TY - JOUR
TI - High Yield of Pathogenic Germline Mutations Causative or Likely
Causative of the Cancer Phenotype in Selected Children with Cancer
AU - Diets, Illja J.
AU - Waanders, Esme
AU - Ligtenberg, Marjolijn J.
AU - van
AU - Bladel, Diede A. G.
AU - Kamping, Eveline J.
AU - Hoogerbrugge, Peter M.
AU - and Hopman, Saskia
AU - Olderode-Berends, Maran J.
AU - Gerkes, Erica H.
AU - and Koolen, David A.
AU - Marcelis, Carlo
AU - Santen, Gijs W.
AU - van
AU - Belzen, Martine J.
AU - Mordaunt, Dylan
AU - McGregor, Lesley and
AU - Thompson, Elizabeth
AU - Kattamis, Antonis
AU - Pastorczak, Agata and
AU - Mlynarski, Wojciech
AU - Ilencikova, Denisa
AU - Vulto-van Silfhout,
AU - Anneke
AU - Gardeitchik, Thatjana
AU - de Bont, Eveline S.
AU - Loeffen,
AU - Jan
AU - Wagner, Anja
AU - Mensenkamp, Arjen R.
AU - Kuiper, Roland P. and
AU - Hoogerbrugge, Nicoline
AU - Jongmans, Marjolijn C.
JO - Clinical Cancer Research
PY - 2018
VL - 24
TODO - 7
SP - 1594-1603
PB - AMER ASSOC CANCER RESEARCH
SN - 1078-0432
TODO - 10.1158/1078-0432.CCR-17-1725
TODO - null
TODO - 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.
ER -