@article{3179320,
    title = "High Yield of Pathogenic Germline Mutations Causative or Likely
Causative of the Cancer Phenotype in Selected Children with Cancer",
    author = "Diets, Illja J. and Waanders, Esme and Ligtenberg, Marjolijn J. and van and Bladel, Diede A. G. and Kamping, Eveline J. and Hoogerbrugge, Peter M. and and Hopman, Saskia and Olderode-Berends, Maran J. and Gerkes, Erica H. and and Koolen, David A. and Marcelis, Carlo and Santen, Gijs W. and van and Belzen, Martine J. and Mordaunt, Dylan and McGregor, Lesley and and Thompson, Elizabeth and Kattamis, Antonis and Pastorczak, Agata and and Mlynarski, Wojciech and Ilencikova, Denisa and Vulto-van Silfhout, and Anneke and Gardeitchik, Thatjana and de Bont, Eveline S. and Loeffen, and Jan and Wagner, Anja and Mensenkamp, Arjen R. and Kuiper, Roland P. and and Hoogerbrugge, Nicoline and Jongmans, Marjolijn C.",
    journal = "Clinical Cancer Research",
    year = "2018",
    volume = "24",
    number = "7",
    pages = "1594-1603",
    publisher = "AMER ASSOC CANCER RESEARCH",
    issn = "1078-0432",
    doi = "10.1158/1078-0432.CCR-17-1725",
    abstract = "Purpose: In many children with cancer and characteristics suggestive of
a genetic predisposition syndrome, the genetic cause is still unknown.
We studied the yield of pathogenic mutations by applying whole-exome
sequencing on a selected cohort of children with cancer.
Experimental Design: To identify mutations in known and novel
cancer-predisposing genes, we performed trio-based whole-exome
sequencing on germline DNA of 40 selected children and their parents.
These children were diagnosed with cancer and had at least one of the
following features: (1) intellectual disability and/or congenital
anomalies, (2) multiple malignancies, (3) family history of cancer, or
(4) an adult type of cancer. We first analyzed the sequence data for
germline mutations in 146 known cancer-predisposing genes. If no
causative mutation was found, the analysis was extended to the whole
exome.
Results: Four patients carried causative mutations in a known
cancer-predisposing gene: TP53 and DICER1 (n = 3). In another 4
patients, exome sequencing revealed mutations causing syndromes that
might have contributed to the malignancy (EP300-based Rubinstein-Taybi
syndrome, ARID1A-based Coffin-Siris syndrome, ACTB-based
Baraitser-Winter syndrome, and EZH2-based Weaver syndrome). In addition,
we identified two genes, KDM3B and TYK2, which are possibly involved in
genetic cancer predisposition.
Conclusions: In our selected cohort of patients, pathogenic germline
mutations causative or likely causative of the cancer phenotype were
found in 8 patients, and two possible novel cancer-predisposing genes
were identified. Therewith, our study shows the added value of
sequencing beyond a cancer gene panel in selected patients, to recognize
childhood cancer predisposition. (C) 2018 AACR."
}