Hallmarks of a genomically distinct subclass of head and neck cancer.

Cancer is caused by an accumulation of somatic mutations and copy number alterations (CNAs). Besides mutations, these copy number changes are key characteristics of cancer development. Nonetheless, some tumors show hardly any CNAs, a remarkable phenomenon in oncogenesis.

Secretome and immune cell attraction analysis of head and neck cancers.

Immune checkpoint inhibitors are approved for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) but the response rate is only 13-18%. For an effective antitumor immune response, trafficking of immune cells to the tumor microenvironment (TME) is essential. We aimed to better understand immune cell migration as well as the involved chemokines in HNSCC.

Immune cell topography of head and neck cancer.

Background: Approximately 50% of head and neck squamous cell carcinomas (HNSCC) recur after treatment with curative intent. Immune checkpoint inhibitors are treatment options for recurrent/metastatic HNSCC; however, less than 20% of patients respond. To increase this response rate, it is fundamental to increase our understanding of the spatial tumor immune microenvironment (TIME).

Genomic Engineering of Oral Keratinocytes to Establish In Vitro Oral Potentially Malignant Disease Models as a Platform for Treatment Investigation.

Precancerous cells in the oral cavity may appear as oral potentially malignant disorders, but they may also present as dysplasia without visual manifestation in tumor-adjacent tissue. As it is currently not possible to prevent the malignant transformation of these oral precancers, new treatments are urgently awaited. Here, we generated precancer culture models using a previously established method for the generation of oral keratinocyte cultures and incorporated CRISPR/Cas9 editing.

The value of regular follow-up of oral leukoplakia for early detection of malignant transformation.

Objectives: Evaluate whether regular follow-up of oral leukoplakia (OL) resulted in early detection of malignant transformation (MT).

Method: Two hundred and twenty-two consecutive patients with OL (147 females, 75 males); median follow-up period of 64 months (range: 12-300). Three groups were distinguished: group A (n = 92) follow-up at the hospital; group B (n = 84) follow-up by their dentist; group C (n = 46) lost to follow-up.

The role of differentiated dysplasia in the prediction of malignant transformation of oral leukoplakia.

Objective: Oral leukoplakia is the most common oral potentially malignant disorder. Malignant transformation of oral leukoplakia occurs at an annual rate of 1%-7%. WHO-defined classic epithelial dysplasia is an important predictor of malignant transformation of oral leukoplakia, but we have previously shown in a proof of concept study that prediction improves by incorporation of an architectural pattern of dysplasia, also coined as differentiated dysplasia.

Elucidating the Genetic Landscape of Oral Leukoplakia to Predict Malignant Transformation.

Purpose: Oral leukoplakia is the most common oral potentially malignant disorder with an annual malignant transformation rate of 1% to 5%. Consequently, oral leukoplakia patients have a 30% to 50% lifetime risk to develop oral squamous cell carcinoma. Although risk factors for malignant transformation of oral leukoplakia have been investigated, no definitive risk stratification model has been proposed.

Oral leukoplakia classification and staging system with incorporation of differentiated dysplasia.

Objectives: A classification and staging system for oral leukoplakia (OL) was introduced to promote uniform reporting. In this system, size and the histopathologic diagnosis are assessed and combined in a staging system. The various stages could be predictive for malignant transformation of OL.

At the Crossroads of Molecular Biology and Immunology: Molecular Pathways for Immunological Targeting of Head and Neck Squamous Cell Carcinoma.

Recent advances in immunotherapy for head and neck squamous cell carcinoma (HNSCC) have led to implementation of anti-programmed death receptor 1 (PD-1) immunotherapy to standard of care for recurrent/metastatic HNSCC. However, the majority of tumors do not respond to these therapies, indicating that these tumors are not immunogenic or other immunosuppressive mechanisms might be at play. Given their role in carcinogenesis as well as in immune modulation, we discuss the relation between the STAT3, PI3K/AKT/mTOR and Wnt signaling pathways to identify potential targets to empower the immune response against HNSCC.

Associations between clinical and histopathological characteristics in oral leukoplakia.

Objectives: To identify possible associations between patients' demographics and habits and the clinical aspects and histopathological characteristics of oral leukoplakia (OL) at patients' first visit.

