Childhood cancer predisposition (ChiCaP) syndromes are increasingly recognized as contributing factors to childhood cancer development. Yet, due to variable availability of germline testing, many ...children with ChiCaP might go undetected today. We report results from the nationwide and prospective ChiCaP study that investigated diagnostic yield and clinical impact of integrating germline whole-genome sequencing (gWGS) with tumor sequencing and systematic phenotyping in children with solid tumors.
gWGS was performed in 309 children at diagnosis of CNS (n = 123, 40%) or extracranial (n = 186, 60%) solid tumors and analyzed for disease-causing variants in 189 known cancer predisposing genes. Tumor sequencing data were available for 74% (227/309) of patients. In addition, a standardized clinical assessment for underlying predisposition was performed in 95% (293/309) of patients.
The prevalence of ChiCaP diagnoses was 11% (35/309), of which 69% (24/35) were unknown at inclusion (diagnostic yield 8%, 24/298). A second-hit and/or relevant mutational signature was observed in 19/21 (90%) tumors with informative data. ChiCaP diagnoses were more prevalent among patients with retinoblastomas (50%, 6/12) and high-grade astrocytomas (37%, 6/16), and in those with non-cancer related features (23%, 20/88), and ≥2 positive ChiCaP criteria (28%, 22/79). ChiCaP diagnoses were autosomal dominant in 80% (28/35) of patients, yet confirmed de novo in 64% (18/28). The 35 ChiCaP findings resulted in tailored surveillance (86%, 30/35) and treatment recommendations (31%, 11/35).
Overall, our results demonstrate that systematic phenotyping, combined with genomics-based diagnostics of ChiCaP in children with solid tumors is feasible in large-scale clinical practice and critically guides personalized care in a sizable proportion of patients.
The study was supported by the Swedish Childhood Cancer Fund and the Ministry of Health and Social Affairs.
Several studies have indicated that broad genomic characterization of childhood cancer provides diagnostically and/or therapeutically relevant information in selected high-risk cases. However, the ...extent to which such characterization offers clinically actionable data in a prospective broadly inclusive setting remains largely unexplored.
We implemented prospective whole-genome sequencing (WGS) of tumor and germline, complemented by whole-transcriptome sequencing (RNA-Seq) for all children diagnosed with a primary or relapsed solid malignancy in Sweden. Multidisciplinary molecular tumor boards were set up to integrate genomic data in the clinical decision process along with a medicolegal framework enabling secondary use of sequencing data for research purposes.
During the study's first 14 months, 118 solid tumors from 117 patients were subjected to WGS, with complementary RNA-Seq for fusion gene detection in 52 tumors. There was no significant geographic bias in patient enrollment, and the included tumor types reflected the annual national incidence of pediatric solid tumor types. Of the 112 tumors with somatic mutations, 106 (95%) exhibited alterations with a clear clinical correlation. In 46 of 118 tumors (39%), sequencing only corroborated histopathological diagnoses, while in 59 cases (50%), it contributed to additional subclassification or detection of prognostic markers. Potential treatment targets were found in 31 patients (26%), most commonly
mutations/fusions (n = 4), RAS/RAF/MEK/ERK pathway mutations (n = 14),
mutations/fusions (n = 5),
mutations (n = 2), and
gene fusions (n = 2). In one patient, the tumor diagnosis was revised based on sequencing. Clinically relevant germline variants were detected in 8 of 94 patients (8.5%).
Up-front, large-scale genomic characterization of pediatric solid malignancies provides diagnostically valuable data in the majority of patients also in a largely unselected cohort.
The risk of diabetic nephropathy (DN) increases with increase in intraglomerular pressure, which may partly be regulated by nitric oxide (NO). NO-production can be affected by polymorphisms in the ...endothelial NO-synthase gene (NOS3), hyperglycaemia and smoking. We therefore studied association between DN and two polymorphisms in NOS3, Glu298Asp and NOS4ab, in Caucasian type 1 diabetes (T1D) patients.
