Abstract
Children diagnosed with cancer are considered for inherited cancer susceptibility testing according to well-established clinical criteria. With increasing efforts to personalize cancer medicine, comprehensive genome analyses will find its way into daily clinical routine in pediatric oncology. Whole genome and exome sequencing unavoidably generates incidental findings. The somatic “molecular make-up” of a tumor genome may suggest a germline mutation in a cancer susceptibility syndrome. At least two mechanisms are well-known, (a) chromothripsis (Li-Fraumeni syndrome) and (b) a high total number of mutational events which exceeds that of other samples of the same tumor type (defective DNA mismatch repair). Hence, pediatricians are faced with the fact that genetic events within the tumor genome itself can point toward underlying germline cancer susceptibility. Whenever genetic testing including next-generation sequencing (NGS) is initiated, the pediatrician has to inform about the benefits, risks, and alternatives, discuss the possibility of incidental findings and its disclosure, and to obtain informed consent prior to testing.
Conclusions: Genetic testing and translational research in pediatric oncology can incidentally uncover an underlying cancer susceptibility syndrome with implications for the entire family. Pediatricians should therefore increase their awareness of chances and risks that accompany the increasingly wide clinical implementation of NGS platforms.
What is Known: • The proportion of cancers in children attributable to an underlying genetic syndrome or inherited susceptibility is unclear. • Pediatricians consider children diagnosed with cancer for inherited cancer susceptibility according to well-established clinical criteria. |
What is New: • Genetic testing of tumor samples can incidentally uncover an underlying cancer susceptibility syndrome. • Findings in tumor genetics can be indicative that the tumor arose on the basis of the child’s germline alteration, (a) chromothripsis and (b) a high total number of mutational events which exceeds that of other samples of the same tumor type. |
Keywords: Cancer susceptibility syndrome, Hereditary, Childhood, Next-generation sequencing, Chromothripsis, Mutation rate
Introduction
Until now, the proportion of cancers in children and adolescents attributable to an underlying genetic syndrome or inherited susceptibility is unclear. In the early 1990s, the inherited fraction of childhood cancer was estimated at 1–10 % [29]. A recent report from the Pediatric Cancer Genome Project/St. Jude Children’s Research Hospital determined an incidence of 16.0 % in patients with solid tumors, 8.6 % with brain tumors, and 3.9 % with leukemias. The report initially focused on 23 well-known cancer predisposition genes and 8 genes that predispose to pediatric cancer with a high penetrance [47]. The most frequently affected genes included TP53, APC, and BRCA2. Additional analyses were expanded to 565 genes that are known to play a role in various steps and pathways of cellular transformation. Identified variants were classified as pathologic, likely pathologic, uncertain significance, likely benign, and benign. Taking the larger gene-set into account, the overall prevalence of an inherited mutation increased only slightly, with a pathologic or likely pathologic variant being detected in 8.6 % of all patients and 4.6 % of patients with leukemia. However, the spectrum of tumors sequenced was not numerically representative of the spectrum of childhood tumors, and the mutation frequencies may be skewed accordingly. In a hereditary cancer risk assessment study in survivors of childhood cancer, a genetic counselor considered 29 % of the survivors as eligible for further genetics evaluation [19].
However, in the era of high-throughput sequencing in which new cancer susceptibility syndromes (CSS) and mechanisms are increasingly discovered—did we so far maybe just see the tip of the iceberg?
Current clinical approach to CSS
Pediatric oncologists consider children diagnosed with cancer and their families for inherited cancer susceptibility according to well-established criteria [20]. These comprise patient-specific constellations including (i) rare tumors commonly associated with cancer predisposition (e.g., adrenocortical carcinoma), (ii) bilateral or multifocal tumors (e.g., Wilms’ tumor), (iii) cancer diagnosis at a younger than expected age (e.g., thyroid carcinoma), (iv) multiple synchronous or metachronous tumors, (v) additional conditions (e.g., axillary freckling) indicative of an underlying syndrome, and (vi) suspicious family features. These might include (a) familial clustering of the same or closely related cancers, (b) cancer diagnoses in two or more first-degree relatives, (c) tumor patterns associated with a specific cancer predisposition syndrome, (d) exceptional young age at diagnosis, (e) sibling with childhood cancer, and (f) consanguineous parents.
Li-Fraumeni syndrome (LFS) is one of the most striking familial cancer predisposition syndromes. It is clinically and genetically heterogeneous and characterized by autosomal dominant inheritance and early onset of tumors, multiple tumors within one individual, and multiple affected family members. LFS presents with a variety of tumor types with soft tissue sarcomas, osteosarcomas, breast cancer, brain tumors, leukemia, and adrenocortical carcinoma being the most common tumor types. Comprehensive surveillance protocols have been implemented and proven efficiency in terms of superior survival [46]. Table 1 lists common hereditary cancer susceptibility syndromes sorted by the underlying mechanism. The American College of Medical Genetics and Genomics and the National Society of Genetic Counselors just published the latest referral indications for cancer predisposition assessment [13]. However, due to de novo mutations, incomplete penetrance of inherited mutations, and variable phenotype/genotype correlations, the family history may not in all cases be helpful. For example, up to 25 % de novo events of TP53 mutations are reported in Li-Fraumeni syndrome [6]. In most other cases of CSS, however, the proportion of inherited susceptibility versus de novo mutations remains unknown.
Table 1.
