Novel non-invasive molecular signatures for oral cavity cancer, by whole transcriptome and small non-coding RNA sequencing analyses: Predicted association with PI3K/AKT/mTOR pathway.

Introduction: Identification of molecular biomarkers in the saliva and serum of oral cavity cancer patients represents a first step in the development of essential and efficient clinical tools for early detection and post-treatment monitoring. We hypothesized that molecular analyses of paired saliva and serum samples from an individual would likely yield better results than analyses of either serum or saliva alone.

Materials And Methods: We performed whole-transcriptome and small non-coding RNA sequencing analyses on 32 samples of saliva and serum collected from the same patients with oral squamous cell carcinoma (OSCC) and healthy controls (HC).

Th2 Cells Are Associated with Tumor Recurrence Following Radiation.

The curative treatment of multiple solid tumors, including head and neck squamous cell carcinoma (HNSCC), utilizes radiation. The outcomes for HPV/p16-negative HNSCC are significantly worse than HPV/p16-positive tumors, with increased radiation resistance leading to worse locoregional recurrence (LRR) and ultimately death. This study analyzed the relationship between immune function and outcomes following radiation in HPV/p16-negative tumors to identify mechanisms of radiation resistance and prognostic immune biomarkers.

Immune infiltration at the primary tumor is associated with clinical outcome of patients with extranodal extension of lymph node metastasis in oral cancer.

Background: Extranodal extension (ENE) of lymph node metastasis is one of the most reliable prognostic indicators for patients with locally advanced oral cancer. Although multiple reports have found a close relationship between immune infiltration of tumors and patient clinical outcomes, its association with ENE is unknown.

Methods: We identified 234 human papillomavirus-negative (HPV-) oral cavity squamous cell carcinoma (OSCC) patients in The Cancer Genome Atlas and investigated the immune infiltration profiles of primary tumors and their association with survival.

Histologic and Genomic Analysis of Conjunctival SCC in African and American Cohorts Reveal UV Light and HPV Signatures and High Tumor Mutation Burden.

Purpose: Conjunctival squamous cell carcinoma (conjSCC) is more prevalent and aggressive in sub-Saharan African countries compared with the rest of the world. This study aims to compare the genomic, immunophenotypic, and histologic features between patients from the United States and Ethiopia, to identify etiopathogenic mechanisms and unveil potential treatment strategies.

Methods: We compared histologic features and mutational profiles using whole exome sequencing, high-risk human papillomavirus (HPV) status, PD-L1 expression, and tumor-infiltrating lymphocytes in conjSCC tumors of patients from Ethiopia (ETH; n = 25) and the United States (from MD Anderson [the MDA cohort]; n = 29).

Deep learning of cell spatial organizations identifies clinically relevant insights in tissue images.

Recent advancements in tissue imaging techniques have facilitated the visualization and identification of various cell types within physiological and pathological contexts. Despite the emergence of cell-cell interaction studies, there is a lack of methods for evaluating individual spatial interactions. In this study, we introduce Ceograph, a cell spatial organization-based graph convolutional network designed to analyze cell spatial organization (for example,.

FAK Drives Resistance to Therapy in HPV-Negative Head and Neck Cancer in a p53-Dependent Manner.

Purpose: Radiation and platinum-based chemotherapy form the backbone of therapy in human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC). We have correlated focal adhesion kinase (FAK/PTK2) expression with radioresistance and worse outcomes in these patients. However, the importance of FAK in driving radioresistance and its effects on chemoresistance in these patients remains unclear.

A Deep Learning Onion Peeling Approach to Measure Oral Epithelium Layer Number.

Head and neck squamous cell carcinoma (HNSCC), specifically in the oral cavity (oral squamous cell carcinoma, OSCC), is a common, complex cancer that significantly affects patients' quality of life. Early diagnosis typically improves prognoses yet relies on pathologist examination of histology images that exhibit high inter- and intra-observer variation. The advent of deep learning has automated this analysis, notably with object segmentation.

Deep Learning of Cell Spatial Organizations Identifies Clinically Relevant Insights in Tissue Images.

Recent advancements in tissue imaging techniques have facilitated the visualization and identification of various cell types within physiological and pathological contexts. Despite the emergence of cell-cell interaction studies, there is a lack of methods for evaluating individual spatial interactions. In this study, we introduce Ceograph, a novel cell spatial organization-based graph convolutional network designed to analyze cell spatial organization (i.

