Familial cancer associated with a polymorphism in ARLTS1.
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.
Calin
George Adrian
GA
Thomas Jefferson University, Philadelphia, USA.
Trapasso
Francesco
F
Shimizu
Masayoshi
M
Dumitru
Calin Dan
CD
Yendamuri
Sai
S
Godwin
Andrew K
AK
Ferracin
Manuela
M
Bernardi
Guido
G
Chatterjee
Devjani
D
Baldassarre
Gustavo
G
Rattan
Shashi
S
Alder
Hansjuerg
H
Mabuchi
Hideaki
H
Shiraishi
Takeshi
T
Hansen
Lise Lotte
LL
Overgaard
Jens
J
Herlea
Vlad
V
Mauro
Francesca Romana
FR
Dighiero
Guillaume
G
Movsas
Benjamin
B
Rassenti
Laura
L
Kipps
Thomas
T
Baffa
Raffaele
R
Fusco
Alfredo
A
Mori
Masaki
M
Russo
Giandomenico
G
Liu
Chang-Gong
CG
Neuberg
Donna
D
Bullrich
Florencia
F
Negrini
Massimo
M
Croce
Carlo M
CM
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
D018389:Codon, Nonsense; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D020727:ADP-Ribosylation Factors; C500039:ARL11 protein, human