Content uploaded by Hartmut Peters
Author content
All content in this area was uploaded by Hartmut Peters on Jun 18, 2015
Content may be subject to copyright.
A preview of the PDF is not available
Cancer spectrum and frequency among children with Noonan, Costello, and cardio-facio-cutaneous syndromes
Abstract
Background:
Somatic mutations affecting components of the Ras-MAPK pathway are a common feature of cancer, whereas germline Ras pathway mutations cause developmental disorders including Noonan, Costello, and cardio-facio-cutaneous syndromes. These 'RASopathies' also represent cancer-prone syndromes, but the quantitative cancer risks remain unknown.
Methods:
We investigated the occurrence of childhood cancer including benign and malignant tumours of the central nervous system in a group of 735 individuals with germline mutations in Ras signalling pathway genes by matching their information with the German Childhood Cancer Registry.
Results:
We observed 12 cases of cancer in the entire RASopathy cohort vs 1.12 expected (based on German population-based incidence rates). This corresponds to a 10.5-fold increased risk of all childhood cancers combined (standardised incidence ratio (SIR)=10.5, 95% confidence interval=5.4-18.3). The specific cancers included juvenile myelomonocytic leukaemia=4; brain tumour=3; acute lymphoblastic leukaemia=2; rhabdomyosarcoma=2; and neuroblastoma=1. The childhood cancer SIR in Noonan syndrome patients was 8.1, whereas that for Costello syndrome patients was 42.4.
Conclusions:
These data comprise the first quantitative evidence documenting that the germline mutations in Ras signalling pathway genes are associated with increased risks of both childhood leukaemia and solid tumours.
... 67 Prader-Willi syndrome was linked to a higher incidence of myeloid leukemia. 65 People with Noonan and Costello syndromes had higher prevalence of childhood cancer (leukemia and solid tumors), 69 while individuals with a PTEN mutation and Cowden syndrome have a higher risk of early-onset colorectal cancer. For Rubinstein-Taybi syndrome, Klippel-Trenaunay syndrome or tuberous sclerosis, no increased risk of cancer was described. ...
... 68 Although both childhood leukemia and solid tumors were found to be increased among individuals with Noonan and Costello syndrome there was evidence to support the effectiveness of specific cancer screening measures for these individuals. 69 The studies focusing on genetic variations within IDrelated disorders, generally contain useful information for genetic counseling and tumor development predictors. Particularly, Chang 34 described that, within XPD, the allele A of codon 312 could be used for the early detection and prediction of bladder cancer. ...
Background
People with intellectual disabilities (ID) face barriers in cancer care contributing to poorer oncological outcomes. Yet, understanding cancer risks in the ID population remains incomplete.
Aim
To provide an overview of cancer incidence and cancer risk assessments in the entire ID population as well as within ID‐related disorders.
Methods
This systematic review examined cancer risk in the entire ID population and ID‐related disorders. We systematically searched PubMed (MEDLINE) and EMBASE for literature from January 1, 2000 to July 15, 2022 using a search strategy combining terms related to cancer, incidence, and ID.
Results
We found 55 articles assessing cancer risks in the ID population at large groups or in subgroups with ID‐related syndromes, indicating that overall cancer risk in the ID population is lower or comparable with that of the general population, while specific disorders (e.g., Down's syndrome) and certain genetic mutations may elevate the risk for particular cancers.
Discussion
The heterogeneity within the ID population challenges precise cancer risk assessment at the population level. Nonetheless, within certain subgroups, such as individuals with specific ID‐related disorders or certain genetic mutations, a more distinct pattern of varying cancer risks compared to the general population becomes apparent.
Conclusion
More awareness, and personalized approach in cancer screening within the ID population is necessary.
... Individuals with CS typically present craniofacial abnormalities such as cerebral cortical atrophy, ventriculomegaly or hydrocephalus in the brain, macrocephaly, and Chiari malformation or demyelination of the basal ganglia [53]. They may also experience seizures and have an increased risk of developing benign or malignant tumors [54]. Cognitive impairment, including mild-to-moderate grade intellectual disability, and affected learning and memory processes are also common features [55] (Table 1). ...