Syndrome | Gene(s) | Inheritance | Clinical characteristics | Tumor types | Cancer risk |
---|---|---|---|---|---|
DNA damage repair defects/genetic instability | |||||
Ataxia telangiectasia (AT) * | ATM | AR | Progressive ataxia, central nervous system degeneration, growth deficiency, ocular and facial telangiectasias, immunodeficiency, infertility, premature aging | Leukemia, lymphoma, carcinoma | 10–38 % overall cancer risk 70-fold increased leukemia risk (T-ALL, T-PLL) 250-fold increased lymphoma risk (B cell) |
Bloom syndrome (BS) | BLM | AR | Short stature, immunodeficiency, malar rash, microcephaly, high-pitched voice, hypogonadism | Leukemia, lymphoma | 50 % overall cancer risk 15 % leukemia risk 15 % lymphoma risk |
Constitutional mismatch repair-deficiency syndrome (CMMR-D) | MLH1, MSH2, MSH6, PMS2 | AR | Multiple café au lait (CAL) spots, features reminiscent of NF1 | Pediatric brain tumors, colorectal cancers, ALL, AML, lymphoma, early onset gastrointestinal or gynecological cancers | Biallelic mutations at very high risk |
Fanconi anemia (FA) | FANCA, C, D1, D2, E, F, G, I, J, L, M, RAD51C, SLX4/BTBD12 FANCB |
AR X-linked |
Bone marrow failure, growth failure, radial ray abnormalities, renal abnormalities, CAL spots, hypopigmentation, congenital heart disease, microphthalmia, ear anomalies/deafness, hypogonadism; up to 25 % phenotypically normal | Leukemia (MDS, AML), squamous cell carcinoma, gynecological tumors, brain tumors, Wilms tumor, neuroblastoma | 25 % cumulative risk of hematologic malignancy by age 45 7 % MDS 9 % (500-fold increased risk of) AML |
Li-Fraumeni syndrome (LFS) | TP53 | AD up to 25 % de novo mutations | beyond classical LFS malignancies phenotypically normal | Soft tissue sarcoma, osteosarcoma, breast cancer, adrenocortical carcinoma (ACC), leukemia, brain tumors (glioblastoma multiforme, high-grade astrocytoma/primitive neuroectodermal tumor, medulloblastoma, choroid plexus carcinoma) | 90 % lifetime risk to develop cancer 1–3 % ALL (hypodiploid ALL) |
Nijmegen breakage syndrome (NBS) | NBS1 | AR | Microcephaly, prominent midface, receding mandible, CAL, recurrent infections, bone marrow failure | NHL, DLBCL, Burkitt lymphoma, T-LBL/-ALL, AML, Hodgkin lymphoma, medulloblastoma, rhabomyosarcoma | 40 % cancer risk by the age of 20 years |
Bone marrow failure (BMF) syndromes: ribosome biogenesis and/or telomere maintenance anomalies | |||||
Congenital amegakaryocytic thrombocytopenia (CAMT) type I / II | MPL | AR | Thrombocytopenia and megakaryocytopenia with no physical anomalies | MDS/AML | Unknown |
Diamond blackfan anemia (DBA) | RPS19, RPS24, RPS17, RPL35A, RPL5, RPL11, RPS7, RPS26, RPS10, GATA1 | AD Majority sporadic | Normochromic macrocytic anemia, reticulocytopenia, and nearly absent erythroid progenitors in the bone marrow, growth retardation, craniofacial, upper limb, heart, and urinary system congenital malformations, persistence of hemoglobin F | Adenocarcinoma of the colon, sarcoma, genital cancer, MDS/AML, ALL | 5.4 %-fold increased cancer risk |
Dyskeratosis congenital (DC) | DKC1, CTC1, TERC, TERT, TINF2, NOP10, NHP2, WRAP53 | X-linked | Triad of abnormal skin pigmentation, nail dystrophy, and leukoplakia of the oral mucosa | MDS/AML | 3–33 % leukemia risk |
Shwachman-Diamond syndrome (SDS) | SBDS | AR (considered) | Exocrine pancreatic insufficiency, hematologic abnormalities (pancytopenia), skeletal abnormalities | MDS/AML, ALL | 5–24 % leukemia risk |
Severe congenital neutropenia (SCN) (Kostmann syndrome) * | ELANE, HAX1 | AD AR | Congenital neutropenia, recurrent/persistent infections, omphalitis | MDS/AML | 8–25 % leukemia risk |
Thrombocytopenia and absent radii syndrome (TAR) | RBM8A and/or microdeletion 1q21.1 | Unclear | Reduction in the number of platelets and absence of the radius | MDS/AML | Unknown |
Cell cycle/differentiation defects (RAS pathway dysfunction) | |||||
CBL syndrome | CBL | AD | Dysmorphic facial features, short neck, developmental delay, hyperextensible joints, and thorax abnormalities with widely spaced nipples | JMML | Unknown |
Neurofibromatosis type I (NF1) | NF1, SPRED1 | AD | CAL, axillary/inguinal frecking, Lisch nodules, bony dysplasia, seizures, learning difficulties, sphenoid wing abnormalities | CMML/JMML, AML, neurofibroma, optic pathway glioma, peripheral nerve sheath tumor, astrocytoma, paraganglioma/pheochromocytoma | 200–500-fold increased JMML risk 11 % MDS 5-fold increased brain tumor risk almost 100 % neurofibroma risk |
Noonan/Noonan-like syndrome | PTPN11, HRAS, KRAS, NRAS, RAF1, SOS1, BRAF, SHOC2, MEPK1 | AD | Short stature, short webbed neck, lymphedema, hypertelorism, coarse facies, CAL, pulmonary valve stenosis, pectus excavatum, wide and low-set nipples, cardiomyopathy, bleeding disorders | Self-resolving myeloproliferative disease (MPD/TMD) and JMML, CMML, ALL, neuroblastoma, rhabdomyosarcoma | MPD/JMML in pts with PTPN11 |
Transcription factors/pure familial leukemia syndromes | |||||
Familial CEBPA leukemia | CEBPA | AD | None | MDS/AML | FAB M1/M2 highly penetrant |
Familial ETV6 / ALL syndrome | ETV6 | AD | Thrombocytopenia | MDS/AML, MPAL, ALL, multiple myeloma, colon cancer | Unknown |
Familial platelet disorder with predisposition to myeloid malignancy (FPD/AML) | RUNX1 (dominant) | AD | Mild to moderate thrombocytopenia, platelet function abnormalities | MDS/AML | 35 % AML risk |
Familial PAX5 syndrome | PAX5 | AD | None | ALL | 30 % penetrance in PAX5 SNP allele carriers PAX5 c.547G > A |
MonoMac | GATA2 | AD | Monocytopenia, NK cell lymphopenia, infections | MDS/AML | 50 % leukemia risk |
Immunodeficiencies | |||||
Wiskott-Aldrich syndrome (WAS) | WAS | X-linked | Eczema, thrombocytopenia, immunodeficiency | Diffuse large B cell lymphomas, non-Hodgkin’s lymphoma of larynx, leukemia, cerebellar astrocytoma, Kaposi sarcoma, smooth muscle tumors | 5–13 % lymphoid malignancies |
X-linked lymphoproliferative (XLP) syndrome type I / II | SH2D1A XIAP, SAP | X-linked | Severe immune dysregulation often after viral infection, typically with Epstein-Barr virus (EBV), severe or fatal mononucleosis, acquired hypogammaglobulinema, (HLH), lymphomatoid granulomatosis | Hemophagocytic lymphohistiocytosis (HLH), non-Hodgkin lymphoma | Unknown |
