Head and neck squamous cell carcinomas (HNSCCs) arise in the mucosal linings of the upper aerodigestive tract and are unexpectedly heterogeneous in nature. Classical risk factors are smoking and ...excessive alcohol consumption, and in recent years, the role of human papillomavirus (HPV) has emerged, particularly in oropharyngeal tumours. HPV-induced oropharyngeal tumours are considered a separate disease entity, which recently has manifested in an adapted prognostic staging system while the results of de-intensified treatment trials are awaited. Carcinogenesis caused by HPV in the mucosal linings of the upper aerodigestive tract remains an enigma, but with some recent observations, a model can be proposed. In 2015, The Cancer Genome Atlas (TCGA) consortium published a comprehensive molecular catalogue on HNSCC. Frequent mutations of novel druggable oncogenes were not demonstrated, but the existence of a subgroup of genetically distinct HPV-negative head and neck tumours with favourable prognoses was confirmed. Tumours can be further subclassified based on genomic profiling. However, the amount of molecular data is currently overwhelming and requires detailed biological interpretation. It also became apparent that HNSCC is a disease characterized by frequent mutations that create neoantigens, indicating that immunotherapies might be effective. In 2016, the first results of immunotherapy trials with immune checkpoint inhibitors were published, and these may be considered as a paradigm shift in head and neck oncology.
Most cancer deaths are caused by haematogenous metastatic spread and subsequent growth of tumour cells at distant organs. Disseminating tumour cells present in the peripheral blood and bone marrow ...can now be detected and characterized at the single-cell level. These cells are highly relevant to the study of the biology of early metastatic spread and provide a diagnostic source in patients with overt metastases. Here we review the evidence that disseminating tumour cells have a variety of uses for understanding tumour biology and improving cancer treatment.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
3.
The molecular biology of head and neck cancer Leemans, C. René; Braakhuis, Boudewijn J. M; Brakenhoff, Ruud H
Nature reviews. Cancer,
01/2011, Letnik:
11, Številka:
1
Journal Article
Recenzirano
Head and neck squamous cell carcinomas (HNSCCs) are caused by tobacco and alcohol consumption and by infection with high-risk types of human papillomavirus (HPV). Tumours often develop within ...preneoplastic fields of genetically altered cells. The persistence of these fields after treatment presents a major challenge, because it might lead to local recurrences and second primary tumours that are responsible for a large proportion of deaths. Aberrant signalling pathways have been identified in HNSCCs and inhibition of epidermal growth factor receptor (EGFR) has proved a successful therapeutic strategy. In this Review, we discuss the recent literature on tumour heterogeneity, field cancerization, molecular pathogenesis and the underlying causative cancer genes that can be exploited for novel and personalized treatments of patients with HNSCC.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
There is a great interest in developing biomarkers to enhance early detection and clinical management of tongue squamous cell carcinoma (TSCC). However, the developmental path towards a clinically ...valid biomarker remains extremely challenging. Ideally, the initial key step in moving a newly discovered biomarker towards clinical implementation is independent replication. Therefore, the focus of this review is on biomarkers that consistently showed clinical relevance in two or more publications.
We searched PubMed database for relevant papers across different TSCC sample sources, i.e., body fluids (saliva, serum/plasma) and tissues. No restriction regarding the date of publication was applied except for immunohistochemistry (IHC); only studies published between 2010 and June 2017 were included.
The search strategy identified 1429 abstracts, of which 96 papers, examining 150 biomarkers, were eventually included. Of these papers, 66% were exploratory studies evaluating single or a panel of biomarkers in one publication. Ultimately, based on studies that had undergone validation for their clinical relevance in at least two independent studies, we identified 10 promising candidates, consisting of different types of molecules (IL-6, IL-8, and Prolactin in liquid samples; HIF-1α, SOX2, E-cadherin, vimentin, MALAT1, TP53, and NOTCH1 in tissue biopsies) CONCLUSIONS: Although more exploratory research is needed with newer methods to identify biomarkers for TSCC, rigorous validation of biomarkers that have already shown unbiased assessment in at least two publications should be considered a high priority. Further research on these promising biomarkers or their combination in multi-institutional studies, could provide new possibilities to develop a specific panel for early diagnosis, prognosis, and individualized treatments.
