BACKGROUND: Improved risk stratification, more effective therapy and better supportive care have resulted in survival rates after childhood cancer of around 80% in developed countries. Treatment however can be harsh, and three in every four childhood cancer survivors (CCS) develop at least one late effect, such as gonadal impairment. Gonadal impairment can cause involuntary childlessness, with serious consequences for the well-being of CCS. In addition, early menopause increases the risk of comorbidities such as cardiovascular disease and osteoporosis. Inter-individual variability in susceptibility to therapy related gonadal impairment suggests a role for genetic variation. Currently, only one candidate gene study investigated genetic determinants in relation to gonadal impairment in female CCS; it yielded one single nucleotide polymorphism (SNP) that was previously linked with the predicted age at menopause in the general population of women, now associated with gonadal impairment in CCS. Additionally, one genome wide association study (GWAS) evaluated an association with premature menopause, but no GWAS has been performed using endocrine measurements for gonadal impairment as the primary outcome in CCS. METHODS: As part of the PanCareLIFE study, the genetic variability of chemotherapy induced gonadal impairment among CCS will be addressed. Gonadal impairment will be determined by anti-Müllerian hormone (AMH) levels or alternatively by fertility and reproductive medical history retrieved by questionnaire. Clinical and genetic data from 837 non-brain or non-bilateral gonadal irradiated long-term CCS will result in the largest clinical European cohort assembled for this late-effect study to date. A candidate gene study will examine SNPs that have already been associated with age at natural menopause and DNA maintenance in the general population. In addition, a GWAS will be performed to identify novel allelic variants. The results will be validated in an independent CCS cohort. DISCUSSION: This international collaboration aims to enhance knowledge of genetic variation which may be included in risk prediction models for gonadal impairment in CCS.
- Klíčová slova
- Childhood cancer survivor, GWAS, Genetic variations, Late effects, SNPs,
- MeSH
- antimülleriánský hormon analýza MeSH
- celogenomová asociační studie MeSH
- dospělí traumatizovaní v dětství MeSH
- jednonukleotidový polymorfismus * MeSH
- lidé MeSH
- předčasná menopauza genetika metabolismus MeSH
- přežívající onkologičtí pacienti MeSH
- průzkumy a dotazníky MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- protokol klinické studie MeSH
- Názvy látek
- antimülleriánský hormon MeSH
Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of early childhood characterized by mutations activating RAS signaling. Established clinical and genetic markers fail to fully recapitulate the clinical and biological heterogeneity of this disease. Here we report DNA methylome analysis and mutation profiling of 167 JMML samples. We identify three JMML subgroups with unique molecular and clinical characteristics. The high methylation group (HM) is characterized by somatic PTPN11 mutations and poor clinical outcome. The low methylation group is enriched for somatic NRAS and CBL mutations, as well as for Noonan patients, and has a good prognosis. The intermediate methylation group (IM) shows enrichment for monosomy 7 and somatic KRAS mutations. Hypermethylation is associated with repressed chromatin, genes regulated by RAS signaling, frequent co-occurrence of RAS pathway mutations and upregulation of DNMT1 and DNMT3B, suggesting a link between activation of the DNA methylation machinery and mutational patterns in JMML.
- MeSH
- antitumorózní látky terapeutické užití MeSH
- biopsie MeSH
- chromatin genetika metabolismus MeSH
- dítě MeSH
- DNA-(cytosin-5-)methyltransferasa metabolismus MeSH
- DNA-(cytosin-5)-methyltransferasa 1 metabolismus MeSH
- DNA-methyltransferasa 3B MeSH
- epigenomika MeSH
- juvenilní myelomonocytární leukemie genetika mortalita patologie terapie MeSH
- kojenec MeSH
- lidé MeSH
- metylace DNA * MeSH
- mutace MeSH
- mutační analýza DNA MeSH
- Noonanové syndrom genetika patologie MeSH
- předškolní dítě MeSH
- prognóza MeSH
- prospektivní studie MeSH
- protoonkogenní proteiny c-cbl MeSH
- protoonkogenní proteiny p21(ras) genetika metabolismus MeSH
- regulace genové exprese u leukemie MeSH
- signální transdukce genetika MeSH
- transplantace hematopoetických kmenových buněk MeSH
- tyrosinfosfatasa nereceptorového typu 11 genetika metabolismus MeSH
- upregulace MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky MeSH
- multicentrická studie MeSH
- pozorovací studie MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antitumorózní látky MeSH
- chromatin MeSH
- DNA-(cytosin-5-)methyltransferasa MeSH
- DNA-(cytosin-5)-methyltransferasa 1 MeSH
- DNMT1 protein, human MeSH Prohlížeč
- KRAS protein, human MeSH Prohlížeč
- protoonkogenní proteiny c-cbl MeSH
- protoonkogenní proteiny p21(ras) MeSH
- PTPN11 protein, human MeSH Prohlížeč
- tyrosinfosfatasa nereceptorového typu 11 MeSH