Autoimmune lymphoproliferative syndrome (ALPS) type IA/B/II | CD95 CD95L CASP10 IL12RB1 | AD AR in ALPS1A | Lymphadenopathy with hepatosplenomegaly and autoimmune cytopenias, hypergammaglobulinema | Hodgkin (HL) and non-Hodgkin (NHL) lymphoma, carcinoma (thyroid, breast, skin, tongue, liver), multiple neoplastic lesions (thyroid/breast adenomas, gliomas) | 14-fold NHL risk 51-fold HL risk |
IL2-inducible T cell kinase deficiency | ITK | AR | Fever, lymphadenopathy, splenomegaly, EBV associated lymphoproliferation | Hodgkin lymphoma, | Unknown |
Unknown | |||||
Familial mosaic monosomy 7 | Unknown | Unknown | Early-childhood onset of bone marrow insufficiency / failure | MDS, AML | Very high, fatal outcome |
Congenital syndromes/aneuploidy | |||||
Beckwith-Wiedemann syndrome (BWS) | p57, H19, LIT1, ICR1, CDKN1C, NSD1 | complex (AD, genomic imprinting, pUPD) | Overgrowth syndrome, marcoglossia, omphalocele, hemihypertrophy, neonatal hypoglycemia | Wilms tumor, hepatoblastoma, adrenal carcinoma, rhabdomyosarcoma | 8.6 % cancer risk, depending on subtypes highest risk in patients with hemihypertrophy and organomegaly |
Cowden syndrome type I-VI (CWS) | PTEN, SDHB, SDHD, KLLN | AD | Hamartomatous polyps of the gastrointestinal tract, mucocutaneous lesions, cobblestone-like papules of the gingiva and buccal mucosa, multiple facial trichilemmomas | Dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos), colon, breast and thyroid cancer | Lifetime risk 25–30 % breast cancer 10 % thyroid cancer 5–10 % endometrial/uterine cancer |
Denys-Drash syndrome (DDS) | WT1 (dominant) | Usually sporadic | Diffuse mesangial sclerosis leading to early endstage renal disease, disorder of sexual development in XY patients | Wilms tumor, gonadoblastoma | Almost 100 % Wilms tumor |
Down syndrome (DS) | Trisomy 21 | n.a. | Facial dysmorphism, mental retardation, hypotonia, congenital heart disease | TMD, AML, ALL | 10 % TMD, 1–2 % ALL/AML 10–20-fold increased leukemia risk 500-fold increased risk of AMKL |
Familial Adenomatous Polyposis (FAP) syndrome | APC | AD | Intestinal polyposis, osteomas, fibromas, sebaceous cysts, dental abnormalities | Colon, thyroid, stomach, and intestinal cancer, hepatoblastoma, desmoid tumors, medulloblastoma | Almost 100 % colorectal cancer |
Familial neuroblastoma | ALK, PHOX2B | AD | None | Neuroblastoma | Unknown |
Familial Pleuropulmonary blastoma tumor predisposition syndrome | DICER1 | AD | Pulmonary cysts, multinodular goiter | PPB, cystic nephroma, Sertoli-Leydig cell tumors, rhabdomyosarcoma, supratentorial primitive neuroectodermal tumor, intraocular medulloepithelioma | Variable penetrance, exact rest unknown |
Hereditary paragangliomas and pheochromocytoma syndrome (HPPS) | SDHB | AD | None | Paraganglioma, pheochromocytoma, renal, thyroid | >70 % with metastatic disease 12 % GISTs |
Multiple endocrine naeoplasia type I (MEN1) | MEN1 | AD | None | Pancreatic islet cell tumor, pituitary adenoma, parathyroid adenoma | 10 % carcinoid tumors |
Multiple endocrine neoplasia type II (MEN2A, MEN2B) | RET | AD | Mucosal neuroma (intestinal tract, tongue, lips), marfanoid habitus | Medullary thyroid carcinoma, pheochromocytoma, parathyroid hyperplasia | 100 % risk of developing medullary thyroid carcinoma in MEN2A |
Nevoid basal cell carcinoma syndrome (NBCCS) / Gorlin syndrome | PTCH1, 2, SUFU | AD | Macrocephaly, hypertelorism, palmar or plantar pits, rib abnormalities, ectopic calcification of the falx cerebri | Basal cell carcinoma, desmoplastic medulloblastoma, ovarian fibromas | 90 % basal-cell carcinoma, 5 % medulloblastoma |
Peutz Jeghers syndrome (PJS) | STK11 | AD | Melanocytic macules of the lips, buccal mucosa, digits, multiple gastrointestinal hamartomatous polyps | Intestinal, ovarian, pancreatic, breast cancers | 55 % gastrointestinal cancer 45 % breast cancer |
Familial retinoblastoma syndrome (RB) | RB1 | AD | Leukocoria | Retinoblastoma, osteosarcoma, melanoma, glioma, carcinoma | 80 % bilateral retinoblastoma 20 % unilateral retinoblastoma |
Rhabdoid tumor predisposition syndrome | SMARCB1/INI1 | Unclear, up to 21 % de novo mutations | None | Rhabdoid tumor, medulloblastoma, choroidplexus tumor, schwannoma | Penetrance unclear |
Rubinstein-Taybi syndrome (RSTS) | CREBBP | AD | Short stature, learning difficulties, distinctive facial features, broad thumbs and first toes, microcephaly, growth retardation | Neuroblastoma, medulloblastoma, oligodendroglioma, meningeoma, pheochromocytoma, rhabdomyosarcoma, leiomyosarcoma, leukemia, lymphoma | Unknown |
Tuberous sclerosis complex (TSC) | TSC1/TSC2 | AD | Tubers, heterotopia, central nervous system migrational/psychomotor delay, seizures, renal/bone cysts | Subependymal giant cell astrocytoma, hamartoma, renal angiomyolipoma, renal cell carcinoma, cardial rhabdomyoma, renal angiomyolipoma | 4 % renal cell carcinoma 14 % giant cell astrocytoma |
Lynch syndrome type I / II | MLH1, MSH2, MSH6, PSM2 | AD | CAL | Colorectal cancer, glioblastoma multiforme, medulloblastoma | Depending on subtype 50.4 % cumulative risk for colorectal cancer at the age of 70 |
WAGR syndrome | WT1 | AD | Aniridia, genitourinary abnormalities, mental retardation | Wilms tumor, gonadoblastoma | High percentage of bilateral Wilms tumors |
*And cell cycle regulation
Personalized medicine
With the ongoing efforts to personalize cancer medicine, comprehensive genome analyses will increasingly find its way into daily clinical routine in pediatric oncology. In the recently established German INdividualized therapy FOr Relapsed Malignancies in childhood (INFORM) project, this idea has been introduced for pediatric patients with relapsed or refractory high-risk disease without further standard of care therapy options. Individual tumor samples are characterized on the molecular level by next-generation sequencing (NGS) to establish a “fingerprint” of the tumor to identify promising targets for a successful relapse therapy [10].
