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2015 ; 373
(24
): 2336-2346
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Germline Mutations in Predisposition Genes in Pediatric Cancer
#MMPMID26580448
Zhang J
; Walsh MF
; Wu G
; Edmonson MN
; Gruber TA
; Easton J
; Hedges D
; Ma X
; Zhou X
; Yergeau DA
; Wilkinson MR
; Vadodaria B
; Chen X
; McGee RB
; Hines-Dowell S
; Nuccio R
; Quinn E
; Shurtleff SA
; Rusch M
; Patel A
; Becksfort JB
; Wang S
; Weaver MS
; Ding L
; Mardis ER
; Wilson RK
; Gajjar A
; Ellison DW
; Pappo AS
; Pui CH
; Nichols KE
; Downing JR
N Engl J Med
2015[Dec]; 373
(24
): 2336-2346
PMID26580448
show ga
BACKGROUND: The prevalence and spectrum of predisposing mutations among children
and adolescents with cancer are largely unknown. Knowledge of such mutations may
improve the understanding of tumorigenesis, direct patient care, and enable
genetic counseling of patients and families. METHODS: In 1120 patients younger
than 20 years of age, we sequenced the whole genomes (in 595 patients), whole
exomes (in 456), or both (in 69). We analyzed the DNA sequences of 565 genes,
including 60 that have been associated with autosomal dominant
cancer-predisposition syndromes, for the presence of germline mutations. The
pathogenicity of the mutations was determined by a panel of medical experts with
the use of cancer-specific and locus-specific genetic databases, the medical
literature, computational predictions, and second hits identified in the tumor
genome. The same approach was used to analyze data from 966 persons who did not
have known cancer in the 1000 Genomes Project, and a similar approach was used to
analyze data from an autism study (from 515 persons with autism and 208 persons
without autism). RESULTS: Mutations that were deemed to be pathogenic or probably
pathogenic were identified in 95 patients with cancer (8.5%), as compared with
1.1% of the persons in the 1000 Genomes Project and 0.6% of the participants in
the autism study. The most commonly mutated genes in the affected patients were
TP53 (in 50 patients), APC (in 6), BRCA2 (in 6), NF1 (in 4), PMS2 (in 4), RB1 (in
3), and RUNX1 (in 3). A total of 18 additional patients had protein-truncating
mutations in tumor-suppressor genes. Of the 58 patients with a predisposing
mutation and available information on family history, 23 (40%) had a family
history of cancer. CONCLUSIONS: Germline mutations in cancer-predisposing genes
were identified in 8.5% of the children and adolescents with cancer. Family
history did not predict the presence of an underlying predisposition syndrome in
most patients. (Funded by the American Lebanese Syrian Associated Charities and
the National Cancer Institute.).
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