Dissecting the metastatic cascade Pantel, Klaus; Brakenhoff, Ruud H
Nature reviews. Cancer,
06/2004, Letnik:
4, Številka:
6
Journal Article
Recenzirano
Despite recent progress in gene-expression profiling studies, the biology underlying the various patterns of metastasis that are observed in different tumour types remains unclear. The detection and ...characterization of disseminated tumour cells in patients with cancer has provided important new information about the cascade of metastatic events. This information has important implications for cancer prognosis and for therapy.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Chromosomal copy number aberrations can be efficiently detected and quantified using low-coverage whole-genome sequencing, but analysis is hampered by the lack of knowledge on absolute DNA copy ...numbers and tumor purity. Here, we describe an analytical tool for Absolute Copy number Estimation, ACE, which scales relative copy number signals from chromosomal segments to optimally fit absolute copy numbers, without the need for additional genetic information, such as SNP data. In doing so, ACE derives an estimate of tumor purity as well. ACE facilitates analysis of large numbers of samples, while maintaining the flexibility to customize models and generate output of single samples.
ACE is freely available via www.bioconductor.org and at www.github.com/tgac-vumc/ACE.
Supplementary data are available at Bioinformatics online.
Objectives
Head and neck squamous cell carcinoma (HNSCC) shows a remarkable heterogeneity between tumors, which may be captured by a variety of quantitative features extracted from diagnostic images, ...termed radiomics. The aim of this study was to develop and validate MRI-based radiomic prognostic models in oral and oropharyngeal cancer.
Materials and Methods
Native T1-weighted images of four independent, retrospective (2005–2013), patient cohorts (
n
= 102,
n
= 76,
n
= 89, and
n
= 56) were used to delineate primary tumors, and to extract 545 quantitative features from. Subsequently, redundancy filtering and factor analysis were performed to handle collinearity in the data. Next, radiomic prognostic models were trained and validated to predict overall survival (OS) and relapse-free survival (RFS). Radiomic features were compared to and combined with prognostic models based on standard clinical parameters. Performance was assessed by integrated area under the curve (iAUC).
Results
In oral cancer, the radiomic model showed an iAUC of 0.69 (OS) and 0.70 (RFS) in the validation cohort, whereas the iAUC in the oropharyngeal cancer validation cohort was 0.71 (OS) and 0.74 (RFS). By integration of radiomic and clinical variables, the most accurate models were defined (iAUC oral cavity, 0.72 (OS) and 0.74 (RFS); iAUC oropharynx, 0.81 (OS) and 0.78 (RFS)), and these combined models outperformed prognostic models based on standard clinical variables only (
p
< 0.001).
Conclusions
MRI radiomics is feasible in HNSCC despite the known variability in MRI vendors and acquisition protocols, and radiomic features added information to prognostic models based on clinical parameters.
Key Points
• MRI radiomics can predict overall survival and relapse-free survival in oral and HPV-negative oropharyngeal cancer.
• MRI radiomics provides additional prognostic information to known clinical variables, with the best performance of the combined models.
• Variation in MRI vendors and acquisition protocols did not influence performance of radiomic prognostic models.
In this study, we investigate the role of radiomics for prediction of overall survival (OS), locoregional recurrence (LRR) and distant metastases (DM) in stage III and IV HNSCC patients treated by ...chemoradiotherapy. We hypothesize that radiomic analysis of (peri-)tumoral tissue may detect invasion of surrounding tissues indicating a higher chance of locoregional recurrence and distant metastasis.