Other such examples in which the detection of specific mutations has already led to a change of therapy of course also exist. Recently, a new leukemia subtype of high-risk B-precursor acute lymphoblastic leukemia (ALL), called Ph-like ALL, was characterized. Besides its Ph- or BCR-ABL-like transcriptional profile, no translocation t(9;22) or BCR/ABL rearrangement, respectively, is present. Instead, multiple other genetic alterations can be detected, which are potentially druggable by tyrosine kinase inhibitors or other targeted therapies [18, 24, 36, 37]. In pediatric low-grade astrocytoma, the BRAF V600E-mutation was identified as a frequent genomic aberration activating the MAPK pathway. Tumors carrying this mutation show significantly increased BRAF and CCND1 levels [33]. Since its discovery, the BRAF V600E-mutation has been described in an increasing number of pediatric central nervous system (CNS) tumors [8, 11, 40, 41]. Targeted therapies such as the BRAF inhibitor vemurafenib and MEK1/2 inhibitors are available and some encouraging examples of effective therapies even in very aggressive tumor types have already been reported, such as the successful treatment of a 12-year-old child with relapsed glioblastoma multiforme with vemurafenib [38]. With the identification of a highly recurrent genetic alteration and its resulting fusion protein in ependymoma, the C11orf95-RELA protein, a further potentially druggable target was identified and specific therapy will hopefully be available in the near future [31]. We might also hypothesize that children with hereditary cancer syndromes like the so-called rasopathies might soon benefit from targeted therapy, as the underlying genetic alterations are highly recurrent [1, 9].
Next-generation sequencing
Due to rapid technical advances in the field of NGS, tumor (including leukemia) genomes can nowadays comprehensively be analyzed within few days. Today’s state of the art in high-throughput sequencing already allows the usage of whole genome sequencing for research projects and of whole exome sequencing for daily clinical routine. However, the likelihood of identifying contemplable mutations is highly dependent on the relative ability of the sequencing approach to find these mutations. Computational processing, analyzing, and interpreting the massive amounts of data and genetic variants produced by NGS still remains challenging and requires comparisons with databases such as dbSNP and 1000 genomes project [3, 16]. Another valuable resource in interpreting own experimental data is the ExAC browser provided by the Broad Institute at www.exac.broadinstitute.org. It meanwhile provides exome data from more than 60,000 unrelated individuals. Before definitive conclusions can be drawn, the functional consequences of identified mutations on protein structure and function often have to be demonstrated experimentally [43]. In addition, a frequent conceptual misunderstanding relates to the fact that even a mutation with profound impact on protein function does not automatically proves its pathogenicity and disease-causing effect.
Each of us carries an average of approximately 3000 single nucleotide polymorphisms (SNPs) in terms of individual SNPs. To generate a personal cancer genome signature for molecular targeted therapy, it is important to discriminate between these individual SNPs and somatic (tumor) mutations. Thus, comparing the NGS data of tumor versus germline DNA is a condition sine qua non to identify the somatically acquired genetic variants of the tumor.
However, NGS not only generates focused genetic results with precise clinical implications for treatment but also so-called incidental findings with possible, limited, or unknown clinical impact or might even uncover an underlying susceptibility to cancer and other hereditary diseases. Such incidental findings are divided into “anticipatable” and “unanticipatable” ones. The former is a finding that is known to be associated with the test and is possible to be found. The latter could not have been anticipated given the current state of scientific knowledge [17]. Hence, treating physicians will increasingly be faced with such incidental genetic findings and the difficulties of interpreting and reporting these results.
Moreover, the pediatric oncologist is confronted with one new situation in particular: the fact that genetic events within the tumor genome itself can point toward underlying germline cancer susceptibility. Thus, even if not initially aimed to detect a CSS, the somatic “molecular make-up” of the tumor genome may suggest a germline mutation in a CSS gene.
Up to now, there are two well-known findings in tumor genetics which can be indicative that the tumor arose on the basis of the child’s germline alteration, (a) chromothripsis and (b) a high total number of mutational events which exceeds that of other samples of the same tumor type.
The phenomenon of chromothripsis was first reported by Stephens in 2011 [44]. The term “chromothripsis” (“chromo” from chromosome; “thripsis” for shattering into pieces) describes the shattering of a chromosome or a chromosomal region into tens to hundreds of pieces and locally clustered reassembling of some of the genomic fragments while others are lost to the cell.
According to Stephens [44], chromothripsis is defined by six features: (1) rearrangements localized within the genome, (2) oscillating changes of the copy number profile between one and two copies, whereby (3) loss of heterozygosity (LOH) causes a copy number of one, and retaining heterozygosity a copy number of two, (4) clustering of breakpoints across the chromosome, (5) conjunction of two remote chromosome fragments, and (6) joining rearrangements between two chromosome arms with clustering at the breakpoints. Rapid oscillations between copy number states one and two within the whole or parts of the chromosome characterizes the copy number profile in case of chromothripsis.