RASopathies, a group of neurodevelopmental congenital disorders stemming from mutations in the RAS/MAPK pathway, present a unique opportunity to delve into the intricacies of complex neurological disorders. Afflicting approximately one in a thousand newborns, RASopathies manifest as abnormalities across multiple organ systems, with a pronounced impact on the central and peripheral nervous system. In the pursuit of understanding RASopathies’ neurobiology and establishing phenotype–genotype relationships, in vivo non-mammalian models have emerged as indispensable tools. Species such as Danio rerio, Drosophila melanogaster, Caenorhabditis elegans, Xenopus species and Gallus gallus embryos have proven to be invaluable in shedding light on the intricate pathways implicated in RASopathies. Despite some inherent weaknesses, these genetic models offer distinct advantages over traditional rodent models, providing a holistic perspective on complex genetics, multi-organ involvement, and the interplay among various pathway components, offering insights into the pathophysiological aspects of mutations-driven symptoms. This review underscores the value of investigating the genetic basis of RASopathies for unraveling the underlying mechanisms contributing to broader neurological complexities. It also emphasizes the pivotal role of non-mammalian models in serving as a crucial preliminary step for the development of innovative therapeutic strategies.
... In rodents, paternal folate deficiency during the periconceptional period is linked to a higher rate of post-implantation embryo loss, fused and abnormal placentas, fetal abnormalities (craniofacial and limb defects), delayed muscle/skeletal development, and an increased vulnerability to anxiety and depression in the offspring [82,83]. In chickens, folic acid supplementation could also impact spermatozoa mRNA expression and induce transgenerational metabolic changes [84,85]. Fathers on a low-protein diet will have pups who are more likely to develop glucose intolerance, metabolic and cardiovascular dysfunction, an impaired skeletal system, and impaired bone deposition [86][87][88][89] with an increased risk of breast cancer in a mouse model [90]. ...
Pregnancy is generally studied as a biological interaction between a mother and a fetus; however, the father, with his characteristics, lifestyle, genetics, and living environment, is by no means unrelated to the outcome of pregnancy. The half of the fetal genetic heritage of paternal derivation can be decisive in cases of inherited chromosomal disorders, and can be the result of de novo genetic alterations. In addition to the strictly pathological aspects, paternal genetics may transmit thrombophilic traits that affect the implantation and vascular construction of the feto-placental unit, lead to placenta-mediated diseases such as pre-eclampsia and fetal growth retardation, and contribute to the multifactorial genesis of preterm delivery. Biological aspects of immunological tolerance to paternal antigens also appear to be crucial for these pathologies. Finally, this review describes the biological findings by which the environment, exposure to pathogens, lifestyle, and nutritional style of the father affect fetal pathophysiological and epigenetic definition.
Neuroblastoma is one of the most common childhood cancers worldwide causing approximately 10% of all pediatric cancer deaths [1–5]. More than 98% of all diagnosed cases are sporadic in nature and the average age at the time of diagnosis is 1–2 years. Over 50% of adolescent patients show metastasis of tumors at the time of diagnosis leading to poor survival [2, 6, 7]. The prognosis depends heavily on the disease stage [8]. In 2014, the overall incidence of pediatric neuroblastoma in USA was 7% making it the third most common type of childhood cancer [7]. The incidence rates of patients up to 19 years old from 2006–2010 were 8.5% for boys and 7.6% for girls, and 5.2%, 9.7%, 6.8% and 5.9% for Hispanic, non-Hispanic (white), non-Hispanic (black) and Asian/Pacific Islander patients, respectively [7]. A population-based study in Netherlands spanning a 25-year period (1990–2014) revealed a 1.6% annual increase in the total incidence of NB since 1990, particularly in patients aged ≥18 months with stage 4 disease along with an improved overall survival from 6 ± 4% (1990–1994) to 43 ± 7% (2010–2014) [9].
Background
Individuals with genetic syndromes can manifest both congenital heart disease (CHD) and cancer attributable to possible common underlying pathways. To date, reliable risk estimates of hematopoietic cancer (HC) among children with CHD based on large population‐based data remain scant. This study sought to quantify the risk of HC by the presence of genetic syndrome among children with CHD.
