BACKGROUND: We conducted a large international study to estimate fractions of head and neck cancers (HNCs) attributable to human papillomavirus (HPV-AFs) using six HPV-related biomarkers of viral detection, transcription, and cellular transformation. METHODS: Formalin-fixed, paraffin-embedded cancer tissues of the oral cavity (OC), pharynx, and larynx were collected from pathology archives in 29 countries. All samples were subject to histopathological evaluation, DNA quality control, and HPV-DNA detection. Samples containing HPV-DNA were further subject to HPV E6*I mRNA detection and to p16(INK4a), pRb, p53, and Cyclin D1 immunohistochemistry. Final estimates of HPV-AFs were based on HPV-DNA, HPV E6*I mRNA, and/or p16(INK4a) results. RESULTS: A total of 3680 samples yielded valid results: 1374 pharyngeal, 1264 OC, and 1042 laryngeal cancers. HPV-AF estimates based on positivity for HPV-DNA, and for either HPV E6*I mRNA or p16(INK4a), were 22.4%, 4.4%, and 3.5% for cancers of the oropharynx, OC, and larynx, respectively, and 18.5%, 3.0%, and 1.5% when requiring simultaneous positivity for all three markers. HPV16 was largely the most common type. Estimates of HPV-AF in the oropharynx were highest in South America, Central and Eastern Europe, and Northern Europe, and lowest in Southern Europe. Women showed higher HPV-AFs than men for cancers of the oropharynx in Europe and for the larynx in Central-South America. CONCLUSIONS: HPV contribution to HNCs is substantial but highly heterogeneous by cancer site, region, and sex. This study, the largest exploring HPV attribution in HNCs, confirms the important role of HPVs in oropharyngeal cancer and drastically downplays the previously reported involvement of HPVs in the other HNCs.
- MeSH
- cyklin D1 analýza MeSH
- DNA virů izolace a purifikace MeSH
- dospělí MeSH
- genotyp MeSH
- imunohistochemie MeSH
- infekce papilomavirem komplikace virologie MeSH
- inhibitor p16 cyklin-dependentní kinasy analýza MeSH
- lidé středního věku MeSH
- lidé MeSH
- lidský papilomavirus 16 izolace a purifikace MeSH
- mezinárodní spolupráce MeSH
- nádorové biomarkery analýza MeSH
- nádorový supresorový protein p53 analýza MeSH
- nádory hlavy a krku virologie MeSH
- nádory orofaryngu chemie virologie MeSH
- Papillomaviridae genetika izolace a purifikace MeSH
- prediktivní hodnota testů MeSH
- průřezové studie MeSH
- senioři MeSH
- slinné proteiny bohaté na prolin analýza MeSH
- spinocelulární karcinom chemie virologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
Aberrant DNA methylation at specific genetic loci is a key molecular feature of juvenile myelomonocytic leukemia (JMML) with poor prognosis. Using quantitative high-resolution mass spectrometry, we identified RASA4 isoform 2, which maps to chromosome 7 and encodes a member of the GAP1 family of GTPase-activating proteins for small G proteins, as a recurrent target of isoform-specific DNA hypermethylation in JMML (51% of 125 patients analyzed). RASA4 isoform 2 promoter methylation correlated with clinical parameters predicting poor prognosis (older age, elevated fetal hemoglobin), with higher risk of relapse after hematopoietic stem cell transplantation, and with PTPN11 mutation. The level of isoform 2 methylation increased in relapsed cases after transplantation. Interestingly, most JMML cases with monosomy 7 exhibited hypermethylation on the remaining RASA4 allele. The results corroborate the significance of epigenetic modifications in the phenotype of aggressive JMML.
- MeSH
- chemorezistence * MeSH
- CpG ostrůvky MeSH
- dítě MeSH
- juvenilní myelomonocytární leukemie diagnóza metabolismus patologie MeSH
- kojenec MeSH
- lidé MeSH
- lidské chromozomy, pár 7 MeSH
- metylace DNA * MeSH
- mladiství MeSH
- monozomie MeSH
- mutace MeSH
- předškolní dítě MeSH
- prognóza MeSH
- promotorové oblasti (genetika) MeSH
- protein - isoformy genetika metabolismus MeSH
- proteiny aktivující GTPasu ras genetika metabolismus MeSH
- tyrosinfosfatasa nereceptorového typu 11 genetika metabolismus MeSH
- umlčování genů MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