In contrast to common theories of cancer evolution through progressive accumulation of genomic alterations such as oncogene activation and tumor suppressor loss through environmental and lifestyle factors in adults, chromothripsis as a single catastrophic event might be involved in the development of a variety of cancers in childhood. It can cause the formation of new gene fusions, disruption of tumor suppressors, and amplification of oncogenes [35, 44]. In adults, 2–3 % of all cancers show evidence of chromothripsis; in bone cancers, this incidence is especially high with 25 % [44]. The impact of chromothripsis on cancer gene function and cancer development in childhood has already been demonstrated for many different tumor entities, e.g., ALL, AML, ependymoma, medulloblastoma, neuroblastoma, and retinoblastoma [4, 23, 26, 28, 30, 31, 35]. In addition, chromothripsis has been associated with poor prognosis in neuroblastoma [28]. A list of pediatric tumors, in which chromothripsis has been described, is given in Table 2. Conversely, alterations in TP53 have been shown for low-hypodiploid ALL but without chromothriptic pattern [15].
-
(b)
To provide a comprehensive landscape of somatic genomic alterations (termed mutational signatures) in cancer genomes, numerous cancers have been profiled by DNA sequencing [2, 34, 45]. The occurring genomic alterations are presumably caused by defective DNA replication or repair and exogenous or endogenous mutagen exposure and include substitutions, insertions or deletions, rearrangements, copy number alterations, completely new sequences from exogenous sources, and combinations of all these possibilities. The prevalence of such mutations is highly variable between cancer (sub)types [2, 22]. Due to extensive exposure to carcinogens, small cell lung cancer (tobacco) and malignant melanoma (ultraviolet light) show the highest somatic mutation prevalence (over 100/Megabase (Mb)). In contrast, the mutation rate in pediatric cancers is lowest (0.1/Mb; approximately one change across the entire exome) as chronic mutagenic exposure plays a minor part in carcinogenesis in childhood [22]. An outline of mutation frequencies in various (pediatric) cancer types is given in Table 3.
Table 2.
Tumor | References |
---|---|
Burkitt lymphoma * | Sarova et al., Cancer Genet 2014 |
Brain tumors • Ependymoma • High-grade gliomas • Medulloblastoma -Sonic-Hedgehog -Group 3 |
• Parker et al., Nature 2014 • Zhao et al., Neuro Oncol 2014 -Rausch et al., Cell 2012 -Northcott et al., Nature 2012 |
Hodgkin lymphoma * | Nagel et al., Genes Chromosomes Cancer 2013 |
Leukemia • AML • ALL (iAMP21) |
• Rausch et al., Cell 2012 • Harrison et al., Blood 2015; Li et al., Nature 2014 |
Neuroblastoma | Ambros et al., Frontiers in Oncology 2014; Boeva et al., PLoS One 2013; Molenaar et al., Nature 2012 |
Osteosarcoma * | Stephens et al., Cell 2011 |
Phaeochromocytoma (PCC) / Paraganglioma (PGL) * | Flynn et al., J Pathol 2014 |
Retinoblastoma | McEvoy et al., Oncotarget 2014 |
*Described in adult tumor samples
Table 3.
Malignancy | Mutations (range) | Reference |
---|---|---|
AMLa | 0.37 per Mb (0.01–10) of coding sequence | Lawrence et al., Nature 2013 |
Ependymoma, intracranialb | 12.8 ± 10.6 mutations (range 5 to 34) per tumor | Bettegowda et al., Oncotarget 2013 |
Ependymoma, spinal cordb | 12.9 ± 6.4 mutations (range 2 to 23) per tumor | Bettegowda et al., Oncotarget 2013 |
Ewinga | 0.15 per Mb of coding sequence | Brohl et al., PLoS Genet 2014 |
Glioblastoma multiformeb | 1.4 per Mb | Cancer Genome Atlas Research Network, Nature 2008 |
Glioblastoma, non-brainstem pediatric | 23.5 ± 11.2 mutations (range 4–46) per tumor | Bettegowda et al., Oncotarget 2013 |
MDSb | 3 (0–12) mutations per sample in 104 cancer genes | Haferlach et al., Leukemia 2014 |
Medulloblastoma | 8.3 non-synonymous SNVs per sample 0.35 non-silent mutations per megabase |
Parsons et al., Science 2011 Pugh et al., Nature 2012 |
Neuroblastoma | 0.60 per Mb of coding regions | Pugh et al., Nature Genet 2013 |
Rhabdoid cancers | 0.19 per Mb (0–0.45) of coding regions | Lee et al., J Clin Invest 2012 |
Xanthoastrocytoma, pleomorphicb | 9.5 ± 8.5 mutations (range 1 to 28) per tumor | Bettegowda et al., Oncotarget 2013 |
aTumor samples not specified
bDescribed in adult tumor samples
Alexandrov et al. [2] described a mutational signature with very large numbers of substitutions and small indels, the latter at short nucleotide repeats and with overlapping microhomology at breakpoint junctions, termed “microsatellite instability,” which is characteristic of cancers with defective DNA mismatch repair and may suggest constitutional mismatch repair-deficiency syndrome (CMMR-D) in childhood.
As was shown by Rausch et al. [35], the single nucleotide variant (SNV) rate of children with Sonic-Hedgehog medulloblastoma (SHH-MB) is clearly higher (24 tumor-specific SNVs) in the case of inherited TP53 mutations compared to sporadic pediatric medulloblastoma samples (average 5.7 non-synonymous SNVs per sample; [32]). Thus, comparing the patient’s SNV with the average SNV rate of a given tumor entity, an increased mutation frequency (SNV rate) detected by NGS of the tumor again may point to an underlying CSS (Li-Fraumeni syndrome).
Ethical and legal issues
“Are our other children at an increased risk of developing cancer?” Parents of a child diagnosed with cancer frequently raise this question. Up to now, pediatric oncologists mostly reassure them that cancer in children usually is not hereditary but an exceptionally bad stroke of fate. However, will this statement still hold true in the future with ever-increasing knowledge about underlying cancer predisposition syndromes and inherited cancer susceptibilities in childhood?
The incidental finding of chromothripsis and its association with Li-Fraumeni syndrome in SHH-MB patients very well demonstrates the far-reaching consequences of translational research and genetic testing in pediatric oncology with its challenges for scientists, treating physicians, and the affected child and his entire family.
