Malignant astrocytic gliomas such as glioblastoma are the most common and lethal intracranial tumors. These cancers exhibit a relentless malignant progression characterized by widespread invasion throughout the brain, resistance to traditional and newer targeted therapeutic approaches, destruction of normal brain tissue, and certain death. The recent confluence of advances in stem cell biology, cell signaling, genome and computational science and genetic model systems have revolutionized our understanding of the mechanisms underlying the genetics, biology and clinical behavior of glioblastoma. This progress is fueling new opportunities for understanding the fundamental basis for development of this devastating disease and also novel therapies that, for the first time, portend meaningful clinical responses.Malignant gliomas are classified and subtyped on the basis of histopathological features and clinical presentation (Fig. 1). The most common and biologically aggressive of these is glioblastoma (GBM), World Health Organization (WHO) grade IV, and is defined by the hallmark features of uncontrolled cellular proliferation, diffuse infiltration, propensity for necrosis, robust angiogenesis, intense resistance to apoptosis, and rampant genomic instability. As reflected in the old moniker "multiforme," GBM presents with significant intratumoral heterogeneity on the cytopathological, transcriptional, and genomic levels. This complexity, combined with a putative cancer stem cell (CSC) subpopulation and an incomplete atlas of (epi)genetic lesions driving GBM pathogenesis, has conspired to make this cancer one of the most difficult to understand and to treat. Despite implementation of intensive therapeutic strategies and supportive care, the median survival of GBM has remained at 12 mo over the past decade.In this review, we summarize current basic and translational challenges and highlight the striking scientific advances that promise to improve the clinical course of this lethal disease. These advances include a more comprehensive view of the altered genes and pathways in glioma and how such alterations drive the hallmark pathobiological features of the disease, the identification of new molecular subtypes in GBM, an improved understanding of the cellular origins of the disease and how CSCs may influence therapeutic responses, refined model systems for use in research and preclinical experimental therapeutics, and novel therapeutic strategies for targeting keystone genetic lesions and their pathways. For reasons of length, we have not discussed the advances in such important areas as tumor immunology, the blood-brain barrier, and tumor imaging. For the first time, there is a strong sentiment that meaningful therapeutic advances will soon flow from this explosion of new molecular and biological knowledge; the remarkable technological advances in

APOBEC3B cytosine deaminase activity has recently emerged as a significant mutagenic factor in human cancer. APOBEC activity is induced in virally infected cells, and APOBEC signature mutations occur at high frequency in cervical cancers (CESC), over 99% of which are caused by human papillomavirus (HPV). We tested whether APOBEC-mediated mutagenesis is particularly important in HPV-associated tumors by comparing the exomes of HPV+ and HPV- head and neck squamous cell carcinomas (HNSCCs) sequenced by The Cancer Genome Atlas project. As expected, HPV- HNSCC displays a smoking-associated mutational signature, whereas our data suggest that reduced exposure to exogenous carcinogens in HPV+ HNSCC creates a selective pressure that favors emergence of tumors with APOBEC-mediated driver mutations. Finally, we provide evidence that APOBEC activity is responsible for the generation of helical domain hot spot mutations in the PIK3CA gene across multiple cancers. Our findings implicate APOBEC activity as a key driver of PIK3CA mutagenesis and HPV-induced transformation.

Oropharyngeal squamous cell carcinoma (OPSCC) comprises cancers of the tonsils, base of tongue, soft palate and uvula (Fig. 1). Like other head and neck squamous cell carcinomas (HNSCCs), OPSCC has historically been linked to alcohol and tobacco consumption. A reduction in the prevalence of smoking in most high-income countries over the past 20 years has led to a decline in the incidence of HNSCC; however, carcinogenic human papillomavirus (HPV) infection has emerged as an important risk factor that has driven an increase in the incidence of OPSCC over the same period. More specifically, HPV now accounts for 71% and 51.8% of all OPSCCs in the USA and UK, respectively [1][2][3][4] . Of these, 85-96% are caused by HPV-16 infections and are therefore expected to be preventable by prophylactic HPV vaccination, which is known to be effective in preventing HPV-associated cervical neoplasia and is now being administered to both boys and girls in several countries 4,5 . The most recent edition of the American Joint Committee on Cancer (AJCC) staging system defined HPV-positive (HPV + ) and HPV-negative (HPV -) OPSCCs as separate entities, with distinct molecular profiles, tumour characteristics and outcomes 6 (Table 1). Importantly, the former is associated with a more favourable prognosis 7 . In this Review, we provide a comprehensive overview of HPV + OPSCC, focusing on how our increasing knowledge of disease biology has informed clinical practice and is guiding the pursuit of improved treatments. Epidemiology Rising incidence, particularly in menAmong all cancers, OPSCC has one of the most rapidly rising incidences in high-income countries 8,9 . An increasing incidence of this disease has been observed in the UK, USA, across Europe, New Zealand and in parts of Asia [9][10][11][12][13][14][15][16][17][18][19] . In both the UK and the USA, the incidence of oropharyngeal cancer in men has surpassed that of cervical cancer in women 8 (Fig. 1). Globally, the percentage of OPSCCs that are HPV + was reported in 2021 to be 33%; however, prevalence varies considerably depending on the geographical region, with estimates ranging from 0% in southern India to 85% in Lebanon 20 .HPV + OPSCC is more prevalent than HPV -OPSCC among those who do not consume tobacco or alcohol; however, a substantial history of tobacco and alcohol use remains prominent in patients with the former and is associated with worse outcomes 21,22 . Furthermore, sexual behaviour is an established risk factor for HPV + OPSCC, with a strong association observed between number of