title: A coding single-nucleotide polymorphism in lysine demethylase KDM4A associates with increased sensitivity to mTOR inhibitors.
abstract: SNPs occur within chromatin-modulating factors; however, little is known about how these variants within the coding sequence affect cancer progression or treatment. Therefore, there is a need to establish their biochemical and/or molecular contribution, their use in subclassifying patients, and their impact on therapeutic response. In this report, we demonstrate that coding SNP-A482 within the lysine tridemethylase gene KDM4A/JMJD2A has different allelic frequencies across ethnic populations, associates with differential outcome in patients with non-small cell lung cancer (NSCLC), and promotes KDM4A protein turnover. Using an unbiased drug screen against 87 preclinical and clinical compounds, we demonstrate that homozygous SNP-A482 cells have increased mTOR inhibitor sensitivity. mTOR inhibitors significantly reduce SNP-A482 protein levels, which parallels the increased drug sensitivity observed with KDM4A depletion. Our data emphasize the importance of using variant status as candidate biomarkers and highlight the importance of studying SNPs in chromatin modifiers to achieve better targeted therapy.
  
  
  CONCLUSIONS
  This report documents the first coding SNP within a lysine demethylase that associates with worse outcome in patients with NSCLC. We demonstrate that this coding SNP alters the protein turnover and associates with increased mTOR inhibitor sensitivity, which identifies a candidate biomarker for mTOR inhibitor therapy and a therapeutic target for combination therapy.
authors.affiliation: Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Capucine
authors.initials: C
authors.lastname: Van Rechem
authors.affiliation: Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Black
authors.affiliation: Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Patricia
authors.initials: P
authors.lastname: Greninger
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Harvard University, Boston, Massachusetts. Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Carlos
authors.initials: C
authors.lastname: Donado
authors.affiliation: Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Burrowes
authors.affiliation: Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Brendon
authors.initials: B
authors.lastname: Ladd
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Harvard University, Boston, Massachusetts. Pulmonary and Critical Care Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: David C
authors.initials: DC
authors.lastname: Christiani
authors.affiliation: Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Cyril H
authors.initials: CH
authors.lastname: Benes
authors.affiliation: Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts. jwhetstine@hms.harvard.edu.
authors.forename: Johnathan R
authors.initials: JR
authors.lastname: Whetstine
mesh_terms: D000483:Alleles; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005787:Gene Frequency; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics* / Q000378:metabolism; D008239:Lysine / Q000235:genetics*; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D016366:Open Reading Frames; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D054875:Ubiquitination
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D056484:Jumonji Domain-Containing Histone Demethylases; C494424:KDM4A protein, human; D058570:TOR Serine-Threonine Kinases; D008239:Lysine