Two comprehensive data sources were used: the Dutch Cancer Society Database (Alp 7072, DESIGN) and "Big Data To Decide" (BD2Decide). The gross tumor volumes (GTV) were delineated on contrast-enhanced CT. Radiomic features were extracted using the RadiomiX Discovery Toolbox (OncoRadiomics, Liege, Belgium). Clinical patient features such as age, gender, performance status etc. were collected. Two machine learning methods were chosen for their ability to handle censored data: Cox proportional hazards regression and random survival forest (RSF). Multivariable clinical and radiomic Cox/ RSF models were generated based on significance in univariable cox regression/ RSF analyses on the held out data in the training dataset. Features were selected according to a decreasing hazard ratio for Cox and relative importance for RSF.
A total of 444 patients with radiotherapy planning CT-scans were included in this study: 301 head and neck squamous cell carcinoma (HNSCC) patients in the training cohort (DESIGN) and 143 patients in the validation cohort (BD2DECIDE). We found that the highest performing model was a clinical model that was able to predict distant metastasis in oropharyngeal cancer cases with an external validation C-index of 0.74 and 0.65 with the RSF and Cox models respectively. Peritumoral radiomics based prediction models performed poorly in the external validation, with C-index values ranging from 0.32 to 0.61 utilizing both feature selection and model generation methods.
Our results suggest that radiomic features from the peritumoral regions are not useful for the prediction of time to OS, LR and DM.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Another NOTCH for Cancer Brakenhoff, Ruud H.
Science (American Association for the Advancement of Science),
08/2011, Letnik:
333, Številka:
6046
Journal Article
Recenzirano
Next-generation sequencing reveals
NOTCH1
as an important tumor suppressor gene in head and neck cancer.
Squamous cell carcinomas of the head and neck (HNSCCs) that arise in the mucosal linings of ...the upper respiratory and digestive tracts are the sixth leading cancer by incidence worldwide, with ∼600,000 new cases each year (
1
). The most important risk factors for these cancers are tobacco use and alcohol consumption, while a subgroup is caused by infection with human papillomaviruses that also cause cervical cancer (
2
). Patients with early-stage disease are treated by either surgery or radiotherapy, whereas patients in advanced stages receive a combination of these modalities or concurrent chemotherapy and localized radiation. Only 40 to 50% of patients will survive for 5 years after treatment (
2
). Antibodies directed against the epidermal growth factor receptor have been the only recent new therapy for this life-threatening disease (
3
). Two papers in this issue—by Agrawal
et al.
(
4
) on page 1154 and Stransky
et al.
(
5
) on page 1157—provide new insight into the genetic changes causing HNSCC that may guide the development of alternative treatment strategies.
•Circulating tumour DNA (ctDNA) can be detected in patients with HNSCC.•Comprehensive analyses of molecular alterations improves ctDNA detection.•Levels of ctDNA correlate with disease stage.
...Tumor-specific genetic aberrations in cell-free DNA (cfDNA) from plasma are promising biomarkers for diagnosis of recurrent head and neck squamous cell carcinoma (HNSCC). However, the sensitivity when using somatic mutations only in cfDNA is suboptimal. Here, we combined detection of copy number aberrations (CNAs), human papillomavirus (HPV) DNA and somatic mutations in a single sequencing workflow.
Pretreatment plasmas of 40 patients and 20 non-cancer controls were used for analysis. Plasma DNA underwent low-coverage whole genome sequencing (lcWGS) to detect both CNAs and HPV-DNA, and deep sequencing to detect mutations in 12 frequently altered cancer driver genes in HNSCC using the same sequencing library. A specific analysis pipeline line was developed for data mining. The corresponding tumors were analyzed using slightly adapted protocols.
Using the developed method, somatic mutations and CNAs were detected in plasma DNA of HNSCC patients in 67% and 52%, respectively. HPV-DNA in plasma was detected in 100% of patients with HPV-positive tumors, and not in plasma of patients with HPV-negative tumors or non-cancer controls. Combined analysis increased the detection rate of tumor DNA in plasma to 78%. The detection rate was significantly associated with the stage of disease of the tumor. Neither HPV status nor location of the primary tumor influenced detection of CNAs or somatic mutations in plasma.
This study demonstrates that the combined analysis of CNAs, HPV and somatic mutations in plasma of HNSCC patients is feasible and contributes to a higher sensitivity of the assay compared to single modality analyses.
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