained by known pathogenic germline variants, and the influence of germline variants on treatment response to immune checkpoint inhibition (ICI) has yet to be fully elucidated.Methods In this case–control study, we performed a germline whole-exome sequencing of 810 UTC patients from the Oncology Research Information Exchange Network. A rare-variant burden test was conducted on the 810 patients and 2354 healthy controls from the Centre d'Etudes du Polymorphisme Humain families, the University of Utah Heritage 1000 Projects, and the 1000 Genomes Project, stratified into discovery and confirmation sets. We used a gene set-based rare-variant association test (GSRVAT) with near-match confirmation, testing for the association of pathways with UTC susceptibility and accounting for multiple testing. We then studied the impact of the identified pathways on tumor biology and clinical course among the 810 cases by analyzing their tumor exomes, transcriptomes, and clinical features.Results GSRVAT revealed forkhead box p3 ( FOXP3) as a susceptibility pathway in 16% of patients with UTC, with an epistasis with DNA mismatch repair. Carriers of germline truncating variants in FOXP3-related susceptibility genes exhibited decreased tumor FOXP3 expression levels, which were associated with a cold tumor microenvironment and significantly reduced overall and progression-free survival following ICI.Conclusions Germline variants in a set of FOXP3-related genes confer inherent susceptibility to UTC and contribute to resistance against ICI. The immune-evading trait resulting from these variants and the downregulation of FOXP3 expression introduce a novel avenue for personalized medicine through germline and tumor sequencing.",
  "authors": [
    {
      "affiliations": [
        "Dermatology, University of Utah Health, Salt Lake City, Utah, USA"
      ],
      "name": "Bing-Jian Feng"
    },
    {
      "affiliations": [
        "University of Utah Health Huntsman Cancer Institute, Salt Lake City, Utah, USA",
        "National TeleOncology Program, Clinical Cancer Genetics Service, Durham VA Medical Center, Durham, North Carolina, USA"
      ],
      "name": "Wendy Kohlmann"
    },
    {
      "affiliations": [
        "University of Utah Health Huntsman Cancer Institute, Salt Lake City, Utah, USA"
      ],
      "name": "David A Nix"
    },
    {
      "affiliations": [
        "University of Utah Health Huntsman Cancer Institute, Salt Lake City, Utah, USA"
      ],
      "name": "Aaron Atkinson"
    },
    {
      "affiliations": [
        "University of Utah Health Huntsman Cancer Institute, Salt Lake City, Utah, USA"
      ],
      "name": "Kenneth M Boucher"
    },
    {
      "affiliations": [
        "Dermatology, University of Utah Health, Salt Lake City, Utah, USA"
      ],
      "name": "Courtney Carroll"
    },
    {
      "affiliations": [
        "University of Utah Health Huntsman Cancer Institute, Salt Lake City, Utah, USA"
      ],
      "name": "Chris J Stubben"
    },
    {
      "affiliations": [
        "Pharmacy, University of Kentucky, Lexington, Kentucky, USA"
      ],
      "name": "Jill Kolesar"
    },
    {
      "affiliations": [
        "Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA",
        "The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA"
      ],
      "name": "Eric A Singer"
    },
    {
      "affiliations": [
        "Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA"
      ],
      "name": "Gregory Riedlinger"
    },
    {
      "affiliations": [
        "Department of Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA"
      ],
      "name": "Stephen Edge"
    },
    {
      "affiliations": [
        "University of Utah Health Huntsman Cancer Institute, Salt Lake City, Utah, USA",
        "Lafayette Family Cancer Center, Brewer, Maine, USA"
      ],
      "name": "Kamal Kant Sahu"
    },
    {
      "affiliations": [
        "Aster Insights, Hudson, Florida, USA"
      ],
      "name": "Michelle Churchman"
    },
    {
      "affiliations": [
        "University of Colorado Cancer Center, Aurora, Colorado, USA"
      ],
      "name": "Laura Graham"
    },
    {
      "affiliations": [
        "University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, USA",
        "Department of Translational Genomics, University of Southern California Keck School of Medicine, Los Angeles, California, USA"
      ],
      "name": "Bodour Salhia"
    },
    {
      "affiliations": [
        "University of Utah Health Huntsman Cancer Institute, Salt Lake City, Utah, USA"
      ],
      "name": "Alejandro Sanchez"
    },
    {
      "affiliations": [
        "University of Iowa Holden Comprehensive Cancer Center, Iowa City, Iowa, USA"
      ],
      "name": "Yousef Zakharia"
    },
    {
      "affiliations": [
        "Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana, USA"
      ],
      "name": "Bryan P Schneider"
    },
    {
      "affiliations": [
        "Department of Genitourinary Oncology, Moffitt Cancer Center, Tampa, Florida, USA"
      ],
      "name": "Rohit Jain"
    },
    {
      "affiliations": [
        "The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA"
      ],
      "name": "Lindsey Byrne"
    },
    {
      "affiliations": [
        "University of Virginia School of Medicine, Charlottesville, Virginia, USA"
      ],
      "name": "Christopher A Moskaluk"
    },
    {
      "affiliations": [
        "University of Iowa Holden Comprehensive Cancer Center, Iowa City, Iowa, USA",
        "Department of Urology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA"
      ],
      "name": "Kenneth Nepple"
    },
    {
      "affiliations": [
        "The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA"
      ],
      "name": "Ahmad Shabsigh"
    },
    {
      "affiliations": [
        "Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Center Inc, Tampa, Florida, USA"
      ],
      "name": "Jad Chahoud"
    },
    {
      "affiliations": [
        "University of Utah Health Huntsman Cancer Institute, Salt Lake City, Utah, USA"
      ],
      "name": "Bradley R Cairns"
    },
    {
      "affiliations": [
        "University of Utah Health Huntsman Cancer Institute, Salt Lake City, Utah, USA",
        "George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, Utah, USA"
      ],
      "name": "Sumati Gupta"
    }
  ],
  "title": "Germline whole-exome sequencing reveals FOXP3-related gene variants conferring urinary cancer susceptibility and associated with immune escape",
  "uid": "0ff672e0-6252-5f0f-9ded-cd0136df88e9"
}