Methods and Results
Data sources were the Canadian CHD database, a nationwide database on CHD (1999–2017), and the CCR (Canadian Cancer Registry). Standardized incidence ratios were calculated for comparing HC incidences in children with CHD with the general pediatric population. A modified Kaplan‐Meier curve was used to estimate the cumulative incidence of HC with death as a competing risk. A total of 143 794 children (aged 0–17 years) with CHD were followed up from birth to age 18 years for 1 314 603 person‐years. Of them, 8.6% had genetic syndromes, and 898 HC cases were observed. Children with known syndromes had a substantially higher risk of incident HC than the general pediatric population (standardized incidence ratio, 13.4 [95% CI, 11.7–15.1]). The cumulative incidence of HC was 2.44% (95% CI, 2.11–2.76) among children with a syndrome and 0.79% (95% CI, 0.72–0.87) among children without a syndrome. Acute myeloid leukemia had a higher cumulative incidence during early childhood than acute lymphoblastic leukemia.
Conclusions
This is the first large population‐based analysis documenting that known genetic syndromes in children with CHD are a significant predictor of HC. The finding could be essential in informing risk‐stratified policy recommendations for cancer surveillance in children with CHD.
RASopathies are a group of malformation syndromes known to lead to nonimmune hydrops fetalis (NIHF) in severe presentations. Pathogenic variants can be de novo or parentally inherited. Despite being a known frequent presentation, the fraction of monogenic NIHF cases due to RASopathies is limited in the literature. Also, the specific parental contribution of RASopathies to NIHF is not well described. Our objective was to review pooled exome sequencing (ES) diagnostic yield of RASopathies for NIHF and to determine the parental contribution of RASopathy to NIHF. We performed a systematic review of prenatal ES studies from January 1, 2000 to August 1, 2022. Thirty‐six studies met inclusion criteria. Cases with RASopathy gene variants were reviewed. NIHF cases were further classified as isolated or non‐isolated. Thirty‐six ES studies including 46 pregnancies with NIHF and a diagnosed RASopathy were reviewed. Forty‐four diagnostic variants and 2 variants of uncertain significance in 12 RASopathy genes were identified. Expanding on what was previously published, a total of 506 NIHF cases were extracted with 191 cases yielding a positive diagnosis by ES. The overall rate of RASopathy diagnosis in clinically diagnosed NIHF cases was 9% (44/506). The rate of RASopathy diagnosis among NIHF cases with positive genetic diagnosis by ES was 23% (44/191). Of the 46 cases identified, 13 (28%) variants were parentally inherited; specifically, 5/13 (38%) maternal, 3/13 (23%) paternal, 2/13 (15%) biparental, and 3/13 (23%) unspecified. Majority of NIHF cases 29/46 (63%) were isolated. Among NIHF cases with positive ES diagnoses, RASopathy diagnostic yield by ES was 23%. NIHF secondary to RASopathies was parentally inherited in 28% of cases. Most cases of NIHF due to RASopathy were isolated, with no prenatal detection of associated anomalies.
Cardiofaciocutaneous (CFC) syndrome is one of the rarest RASopathies characterized by multiple congenital ectodermal, cardiac and craniofacial abnormalities with a mild to severe ocular, gastrointestinal and neurological involvement. It is an autosomal dominant syndrome, with complete penetrance, caused by heterozygous pathogenic variants in the genes BRAF, MAP2K1/MEK1, MAP2K2/MEK2, KRAS or, rarely, YWHAZ, all part of the RAS-MAPK pathway. This pathway is a signal transduction cascade that plays a crucial role in normal cellular processes such as cell growth, proliferation, differentiation, survival, metabolism and migration. CFC syndrome overlaps with Noonan syndrome, Costello syndrome, neurofibromatosis type 1 and Legius syndrome, therefore making the diagnosis challenging. Neurological involvement in CFC is more severe than in other RASopathies. Phenotypic variability in CFC patients is related to the specific gene affected, without a recognized genotype-phenotype correlation for distinct pathogenic variants. Currently, there is no specific treatment for CFC syndrome. Encouraging zebrafish model system studies suggested that, in the future, MEK inhibitors could be a suitable treatment of progressive phenotypes of CFC in children. A multidisciplinary care is necessary for appropriate medical management.
Background Infants with Noonan syndrome (NS) are predisposed to developing juvenile myelomonocytic leukaemia (JMML) or JMML-like myeloproliferative disorders (MPD). Whereas sporadic JMML is known to be aggressive, JMML occurring in patients with NS is often considered as benign and transitory. However, little information is available regarding the occurrence and characteristics of JMML in NS.
