Germline Mutations in Predisposition Genes in Pediatric Cancer

By Jinghui Zhang, M. Walsh, Gang Wu, Michael N. Edmonson, T. Gruber, J. Easton, D. Hedges, Xiaotu Ma, Xin Zhou, D. Yergeau and 22 more. New England Journal of Medicine, 2015

1,123 citations recorded by the source corpus.

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.)

Subfields: Genetics, Oncology

View Paper: https://www.semanticscholar.org/paper/56ee3d49335db77d82f108d2b8d7720cdfa1d183

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Citations in the corpus

Identification of potentially oncogenic alterations from tumor-only samples reveals Fanconi anemia pathway mutations in bladder carcinomas (2017, background): “To be classified as an SLG variant, a FP variant needed a germline VAF of at least 30% to decrease the probability that the germline variant represented tumor contamination or artifacts.(24) Since certain germline variants highly increase predisposition to cancer, 41 we analyzed SLG variants for enr”
Immune Checkpoint Inhibition for Hypermutant Glioblastoma Multiforme Resulting From Germline Biallelic Mismatch Repair Deficiency. (2016, neutral): “occur in the context of cancer predisposition syndromes.(2) Pediatric GBMs are associated with”
THE GENOMIC LANDSCAPE OF PEDIATRIC AND YOUNG ADULT T-LINEAGE ACUTE LYMPHOBLASTIC LEUKEMIA (2017, positive): “To determine whether germline sequence mutations may influence a person’s risk of developing T-ALL, we analyzed 89 genes ( Supplementary Table 10 ), including 60 associated with autosomal dominant cancer predisposition syndromes 55 and the 35 most frequent targets of somatic mutation in this study.”
Pathogenic germline variants in 10,389 adult cancers (2018, background): “Further, in total, we curated 152 genes that contribute to cancer susceptibility, adding 15 genes from the St. Jude PCGP germline study (Zhang et al., 2015), 11 from Cancer Gene Census-Germline, and 12 from recent literature (reference listed in Table S1) to a published list of 114 known predisposit”
The landscape of genomic alterations across childhood cancers (2018, positive): “Accordingly, in our cohort ( n = 914 individual patients, about 25% of samples over-lapping with the previous study), 7.6% of samples were determined as being likely to be associated with a pathogenic germline variant 5,19 (162 genes investigated; Supplementary Tables 6, 7).”
Comprehensive Analysis of Hypermutation in Human Cancer (2017, neutral): “POLD1 germline variants of unknown significance in children with cancer (Zhang et al., 2016).”