Deep learning-based pathology image analysis predicts cancer progression risk in patients with oral leukoplakia.

Background: Oral leukoplakia (OL) is associated with an increased risk for oral cancer (OC) development. Prediction of OL cancer progression may contribute to decreased OC morbidity and mortality by favoring early intervention. Current OL progression risk assessment approaches face large interobserver variability and is weakly prognostic.

Mutations Define a Distinct Subgroup in Head and Neck Squamous Cell Carcinoma.

Purpose: In head and neck squamous cell carcinoma (HNSCC), mutation is a new actionable oncogene driver. We aimed to evaluate mutational variants, comutation profile, and survival outcomes of this molecularly defined population.

Methods: We leveraged four deidentified patient data sets with -mutant HNSCC, MD Anderson Cancer Center, Kura Oncology, Inc trial, Foundation Medicine, and American Association for Cancer Research GENIE v.

Prognostic Significance of p16 and Its Relationship with Human Papillomavirus Status in Patients with Penile Squamous Cell Carcinoma: Results of 5 Years Follow-Up.

Penile Squamous Cell Carcinoma (PSCC) is associated with high-risk human papillomavirus (HR-HPV). The immunohistochemical (IHC) test for p16 (p16) is highly correlated with HR-HPV expression in other SCCs. To investigate whether the expression of p16 IHC or HR-HPV is associated with survival in PSCC, we conducted a single institution analysis of 143 patients with a diagnosis of PSCC and, available tissue were tested for p16 IHC staining patterns, histological subtype, tumor grade, and lymphovascular invasion (LVI) by an experienced pathologist.

Evolutionary Action Score of Analysis in Pathologically High-Risk Human Papillomavirus-Negative Head and Neck Cancer From a Phase 2 Clinical Trial: NRG Oncology Radiation Therapy Oncology Group 0234.

Purpose: An evolutionary action scoring algorithm (EAp53) based on phylogenetic sequence variations stratifies patients with head and neck squamous cell carcinoma (HNSCC) bearing missense mutations as high-risk, associated with poor outcomes, or low-risk, with similar outcomes as wild-type, and has been validated as a reliable prognostic marker. We performed this study to further validate prior findings demonstrating that EAp53 is a prognostic marker for patients with locally advanced HNSCC and explored its predictive value for treatment outcomes to adjuvant bio-chemoradiotherapy.

Methods And Materials: Eighty-one resection samples from patients treated surgically for stage III or IV human papillomavirus-negative HNSCC with high-risk pathologic features, who received either radiation therapy + cetuximab + cisplatin (cisplatin) or radiation therapy + cetuximab + docetaxel (docetaxel) as adjuvant treatment in a phase 2 study were subjected to targeted sequencing and EAp53 scoring to correlate with clinical outcomes.

Mildly dysplastic oral lesions with optically-detectable abnormalities share genetic similarities with severely dysplastic lesions.

Objective: Optical imaging studies of oral premalignant lesions have shown that optical markers, including loss of autofluorescence and altered morphology of epithelial cell nuclei, are predictive of high-grade pathology. While these optical markers are consistently positive in lesions with moderate/severe dysplasia or cancer, they are positive only in a subset of lesions with mild dysplasia. This study compared the gene expression profiles of lesions with mild dysplasia (stratified by optical marker status) to lesions with severe dysplasia and without dysplasia.

Clinical Trial Development in TP53-Mutated Locally Advanced and Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma.

TP53 mutation is the most frequent genetic event in head and neck squamous cell carcinoma (HNSCC), found in more than 80% of patients with human papillomavirus-negative disease. As mutations in the TP53 gene are associated with worse outcomes in HNSCC, novel therapeutic approaches are needed for patients with TP53-mutated tumors. The National Cancer Institute sponsored a Clinical Trials Planning Meeting to address the issues of identifying and developing clinical trials for patients with TP53 mutations.

Combined TRIP13 and Aurora Kinase Inhibition Induces Apoptosis in Human Papillomavirus-Driven Cancers.

Purpose: Human papillomavirus (HPV) causes >5% of cancers, but no therapies uniquely target HPV-driven cancers.

