Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome.
BACKGROUND
Rothmund-Thomson syndrome (RTS) is an autosomal recessive disorder associated with an increased predisposition to osteosarcoma. Children with RTS typically present with a characteristic skin rash (poikiloderma), small stature, and skeletal dysplasias. Mutations in the RECQL4 gene, which encodes a RecQ DNA helicase, have been reported in a few RTS patients. We examined whether a predisposition to developing osteosarcoma among an international cohort of RTS patients was associated with a distinctive pattern of mutations in the RECQL4 gene.


METHODS
We obtained clinical information about and biologic samples from 33 RTS patients (age range = 1-30 years). Eleven patients were diagnosed with osteosarcoma. All 21 exons and 13 short introns of the RECQL4 gene were sequenced from the genomic DNA of all subjects. Kaplan-Meier survival analysis was used to estimate the incidence of osteosarcoma among patients with and without mutations predicted to produce a truncated RECQL4 protein.


RESULTS
Twenty-three RTS patients, including all 11 osteosarcoma patients, carried at least one of 19 truncating mutations in their RECQL4 genes. The incidence of osteosarcoma was 0.00 per year in truncating mutation-negative patients (100 person-years of observation) and 0.05 per year in truncating mutation-positive patients (230 person-years of observation) (P =.037; two-sided log-rank test).


CONCLUSIONS
Mutations predicted to result in the loss of RECQL4 protein function occurred in approximately two-thirds of RTS patients and are associated with risk of osteosarcoma. Molecular diagnosis has the potential to identify those children with RTS who are at high risk of this cancer.
Wang
Lisa L
LL
Texas Children's Cancer Center and Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Gannavarapu
Anu
A
Kozinetz
Claudia A
CA
Levy
Moise L
ML
Lewis
Richard A
RA
Chintagumpala
Murali M
MM
Ruiz-Maldanado
Ramon
R
Contreras-Ruiz
Jose
J
Cunniff
Christopher
C
Erickson
Robert P
RP
Lev
Dorit
D
Rogers
Maureen
M
Zackai
Elaine H
EH
Plon
Sharon E
SE
D000251:Adenosine Triphosphatases / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000483:Alleles; D015139:Blotting, Southern; D001859:Bone Neoplasms / Q000201:enzymology / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004265:DNA Helicases / Q000235:genetics*; D018076:DNA, Complementary / Q000032:analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D015994:Incidence; D007223:Infant; D008297:Male; D009154:Mutation; D012516:Osteosarcoma / Q000201:enzymology / Q000235:genetics*; D053484:RecQ Helicases; D011038:Rothmund-Thomson Syndrome / Q000201:enzymology / Q000235:genetics*; D017422:Sequence Analysis, DNA
D018076:DNA, Complementary; D000251:Adenosine Triphosphatases; C506731:RECQL4 protein, human; D004265:DNA Helicases; D053484:RecQ Helicases