title: Genetic variants associated with colorectal brain metastases susceptibility and survival.
abstract: Colorectal brain metastases (BM) are rare (1-2%) and a late-stage disease manifestation. Molecular mechanisms for BM development are not well understood. We tested whether variants within genes involved in overcoming the blood-brain barrier (BBB) are associated with BM susceptibility and survival in patients with BM. Germline single-nucleotide polymorphisms (SNPs, n=17) in seven genes (CXCR4, MMP9, ST6GALNAC5, ITGAV, ITGB1, ITGB3, KLF4) were analyzed from germline DNA in patients with resected BM (n=70) or no clinical evidence of BM after at least 24 months from diagnosis (control group, n=45). SNPs were evaluated for association with BM susceptibility and overall survival (OS) from BM diagnosis. ST6GALNAC5 rs17368584 and ITGB3 rs3809865 were significantly associated with BM susceptibility. In multivariable analysis adjusted for patient characteristics, KLF4 rs2236599, ITGAV rs10171481, ST6GALNAC5 rs1883778, CXCR4 rs2680880 and ITGB3 rs5918 were significant for OS. This study shows for the first time that variants within genes involved in breaching the BBB are associated with BM susceptibility and survival. These findings warrant further validation to develop better screening guidelines and to identify novel therapy targets for patients with BM.
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.|Department of Surgery, Medical University Vienna, Vienna, Austria.|Comprehensive Cancer Center Vienna, Medical University Vienna, Vienna, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Stremitzer
authors.affiliation: Comprehensive Cancer Center Vienna, Medical University Vienna, Vienna, Austria.|Clinical Institute of Neurology, Medical University Vienna, Vienna, Austria.
authors.forename: A S
authors.initials: AS
authors.lastname: Berghoff
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: N B
authors.initials: NB
authors.lastname: Volz
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Yang
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Stintzing
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Ning
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Sunakawa
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Yamauchi
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Sebio
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Matsusaka
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Okazaki
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: D
authors.identifier: 0000-0003-2681-5032
authors.initials: D
authors.lastname: Hanna
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Parekh
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Mendez
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Berger
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: El-Khoueiry
authors.affiliation: Comprehensive Cancer Center Vienna, Medical University Vienna, Vienna, Austria.|Department of Pathology, Medical University Vienna, Vienna, Austria.
authors.forename: P
authors.initials: P
authors.lastname: Birner
authors.affiliation: Comprehensive Cancer Center Vienna, Medical University Vienna, Vienna, Austria.|Department of Medicine I, Medical University Vienna, Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Preusser
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Lenz
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D001812:Blood-Brain Barrier / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics* / Q000401:mortality / Q000556:secondary*; D016009:Chi-Square Distribution; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D053208:Kaplan-Meier Estimate; D000090062:Kruppel-Like Factor 4; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors
chemical_list: D014408:Biomarkers, Tumor; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4