title: Familial cancer associated with a polymorphism in ARLTS1.
abstract: BACKGROUND
  The finding of hemizygous or homozygous deletions at band 14 on chromosome 13 in a variety of neoplasms suggests the presence of a tumor-suppressor locus telomeric to the RB1 gene.
  
  
  METHODS
  We studied samples from 216 patients with various types of sporadic tumors or idiopathic pancytopenia, peripheral-blood samples from 109 patients with familial cancer or multiple cancers, and control blood samples from 475 healthy people or patients with diseases other than cancer. We performed functional studies of cell lines lacking ARLTS1 expression with the use of both the full-length ARLTS1 gene and a truncated variant.
  
  
  RESULTS
  We found a gene at 13q14, ARLTS1, a member of the ADP-ribosylation factor family, with properties of a tumor-suppressor gene. We analyzed 800 DNA samples from tumors and blood cells from patients with sporadic or familial cancer and controls and found that the frequency of a nonsense polymorphism, G446A (Trp149Stop), was similar in controls and patients with sporadic tumors but was significantly more common among patients with familial cancer than among those in the other two groups (P=0.02; odds ratio, 5.7; 95 percent confidence interval, 1.3 to 24.8). ARLTS1 was down-regulated by promoter methylation in 25 percent of the primary tumors we analyzed. Transfection of wild-type ARLTS1 into A549 lung-cancer cells suppressed tumor formation in immunodeficient mice and induced apoptosis, whereas transfection of truncated ARLTS1 had a limited effect on apoptosis and tumor suppression. Microarray analysis revealed that the wild-type and Trp149Stop-transfected clones had different expression profiles.
  
  
  CONCLUSIONS
  A genetic variant of ARLTS1 predisposes patients to familial cancer.
authors.affiliation: Thomas Jefferson University, Philadelphia, USA.
authors.forename: George Adrian
authors.initials: GA
authors.lastname: Calin
authors.forename: Francesco
authors.initials: F
authors.lastname: Trapasso
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Shimizu
authors.forename: Calin Dan
authors.initials: CD
authors.lastname: Dumitru
authors.forename: Sai
authors.initials: S
authors.lastname: Yendamuri
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Godwin
authors.forename: Manuela
authors.initials: M
authors.lastname: Ferracin
authors.forename: Guido
authors.initials: G
authors.lastname: Bernardi
authors.forename: Devjani
authors.initials: D
authors.lastname: Chatterjee
authors.forename: Gustavo
authors.initials: G
authors.lastname: Baldassarre
authors.forename: Shashi
authors.initials: S
authors.lastname: Rattan
authors.forename: Hansjuerg
authors.initials: H
authors.lastname: Alder
authors.forename: Hideaki
authors.initials: H
authors.lastname: Mabuchi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shiraishi
authors.forename: Lise Lotte
authors.initials: LL
authors.lastname: Hansen
authors.forename: Jens
authors.initials: J
authors.lastname: Overgaard
authors.forename: Vlad
authors.initials: V
authors.lastname: Herlea
authors.forename: Francesca Romana
authors.initials: FR
authors.lastname: Mauro
authors.forename: Guillaume
authors.initials: G
authors.lastname: Dighiero
authors.forename: Benjamin
authors.initials: B
authors.lastname: Movsas
authors.forename: Laura
authors.initials: L
authors.lastname: Rassenti
authors.forename: Thomas
authors.initials: T
authors.lastname: Kipps
authors.forename: Raffaele
authors.initials: R
authors.lastname: Baffa
authors.forename: Alfredo
authors.initials: A
authors.lastname: Fusco
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.forename: Giandomenico
authors.initials: G
authors.lastname: Russo
authors.forename: Chang-Gong
authors.initials: CG
authors.lastname: Liu
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Florencia
authors.initials: F
authors.lastname: Bullrich
authors.forename: Massimo
authors.initials: M
authors.lastname: Negrini
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
mesh_terms: D020727:ADP-Ribosylation Factors / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002872:Chromosome Deletion; D002882:Chromosomes, Human, Pair 13; D018389:Codon, Nonsense; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010198:Pancytopenia / Q000235:genetics; D010375:Pedigree; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D018389:Codon, Nonsense; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D020727:ADP-Ribosylation Factors; C500039:ARL11 protein, human