title: Clinical Implications of Rabphillin-3A-Like Gene Alterations in Breast Cancer.
abstract: For the rabphillin-3A-like (RPH3AL) gene, a putative tumor suppressor, the clinical significance of genetic alterations in breast cancers was evaluated. DNA and RNA were extracted from formalin-fixed, paraffin-embedded (FFPE) cancers and matching normal tissues. DNA samples were assessed for loss of heterozygosity (LOH) at the 17p13.3 locus of RPH3AL and the 17p13.1 locus of the tumor suppressor, TP53. RPH3AL was sequenced, and single nucleotide polymorphisms (SNPs) were genotyped. RNA samples were evaluated for expression of RPH3AL, and FFPE tissues were profiled for its phenotypic expression. Alterations in RPH3AL were correlated with clinicopathological features, LOH of TP53, and patient survival. Of 121 cancers, 80 had LOH at one of the RPH3AL locus. LOH of RHP3AL was associated with nodal metastasis, advanced stage, large tumor size, and poor survival. Although ~50% were positive for LOH at the RPH3AL and TP53 loci, 19 of 105 exhibited LOH only at the RPH3AL locus. Of these, 12 were non-Hispanic Caucasians (Whites), 15 had large tumors, and 12 were older (>50 years). Patients exhibiting LOH at both loci had shorter survival than those without LOH at these loci (log-rank, P = 0.014). LOH at the TP53 locus alone was not associated with survival. Analyses of RPH3AL identified missense point mutations in 19 of 125 cases, a SNP (C>A) in the 5'untranslated region at -25 (5'UTR-25) in 26 of 104, and a SNP (G>T) in the intronic region at 43 bp downstream to exon-6 (intron-6-43) in 79 of 118. Genotype C/A or A/A of the SNP at 5'UTR-25 and genotype T/T of a SNP at intron-6-43 were predominantly in Whites. Low levels of RNA and protein expression of RPH3AL were present in cancers relative to normal tissues. Thus, genetic alterations in RPH3AL are associated with aggressive behavior of breast cancers and with short survival of patients.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Balananda-Dhurjati Kumar
authors.initials: BD
authors.lastname: Putcha
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Xu
authors.initials: X
authors.lastname: Jia
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Venkat Rao
authors.initials: VR
authors.lastname: Katkoori
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Chura
authors.initials: C
authors.lastname: Salih
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Chandrakumar
authors.initials: C
authors.lastname: Shanmugam
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Trafina
authors.initials: T
authors.lastname: Jadhav
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Liselle C
authors.initials: LC
authors.lastname: Bovell
authors.affiliation: Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Behring
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Tom
authors.initials: T
authors.lastname: Callens
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Ludwine
authors.initials: L
authors.lastname: Messiaen
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Sejong
authors.initials: S
authors.lastname: Bae
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: William E
authors.initials: WE
authors.lastname: Grizzle
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Karan P
authors.initials: KP
authors.lastname: Singh
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Upender
authors.initials: U
authors.lastname: Manne
mesh_terms: D020121:5' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000483:Alleles; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D002886:Chromosomes, Human, Pair 17; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D019656:Loss of Heterozygosity; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D047368:Tumor Burden; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D020691:rab GTP-Binding Proteins / Q000235:genetics*
chemical_list: D020121:5' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing; C120704:RPH3AL protein, human; D016159:Tumor Suppressor Protein p53; D020691:rab GTP-Binding Proteins