Methods and results Within a large prospective cohort of 641 patients with a germline PTPN11 mutation, we identified MPD features in 36 (5.6%) patients, including 20 patients (3%) who fully met the consensus diagnostic criteria for JMML. Sixty percent of the latter (12/20) had severe neonatal manifestations, and 10/20 died in the first month of life. Almost all (11/12) patients with severe neonatal JMML were males. Two females who survived MPD/JMML subsequently developed another malignancy during childhood. Although the risk of developing MPD/JMML could not be fully predicted by the underlying PTPN11 mutation, some germline PTPN11 mutations were preferentially associated with myeloproliferation: 10/48 patients with NS (20.8%) with a mutation in codon Asp61 developed MPD/JMML in infancy. Patients with a p.Thr73Ile mutation also had more chances of developing MPD/JMML but with a milder clinical course. SNP array and whole exome sequencing in paired tumoral and constitutional samples identified no second acquired somatic mutation to explain the occurrence of myeloproliferation.
Conclusions JMML represents the first cause of death in PTPN11-associated NS. Few patients have been reported so far, suggesting that JMML may sometimes be overlooked due to early death, comorbidities or lack of confirmatory tests.
RASopathies, a family of disorders characterized by cardiac defects, defective growth, facial dysmorphism, variable cognitive
deficits and predisposition to certain malignancies, are caused by constitutional dysregulation of RAS signalling predominantly
through the RAF/MEK/ERK (MAPK) cascade. We report on two germline mutations (p.Gly39dup and p.Val55Met) in RRAS, a gene encoding a small monomeric GTPase controlling cell adhesion, spreading and migration, underlying a rare (2 subjects
among 504 individuals analysed) and variable phenotype with features partially overlapping Noonan syndrome, the most common
RASopathy. We also identified somatic RRAS mutations (p.Gly39dup and p.Gln87Leu) in 2 of 110 cases of non-syndromic juvenile myelomonocytic leukaemia, a childhood myeloproliferative/myelodysplastic
disease caused by upregulated RAS signalling, defining an atypical form of this haematological disorder rapidly progressing
to acute myeloid leukaemia. Two of the three identified mutations affected known oncogenic hotspots of RAS genes and conferred variably enhanced RRAS function and stimulus-dependent MAPK activation. Expression of an RRAS mutant
homolog in Caenorhabditis elegans enhanced RAS signalling and engendered protruding vulva, a phenotype previously linked to the RASopathy-causing SHOC2S2G mutant. Overall, these findings provide evidence of a functional link between RRAS and MAPK signalling and reveal an unpredicted
role of enhanced RRAS function in human disease.
So far, two genes associated with familial melanoma have been identified, accounting for a minority of genetic risk in families. Mutations in CDKN2A account for approximately 40% of familial cases, and predisposing mutations in CDK4 have been reported in a very small number of melanoma kindreds. Here we report the whole-genome sequencing of probands from several melanoma families, which we performed in order to identify other genes associated with familial melanoma. We identify one individual carrying a novel germline variant (coding DNA sequence c.G1075A; protein sequence p.E318K; rs149617956) in the melanoma-lineage-specific oncogene microphthalmia-associated transcription factor (MITF). Although the variant co-segregated with melanoma in some but not all cases in the family, linkage analysis of 31 families subsequently identified to carry the variant generated a log of odds (lod) score of 2.7 under a dominant model, indicating E318K as a possible intermediate risk variant. Consistent with this, the E318K variant was significantly associated with melanoma in a large Australian case-control sample. Likewise, it was similarly associated in an independent case-control sample from the United Kingdom. In the Australian sample, the variant allele was significantly over-represented in cases with a family history of melanoma, multiple primary melanomas, or both. The variant allele was also associated with increased naevus count and non-blue eye colour. Functional analysis of E318K showed that MITF encoded by the variant allele had impaired sumoylation and differentially regulated several MITF targets. These data indicate that MITF is a melanoma-predisposition gene and highlight the utility of whole-genome sequencing to identify novel rare variants associated with disease susceptibility.
Ras genes are the most common targets for somatic gain-of-function mutations in human cancer. Recently, germline mutations that affect components of the Ras-Raf-mitogen-activated and extracellular-signal regulated kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) pathway were shown to cause several developmental disorders, including Noonan, Costello and cardio-facio-cutaneous syndromes. Many of these mutant alleles encode proteins with aberrant biochemical and functional properties. Here we will discuss the implications of germline mutations in the Ras-Raf-MEK-ERK pathway for understanding normal developmental processes and cancer pathogenesis.