By detecting chromothripsis in a tumor, further genetic testing for germline p53 mutations is highly advisable as this phenomenon might be attributable to an underlying Li-Fraumeni syndrome. The latter obviously represents an important piece of clinical information as it will guide treatment, surveillance, and further early cancer screening programs [21, 46].
According to the recommendations of national and international human genetic societies and the legislation of most European countries, prior to genetic testing, the child (wherever possible) and the parents must be informed in detail, preferences as to which findings should be reported must be assessed, and written informed consent must be obtained. This is a well-established standard of care for targeted molecular testing an affected individual or suspected carrier for a specific hereditary condition. However, NGS is likely, apart from the initial indication to perform it, to uncover incidental findings, such as an underlying CSS as well as non-cancer-related germline mutations (e.g., CFTR, Huntington’s disease) with varying clinical importance for the patient. In order to comply with the aforementioned recommendations, this would require extensive genetic counseling of the child/parents of a child diagnosed with cancer undergoing NGS of the tumor prior to testing, which would have to encompass both incidental findings with possible, limited, or unknown clinical impact and numerous results unrelated to the indication for NGS [42]. We believe that this is highly impractical in the daily life of a pediatric hemato-oncologist as disclosing the diagnosis of cancer itself is overwhelming and dramatically limits the child’s/parents’ receptivity, and NGS of the tumor often has to be initiated at the time of diagnosis. However, whenever NGS is initiated, the treating physician has an obligation to discuss the full range of generated data and the possibility of incidental findings and its disclosure with the child/parents. Furthermore, the ordering physician is responsible for obtaining informed consent and providing pre- and post-test counseling. Thus, regarding the child’s/parents’ autonomy and both their right to access all NGS data and their “right not to know,” they should be informed of the benefits, risks, and alternatives of genetic testing in detail [5, 7, 12]. When the patient/parent refuses to be informed about incidental findings, even if disclosure leads to beneficial interventions, the physician must ensure that adequate information has preceded this refusal. However, most clinicians do not have sufficient training in NGS and need to be extensively trained for clinical translation and reporting of NGS data.
In contrast to the standards for genetic testing in adults, predictive testing in pediatric patients is only recommended when the disease is associated with childhood onset and only with available effective screening and/or intervention options [7, 39]. Refraining from predictive testing of children allows them to autonomously make this decision once they reach adulthood.
Last but not least, identifying children with hereditary cancer predispositions has immediate consequences for the entire family (siblings, parents, and extended family) [20, 25, 42]. Due to the young age of the index patient, potentially affected relatives might as well be young and yet asymptomatic. Having been tested themselves might—depending on the outcome—influence their family planning but will of course also provide an excellent opportunity to initiate early cancer surveillance programs which they will benefit from. However, genetic testing and tumor surveillance can have deeply affecting psychological consequences for the child and the family, emotional support should thus be in place for the families.
Clear legislation on returning genetic results in oncology are still missing. Lolkema et al. have thoroughly addressed the accompanying ethical, legal, and counseling challenges [25]. Comprehensive ethical recommendations on how to report research results to patients and parents are, for example, given by the American College of Medical Genetics and Genomics, the Boston Children’s Hospital, the American Academy of Pediatrics, the “EURAT” (Ethical and legal aspects of whole human genome sequencing) project of the Marsilius Kolleg of Heidelberg University, and the Leopoldina National Academy of Sciences Germany [5, 12, 14, 27, 39]. However, their practical implementation in day-to-day clinical life remains challenging.
Conclusions
Genetic testing and translational research in pediatric oncology provides new and exciting insights into the evolution and pathogenesis of childhood cancer. On the other hand, it can incidentally uncover an underlying cancer susceptibility syndrome with implications not only for the child but also for the entire family. Pediatric oncologists should therefore increase their awareness of chances and risks that accompany the increasingly wide clinical implementation of NGS platforms [42, 43].
Acknowledgments
The authors thank Dr. Jessica I. Höll for critical reading of the manuscript and editorial assistance. AB is supported by the German Research Consortium of Translational Cancer Research, DKTK.
Conflict of interest
The authors declare that they have no conflict of interest.
Authors’ contributions
MK screened the literature, collected the data, and drafted the manuscript. AB revised the manuscript. Both authors read and approved the final manuscript.
Abbreviations
- ALL
Acute lymphoblastic leukemia
- CMMR-D
Constitutional mismatch repair-deficiency
- CSS
Cancer susceptibility syndromes
- DGV
Database of genomic variants
- INFORM
Individualized therapy for relapsed malignancies in childhood
- LFS
Li-Fraumeni syndrome
- LOH
Loss of heterozygosity
- Mb
Megabase
- NGS
Next-generation sequencing
- SHH-MB
Sonic-Hedgehog medulloblastoma
- SNPs
Single nucleotide polymorphisms
- SNVs
Single nucleotide variants
Footnotes
Revisions received: 18 04 April 2015 / 06 May 2015
Contributor Information
Michaela Kuhlen, Phone: +49 211 81 16491, Email: Michaela.Kuhlen@med.uni-duesseldorf.de.
Arndt Borkhardt, Email: Arndt.Borkhardt@med.uni-duesseldorf.de.