A total of 1510 Finnish and Swedish T1D patients were included in a cross-sectional case-control study. Incipient DN was defined as an albumin excretion rate (AER) of 20-200 microg/min (n = 336). Overt DN = AER>200 microg/min or renal replacement therapy (n = 619). All patients with DN were considered as cases. The controls were T1D patients with diabetes duration 20 years, AER<20 microg/min and without antihypertensive treatment (n = 555). The genetic markers studied were a 27 bp repeat (NOS4ab) and Glu298Asp (rs1799983).
Age at onset of diabetes, male sex, duration of diabetes, HbA1c, blood pressure and smoking were assessed as possible confounders in the logistic regression analysis, which showed that homozygosity for the Glu-allele of the Glu298Asp-polymorphism was independently associated with increased risk of DN (OR = 1.46; 95% CI = 1.12-1.91). The variables smoking (OR = 2.13; 95% CI = 1.63-2.78), male sex (OR = 1.61; 95% CI = 1.23-2.10), HbA1c (OR per % increase above upper limit of the normal reference range = 1.02; 95% CI = 1.02-1.03), systolic (OR = 1.05; 95% CI = 1.04-1.06) and diastolic blood pressure (OR = 1.04; 95% CI = 1.02-1.05) also significantly and independently increased the risk of DN when taking age at diabetes onset and diabetes duration into account. The NOS4 a-allele was not associated with DN.
The Glu/Glu-genotype of the NOS3 Glu298Asp polymorphism may increase the risk of developing DN independently of other known risk factors.
Autosomal recessive congenital ichthyosis (ARCI) is a rare, clinically and genetically heterogeneous genodermatosis. One gene (transglutaminase 1, on 14q11) and one additional locus (on 2q33-35, with ...an unidentified gene) have been shown to be associated with a lamellar, nonerythrodermic type of ARCI. We performed a genomewide scan, with 370 highly polymorphic microsatellite markers, on five affected individuals from one large Finnish family with nonerythrodermic, nonlamellar ARCI. The only evidence for linkage emerged from markers in a 6.0-cM region on chromosome 19p13.1-2. The maximum two-point LOD score of 7.33 was obtained with the locus D19S252, and multipoint likelihood calculations gave a maximum location score of 5.2. The affected individuals share two common core haplotypes, which makes compound heterozygosity possible. The novel disease locus is the third locus linked to ARCI, supporting previous evidence for genetic heterogeneity of ARCI. This is also the first locus for a nonlamellar, nonerythrodermic phenotype of ARCI.
Our main aim was to evaluate whether maternal whole venous blood could be used for determination of fetal sex, when no enrichment of fetal cells was attempted and when "standard" interphase ...cytogenetics and PCR analysis were adopted. Altogether 39 pregnant women were studied by using ISH and 59 by using PCR. Out of the 59 pregnant women, 26 carried a male fetus and 33 a female fetus. By ISH, Y-positive cells were detected in 12 of 19 pregnancies with a male fetus and in two of the 20 pregnancies with a female fetus. The frequency of the fetal cells ranged from 1 in 639 to 1 in 100,000. By nested PCR with primers flanking a Y-specific repeat sequence, the positive band indicating a male fetus was found in one of the 26 pregnancies with a male fetus and in one of the 33 pregnancies with a female fetus. According to our results, fetal cells in maternal blood cannot be reliably used for prenatal diagnosis without enrichment of fetal cells.
Our aim was to evaluate whether the sex of a fetus could be determined in maternal whole venous blood by in situ hybridization without enrichment of fetal cells. This procedure is virtually without ...risks to the fetus or the mother. Blood samples were obtained from 59 women at different stages of pregnancy. Twenty preparations were discarded because they were technically unfit for in situ hybridization. Of the remaining 39 pregnant women, 18 had a male fetus, one had male twins, and 20 had a female fetus. Y-positive cells were detected in 12 of the 19 pregnancies with male fetuses and in two of the 20 pregnancies with a female fetus. The frequencies of cells with Y-signals ranged from 1 in 100,000 to 1 in 639. Our results show that fetal cells in maternal blood cannot be reliably used for prenatal diagnosis without prior enrichment of fetal cells.
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