Experimental Design: We tested the cytotoxic effect of 864 drugs in 16 HPV-positive and 17 HPV-negative human squamous cancer cell lines. We confirmed apoptosis in vitro and in vivo using patient-derived xenografts.

High enhancer activity is an epigenetic feature of HPV negative atypical head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease with significant mortality and frequent recurrence. Prior efforts to transcriptionally classify HNSCC into groups of varying prognoses have identified four accepted molecular subtypes of the disease: Atypical (AT), Basal (BA), Classical (CL), and Mesenchymal (MS). Here, we investigate the active enhancer landscapes of these subtypes using representative HNSCC cell lines and identify samples belonging to the AT subtype as having increased enhancer activity compared to the other 3 HNSCC subtypes.

Mutant p53 drives an immune cold tumor immune microenvironment in oral squamous cell carcinoma.

The critical role of the tumor immune microenvironment (TIME) in determining response to immune checkpoint inhibitor (ICI) therapy underscores the importance of understanding cancer cell-intrinsic mechanisms driving immune-excluded ("cold") TIMEs. One such cold tumor is oral cavity squamous cell carcinoma (OSCC), a tobacco-associated cancer with mutations in the TP53 gene which responds poorly to ICI therapy. Because altered TP53 function promotes tumor progression and plays a potential role in TIME modulation, here we developed a syngeneic OSCC models with defined Trp53 (p53) mutations and characterized their TIMEs and degree of ICI responsiveness.

Fusobacterium is enriched in oral cancer and promotes induction of programmed death-ligand 1 (PD-L1).

Recently, increased number of studies have demonstrated a relationship between the oral microbiome and development of head and neck cancer, however, there are few studies to investigate the role of oral bacteria in the context of the tumor microenvironment in a single head and neck subsite. Here, paired tumor and adjacent normal tissues from thirty-seven oral tongue squamous cell carcinoma (SCC) patients were subjected to 16S rRNA gene sequencing and whole exome sequencing (WES), in addition to RNA sequencing for tumor samples. We observed that Fusobacterium was significantly enriched in oral tongue cancer and that Rothia and Streptococcus were enriched in adjacent normal tissues.

Induction chemotherapy with or without erlotinib in patients with head and neck squamous cell carcinoma amenable for surgical resection.

Purpose: Neoadjuvant chemotherapy prior to definitive surgery has been utilized widely for locally advanced oral squamous cell carcinoma (OSCC). We evaluated neoadjuvant erlotinib with platinum-docetaxel vs. placebo with platinum-docetaxel in stage III-IVB OSCC patients.

A general calculus of fitness landscapes finds genes under selection in cancers.

Genetic variants drive the evolution of traits and diseases. We previously modeled these variants as small displacements in fitness landscapes and estimated their functional impact by differentiating the evolutionary relationship between genotype and phenotype. Conversely, here we integrate these derivatives to identify genes steering specific traits.

Genetic Changes Driving Immunosuppressive Microenvironments in Oral Premalignancy.

Oral premalignant lesions (OPLs) are the precursors to oral cavity cancers, and have variable rates of progression to invasive disease. As an intermediate state, OPLs have acquired a subset of the genomic alterations while arising in an oral inflammatory environment. These specific genomic changes may facilitate the transition to an immune microenvironment that permits malignant transformation.

Inhibition of histone acetyltransferase function radiosensitizes CREBBP/EP300 mutants via repression of homologous recombination, potentially targeting a gain of function.

Despite radiation forming the curative backbone of over 50% of malignancies, there are no genomically-driven radiosensitizers for clinical use. Herein we perform in vivo shRNA screening to identify targets generally associated with radiation response as well as those exhibiting a genomic dependency. This identifies the histone acetyltransferases CREBBP/EP300 as a target for radiosensitization in combination with radiation in cognate mutant tumors.

Biology of the Radio- and Chemo-Responsiveness in HPV Malignancies.

In multiple anatomic sites, patients with cancers associated with the Human Papillomavirus (HPV) experience better locoregional control and overall survival after radiotherapy and/or chemoradiotherapy than patients with HPV-negative cancers. These improved outcomes suggest that relatively unique biological features in HPV-positive cancers may increase sensitivity to DNA damaging agents as well as an impaired DNA damage response. This review will address potential biological mechanisms driving this increased sensitivity of HPV-positive cancer to radiation and/or chemotherapy.