References
- 1.Agarwal R, Liebe S, Turski ML, Vidwans SJ, Janku F, Garrido-Laguna I, Munoz J, Schwab R, Rodon J, Kurzrock R, Subbiah V, Pan-Cancer Working G. Targeted therapy for hereditary cancer syndromes: neurofibromatosis type 1, neurofibromatosis type 2, and Gorlin syndrome. Discov Med. 2014;18:323–330. [PubMed] [Google Scholar]
- 2.Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, Bignell GR, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415–421. doi: 10.1038/nature12477. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Biesecker LG, Burke W, Kohane I, Plon SE, Zimmern R. Next-generation sequencing in the clinic: are we ready? Nat Rev Genet. 2012;13:818–824. doi: 10.1038/nrg3357. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Boeva V, Jouannet S, Daveau R, Combaret V, Pierre-Eugene C, Cazes A, Louis-Brennetot C, Schleiermacher G, Ferrand S, Pierron G, Lermine A, Rio Frio T, Raynal V, Vassal G, Barillot E, Delattre O, Janoueix-Lerosey I. Breakpoint features of genomic rearrangements in neuroblastoma with unbalanced translocations and chromothripsis. PLoS One. 2013;8:e72182. doi: 10.1371/journal.pone.0072182. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Burke W, Antommaria AH, Bennett R, Botkin J, Clayton EW, Henderson GE, Holm IA, Jarvik GP, Khoury MJ, Knoppers BM, Press NA, Ross LF, Rothstein MA, Saal H, Uhlmann WR, Wilfond B, Wolf SM, Zimmern R. Recommendations for returning genomic incidental findings? we need to talk! Genet Med. 2013;15:854–859. doi: 10.1038/gim.2013.113. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Chompret A, Brugieres L, Ronsin M, Gardes M, Dessarps-Freichey F, Abel A, Hua D, Ligot L, Dondon MG, Bressac-de Paillerets B, Frebourg T, Lemerle J, Bonaiti-Pellie C, Feunteun J. P53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br J Cancer. 2000;82:1932–1937. doi: 10.1054/bjoc.2000.1167. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Clayton EW, McCullough LB, Biesecker LG, Joffe S, Ross LF, Wolf SM, Clinical Sequencing Exploratory Research Consortium Pediatrics Working G Addressing the ethical challenges in genetic testing and sequencing of children. Am J Bioeth. 2014;14:3–9. doi: 10.1080/15265161.2013.879945. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Dahiya S, Emnett RJ, Haydon DH, Leonard JR, Phillips JJ, Perry A, Gutmann DH. BRAF-V600E mutation in pediatric and adult glioblastoma. Neuro Oncol. 2014;16:318–319. doi: 10.1093/neuonc/not146. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Dilworth JT, Kraniak JM, Wojtkowiak JW, Gibbs RA, Borch RF, Tainsky MA, Reiners JJ, Jr, Mattingly RR. Molecular targets for emerging anti-tumor therapies for neurofibromatosis type 1. Biochem Pharmacol. 2006;72:1485–1492. doi: 10.1016/j.bcp.2006.04.010. [DOI] [PubMed] [Google Scholar]
- 10.DKFZ (2015) DKFZ Inform 20 - Eine zweite Chance für krebskranke Kinder
- 11.Dougherty MJ, Santi M, Brose MS, Ma C, Resnick AC, Sievert AJ, Storm PB, Biegel JA. Activating mutations in BRAF characterize a spectrum of pediatric low-grade gliomas. Neuro Oncol. 2010;12:621–630. doi: 10.1093/neuonc/noq007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL, McGuire AL, Nussbaum RL, O’Daniel JM, Ormond KE, Rehm HL, Watson MS, Williams MS, Biesecker LG, American College of Medical G, Genomics ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 2013;15:565–574. doi: 10.1038/gim.2013.73. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015;17:70–87. doi: 10.1038/gim.2014.147. [DOI] [PubMed] [Google Scholar]
- 14.Holm IA, Savage SK, Green RC, Juengst E, McGuire A, Kornetsky S, Brewster SJ, Joffe S, Taylor P. Guidelines for return of research results from pediatric genomic studies: deliberations of the Boston Children’s Hospital Gene Partnership Informed Cohort Oversight Board. Genet Med. 2014;16:547–552. doi: 10.1038/gim.2013.190. [DOI] [PubMed] [Google Scholar]
- 15.Holmfeldt L, Wei L, Diaz-Flores E, Walsh M, Zhang J, Ding L, Payne-Turner D, et al. The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet. 2013;45:242–252. doi: 10.1038/ng.2532. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Idris SF, Ahmad SS, Scott MA, Vassiliou GS, Hadfield J. The role of high-throughput technologies in clinical cancer genomics. Expert Rev Mol Diagn. 2013;13:167–181. doi: 10.1586/erm.13.1. [DOI] [PubMed] [Google Scholar]
- 17.Issues PCftSoB (2013) Anticipate and communicate ethical management of incidental and secondary findings in the clinical, research, and direct-to-consumer contexts [DOI] [PubMed]
- 18.Izraeli S, Shochat C, Tal N, Geron I. Towards precision medicine in childhood leukemia–insights from mutationally activated cytokine receptor pathways in acute lymphoblastic leukemia. Cancer Lett. 2014;352:15–20. doi: 10.1016/j.canlet.2014.02.009. [DOI] [PubMed] [Google Scholar]
- 19.Knapke S, Nagarajan R, Correll J, Kent D, Burns K. Hereditary cancer risk assessment in a pediatric oncology follow-up clinic. Pediatr Blood Cancer. 2012;58:85–89. doi: 10.1002/pbc.23283. [DOI] [PubMed] [Google Scholar]
- 20.Knapke S, Zelley K, Nichols KE, Kohlmann W, Schiffman JD (2012) Identification, management, and evaluation of children with cancer-predisposition syndromes. Am Soc Clin Oncol Educ Book:576–584 [DOI] [PubMed]
- 21.Lammens CR, Bleiker EM, Aaronson NK, Wagner A, Sijmons RH, Ausems MG, Vriends AH, Ruijs MW, van Os TA, Spruijt L, Gomez Garcia EB, Cats A, Nagtegaal T, Verhoef S. Regular surveillance for Li-Fraumeni syndrome: advice, adherence and perceived benefits. Fam Cancer. 2010;9:647–654. doi: 10.1007/s10689-010-9368-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, Carter SL, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499:214–218. doi: 10.1038/nature12213. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Li Y, Schwab C, Ryan SL, Papaemmanuil E, Robinson HM, Jacobs P, Moorman AV, et al. Constitutional and somatic rearrangement of chromosome 21 in acute lymphoblastic leukaemia. Nature. 2014;508:98–102. doi: 10.1038/nature13115. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Loh ML, Zhang J, Harvey RC, Roberts K, Payne-Turner D, Kang H, Wu G, et al. Tyrosine kinome sequencing of pediatric acute lymphoblastic leukemia: a report from the Children’s Oncology Group TARGET Project. Blood. 2013;121:485–488. doi: 10.1182/blood-2012-04-422691. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Lolkema MP, Gadellaa-van Hooijdonk CG, Bredenoord AL, Kapitein P, Roach N, Cuppen E, Knoers NV, Voest EE. Ethical, legal, and counseling challenges surrounding the return of genetic results in oncology. J Clin Oncol. 2013;31:1842–1848. doi: 10.1200/JCO.2012.45.2789. [DOI] [PubMed] [Google Scholar]