Nat. Genet. 34, 148–150 (2003). The subpanels in Figure 1 were labeled incorrectly. A corrected version appears below.
Genome-wide association studies have uncovered hundreds of common genetic variants involved in complex diseases. However, for most complex diseases, these common genetic variants only marginally contribute to disease susceptibility. It is now argued that rare variants located in different genes could in fact play a more important role in disease susceptibility than common variants. These rare genetic variants were not captured by genome-wide association studies using single nucleotide polymorphism-chips but with the advent of next-generation sequencing technologies, they have become detectable. It is now possible to study their contribution to common disease by resequencing samples of cases and controls or by using new genotyping exome arrays that cover rare alleles. In this review, we address the question of the contribution of rare variants in common disease by taking the examples of different diseases for which some resequencing studies have already been performed, and by summarizing the results of simulation studies conducted so far to investigate the genetic architecture of complex traits in human. So far, empirical data have not allowed the exclusion of many models except the most extreme ones involving only a small number of rare variants with large effects contributing to complex disease. To unravel the genetic architecture of complex disease, case-control data will not be sufficient, and alternative study designs need to be proposed together with methodological developments.
RAS GTPases mediate a wide variety of cellular functions, including cell proliferation, survival, and differentiation. Recent studies have revealed that germline mutations and mosaicism for classical RAS mutations, including those in HRAS, KRAS, and NRAS, cause a wide spectrum of genetic disorders. These include Noonan syndrome and related disorders (RAS/mitogen-activated protein kinase [RAS/MAPK] pathway syndromes, or RASopathies), nevus sebaceous, and Schimmelpenning syndrome. In the present study, we identified a total of nine missense, nonsynonymous mutations in RIT1, encoding a member of the RAS subfamily, in 17 of 180 individuals (9%) with Noonan syndrome or a related condition but with no detectable mutations in known Noonan-related genes. Clinical manifestations in the RIT1-mutation-positive individuals are consistent with those of Noonan syndrome, which is characterized by distinctive facial features, short stature, and congenital heart defects. Seventy percent of mutation-positive individuals presented with hypertrophic cardiomyopathy; this frequency is high relative to the overall 20% incidence in individuals with Noonan syndrome. Luciferase assays in NIH 3T3 cells showed that five RIT1 alterations identified in children with Noonan syndrome enhanced ELK1 transactivation. The introduction of mRNAs of mutant RIT1 into 1-cell-stage zebrafish embryos was found to result in a significant increase of embryos with craniofacial abnormalities, incomplete looping, a hypoplastic chamber in the heart, and an elongated yolk sac. These results demonstrate that gain-of-function mutations in RIT1 cause Noonan syndrome and show a similar biological effect to mutations in other RASopathy-related genes.
Noonan syndrome is a genetic multisystem disorder characterised by distinctive facial features, developmental delay, learning difficulties, short stature, congenital heart disease, renal anomalies, lymphatic malformations, and bleeding difficulties. Mutations that cause Noonan syndrome alter genes encoding proteins with roles in the RAS-MAPK pathway, leading to pathway dysregulation. Management guidelines have been developed. Several clinically relevant genotype-phenotype correlations aid risk assessment and patient management. Increased understanding of the pathophysiology of the disease could help development of pharmacogenetic treatments.
The population-based German Childhood Cancer Registry
(GCCR) has been in operation since 1980. It covers all of
Germany, is almost complete, and fulfils the international
criteria for a high quality registry. The current population
basis is 13 million children,and so far more than 35,000 cases
are registered. Cancer registration of children in Germany works
very well, while it has been generally more difficult for adults
so far. The reason is the close cooperation with the Pediatric
Oncology Association and its therapy optimization trials,
neither of which have been similarly established for adults. The
regular data exchange with multicenter trials creates synergies
benefiting the completeness of the cases as well as the quality
of the records. This permits the epidemiologic database to be
augmented by clinical information. Another important aspect is
the implementation of an active, open-end, long-term follow-up
well into adulthood, which provides us with useful data for
epidemiology and clinical research. This also creates
considerable interest in the data on the part of the reporting
clinics. Further helpful aspects are the relatively small number
of clinics involved, the great cooperation from the parents, and
the generally high public interest in childhood cancer.