Method: A total of 140 consecutive patients with OL at a single institute between 1997 and 2019. All biopsies were microscopically examined for classic dysplasia (CD) (WHO definition oral epithelial dysplasia) and differentiated dysplasia (DD) known from differentiated vulvar intraepithelial neoplasia.

Annual malignant transformation rate of oral leukoplakia remains consistent: A long-term follow-up study.

Objectives: Numerous clinical and histopathological characteristics have been associated with malignant transformation (MT) of oral leukoplakia (OL), including classic and differentiated epithelial dysplasia, but MT predictions remain suboptimal. The objective of this study was to determine the annual MT rate of OL and to identify clinicopathological risk factors associated with MT.

Patients And Methods: 170 patients with OL were included in this retrospective cohort study, 117 females and 53 males.

Comprehensive multiparameter genetic analysis improves circulating tumor DNA detection in head and neck cancer patients.

Introduction: 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.

Incorporation of differentiated dysplasia improves prediction of oral leukoplakia at increased risk of malignant progression.

Oral leukoplakia is the most common oral potentially malignant disorder with a malignant transformation rate into oral squamous cell carcinoma of 1-3% annually. The presence and grade of World Health Organization defined dysplasia is an important histological marker to assess the risk for malignant transformation, but is not sufficiently accurate to personalize treatment and surveillance. Differentiated dysplasia, known from differentiated vulvar intraepithelial neoplasia, is hitherto not used in oral dysplasia grading.

Characterization of a head and neck cancer-derived cell line panel confirms the distinct TP53-proficient copy number-silent subclass.

Introduction: Head and neck squamous cell carcinomas (HNSCC) arise in the mucosal lining of the upper aerodigestive tract. Risk factors are exogenous carcinogen exposure, human papillomavirus (HPV) infection, and genetic predisposition such as Fanconi anemia (FA). Clinically, tumors are stratified based on stage, site and HPV-status.

Molecular Characterization of Locally Relapsed Head and Neck Cancer after Concomitant Chemoradiotherapy.

Purpose: To investigate the pathobiological origin of local relapse after chemoradiotherapy, we studied genetic relationships of primary tumors (PT) and local relapses (LR) of patients treated with chemoradiotherapy.

Experimental Design: First, low-coverage whole genome sequencing was performed on DNA from 44 biopsies of resected head and neck squamous cell carcinoma (HNSCC) specimens (median 3 biopsies/tumor) to assess suitability of copy number alterations (CNAs) as biomarker for genetic relationships. CNAs were compared within and between tumors and an algorithm was developed to assess genetic relationships with consideration of intratumor heterogeneity.

ACE: absolute copy number estimation from low-coverage whole-genome sequencing data.

Summary: 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.

Sensitizing Triple-Negative Breast Cancer to PI3K Inhibition by Cotargeting IGF1R.

Targeted therapies have proven invaluable in the treatment of breast cancer, as exemplified by tamoxifen treatment for hormone receptor-positive tumors and trastuzumab treatment for HER2-positive tumors. In contrast, a subset of breast cancer negative for these markers, triple-negative breast cancer (TNBC), has met limited success with pathway-targeted therapies. A large fraction of TNBCs depend on the PI3K pathway for proliferation and survival, but inhibition of PI3K alone generally has limited clinical benefit.

Correction: A Functional Screen Identifies Specific MicroRNAs Capable of Inhibiting Human Melanoma Cell Viability.

[This corrects the article DOI: 10.1371/journal.pone.

A functional screen identifies specific microRNAs capable of inhibiting human melanoma cell viability.

Malignant melanoma is an aggressive form of skin cancer with poor prognosis. Despite improvements in awareness and prevention of this disease, its incidence is rapidly increasing. MicroRNAs (miRNAs) are a class of small RNA molecules that regulate cellular processes by repressing messenger RNAs (mRNAs) with partially complementary target sites.

Functional microRNA screening using a comprehensive lentiviral human microRNA expression library.

Background: MicroRNAs (miRNAs) are a class of small regulatory RNAs that target sequences in messenger RNAs (mRNAs) to inhibit their protein output. Dissecting the complexities of miRNA function continues to prove challenging as miRNAs are predicted to have thousands of targets, and mRNAs can be targeted by dozens of miRNAs.

Results: To systematically address biological function of miRNAs, we constructed and validated a lentiviral miRNA expression library containing 660 currently annotated and 422 candidate human miRNA precursors.