- 26.McEvoy J, Nagahawatte P, Finkelstein D, Richards-Yutz J, Valentine M, Ma J, Mullighan C, et al. RB1 gene inactivation by chromothripsis in human retinoblastoma. Oncotarget. 2014;5:438–450. doi: 10.18632/oncotarget.1686. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.McGuire AL, Joffe S, Koenig BA, Biesecker BB, McCullough LB, Blumenthal-Barby JS, Caulfield T, Terry SF, Green RC. Point-counterpoint. ethics and genomic incidental findings. Science. 2013;340:1047–1048. doi: 10.1126/science.1240156. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Molenaar JJ, Koster J, Zwijnenburg DA, van Sluis P, Valentijn LJ, van der Ploeg I, Hamdi M, van Nes J, Westerman BA, van Arkel J, Ebus ME, Haneveld F, Lakeman A, Schild L, Molenaar P, Stroeken P, van Noesel MM, Ora I, Santo EE, Caron HN, Westerhout EM, Versteeg R. Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes. Nature. 2012;483:589–593. doi: 10.1038/nature10910. [DOI] [PubMed] [Google Scholar]
- 29.Narod SA, Stiller C, Lenoir GM. An estimate of the heritable fraction of childhood cancer. Br J Cancer. 1991;63:993–999. doi: 10.1038/bjc.1991.216. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Northcott PA, Shih DJ, Peacock J, Garzia L, Morrissy AS, Zichner T, Stutz AM, et al. Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature. 2012;488:49–56. doi: 10.1038/nature11327. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Parker M, Mohankumar KM, Punchihewa C, Weinlich R, Dalton JD, Li Y, Lee R, et al. C11orf95-RELA fusions drive oncogenic NF-kappaB signalling in ependymoma. Nature. 2014;506:451–455. doi: 10.1038/nature13109. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Parsons DW, Li M, Zhang X, Jones S, Leary RJ, Lin JC, Boca SM, et al. The genetic landscape of the childhood cancer medulloblastoma. Science. 2011;331:435–439. doi: 10.1126/science.1198056. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Pfister S, Janzarik WG, Remke M, Ernst A, Werft W, Becker N, Toedt G, Wittmann A, Kratz C, Olbrich H, Ahmadi R, Thieme B, Joos S, Radlwimmer B, Kulozik A, Pietsch T, Herold-Mende C, Gnekow A, Reifenberger G, Korshunov A, Scheurlen W, Omran H, Lichter P. BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest. 2008;118:1739–1749. doi: 10.1172/JCI33656. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Pleasance ED, Cheetham RK, Stephens PJ, McBride DJ, Humphray SJ, Greenman CD, Varela I, et al. A comprehensive catalogue of somatic mutations from a human cancer genome. Nature. 2010;463:191–196. doi: 10.1038/nature08658. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Rausch T, Jones DT, Zapatka M, Stutz AM, Zichner T, Weischenfeldt J, Jager N, et al. Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell. 2012;148:59–71. doi: 10.1016/j.cell.2011.12.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Roberts KG, Li Y, Payne-Turner D, Harvey RC, Yang YL, Pei D, McCastlain K, et al. Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med. 2014;371:1005–1015. doi: 10.1056/NEJMoa1403088. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Roberts KG, Morin RD, Zhang J, Hirst M, Zhao Y, Su X, Chen SC, et al. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell. 2012;22:153–166. doi: 10.1016/j.ccr.2012.06.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Robinson GW, Orr BA, Gajjar A. Complete clinical regression of a BRAF V600E-mutant pediatric glioblastoma multiforme after BRAF inhibitor therapy. BMC Cancer. 2014;14:258. doi: 10.1186/1471-2407-14-258. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Ross LF, Saal HM, David KL, Anderson RR, American Academy of P, American College of Medical G, Genomics Technical report: ethical and policy issues in genetic testing and screening of children. Genet Med. 2013;15:234–245. doi: 10.1038/gim.2012.176. [DOI] [PubMed] [Google Scholar]
- 40.Schiffman JD, Hodgson JG, VandenBerg SR, Flaherty P, Polley MY, Yu M, Fisher PG, Rowitch DH, Ford JM, Berger MS, Ji H, Gutmann DH, James CD. Oncogenic BRAF mutation with CDKN2A inactivation is characteristic of a subset of pediatric malignant astrocytomas. Cancer Res. 2010;70:512–519. doi: 10.1158/0008-5472.CAN-09-1851. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Schindler G, Capper D, Meyer J, Janzarik W, Omran H, Herold-Mende C, Schmieder K, Wesseling P, Mawrin C, Hasselblatt M, Louis DN, Korshunov A, Pfister S, Hartmann C, Paulus W, Reifenberger G, von Deimling A. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol. 2011;121:397–405. doi: 10.1007/s00401-011-0802-6. [DOI] [PubMed] [Google Scholar]
- 42.Scollon S, Bergstrom K, Kerstein RA, Wang T, Hilsenbeck SG, Ramamurthy U, Gibbs RA, Eng CM, Chintagumpala MM, Berg SL, McCullough LB, McGuire AL, Plon SE, Parsons DW. Obtaining informed consent for clinical tumor and germline exome sequencing of newly diagnosed childhood cancer patients. Genome Med. 2014;6:69. doi: 10.1186/s13073-014-0069-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Stadler ZK, Schrader KA, Vijai J, Robson ME, Offit K. Cancer genomics and inherited risk. J Clin Oncol. 2014;32:687–698. doi: 10.1200/JCO.2013.49.7271. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ, Pleasance ED, et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell. 2011;144:27–40. doi: 10.1016/j.cell.2010.11.055. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Stratton MR, Campbell PJ, Futreal PA. The cancer genome. Nature. 2009;458:719–724. doi: 10.1038/nature07943. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Villani A, Tabori U, Schiffman J, Shlien A, Beyene J, Druker H, Novokmet A, Finlay J, Malkin D. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. Lancet Oncol. 2011;12:559–567. doi: 10.1016/S1470-2045(11)70119-X. [DOI] [PubMed] [Google Scholar]
- 47.Walsh M, Wu G, Edmonson M, Gruber TA, Easton J, Yergeau D, Vadodaria B, et al. (2014) Incidence of germline mutations in cancer-predisposition genes in children with hematologic malignancies: a report from the pediatric cancer genome project