Analysis of the novel fanconi anemia gene SLX4/FANCP in familial breast cancer cases.
SLX4/FANCP is a recently discovered novel disease gene for Fanconi anemia (FA), a rare recessive disorder characterized by chromosomal instability and increased cancer susceptibility. Three of the 15 FA genes are breast cancer susceptibility genes in heterozygous mutation carriers--BRCA2, PALB2, and BRIP1. To investigate if defects in SLX4 also predispose to breast cancer, the gene was sequenced in a cohort of 729 BRCA1/BRCA2-negative familial breast cancer cases. We identified a single splice site mutation (c.2013+2T>A), which causes a frameshift by skipping of exon 8. We also identified 39 missense variants, four of which were selected for functional testing in a Mitomycin C-induced growth inhibition assay, and appeared indistinguishable from wild type. Although this is the first study that describes a truncating SLX4 mutation in breast cancer patients, our data indicate that germline mutations in SLX4 are very rare and are unlikely to make a significant contribution to familial breast cancer.
Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
Janine L
JL
Bakker
Saskia E
SE
van Mil
Gerry
G
Crossan
Nelly
N
Sabbaghian
Kim
K
De Leeneer
Bruce
B
Poppe
Muriel
M
Adank
Hans
H
Gille
Henk
H
Verheul
Hanne
H
Meijers-Heijboer
Johan P
JP
de Winter
Kathleen
K
Claes
Marc
M
Tischkowitz
Quinten
Q
Waisfisz
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics*; D018567:Breast Neoplasms, Male / Q000235:genetics*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005192:Family Health; D005199:Fanconi Anemia / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D022821:RNA Splice Sites / Q000235:genetics; D045522:Recombinases / Q000235:genetics*
D022821:RNA Splice Sites; D045522:Recombinases; C542319:SLX4 protein, human