The International Agency for Research on Cancer (IARC) and the US National Cancer Institute (NCI) have initiated a series of cancer-focused seminars [Scelo G, Hofmann JN, Banks RE et al. International cancer seminars: a focus on kidney cancer. Ann Oncol 2016; 27(8): 1382–1385]. In this, the second seminar, IARC and NCI convened a workshop in order to examine the state of the current science on esophageal squamous cell carcinoma etiology, genetics, early detection, treatment, and palliation, was reviewed to identify the most critical open research questions. The results of these discussions were summarized by formulating a series of ‘difficult questions’, which should inform and prioritize future research efforts.

Hypoxia is an inherent condition of tumors and contributes to cancer development and progression. Hypoxia-inducible factors (HIFs) are the major transcription factors involved in response to low O₂ levels, orchestrating the expression of hundreds of genes involved in cancer hallmarks’ acquisition and modulation of epigenetic mechanisms. Epigenetics refers to inheritable mechanisms responsible for regulating gene expression, including genes involved in the hypoxia response, without altering the sequence of DNA bases. The main epigenetic mechanisms are DNA methylation, non-coding RNAs, and histone modifications. These mechanisms are highly influenced by cell microenvironment, such as O₂ levels. The balance and interaction between these pathways is essential for homeostasis and is directly linked to cellular metabolism. Some of the major players in the regulation of HIFs, such as prolyl hydroxylases, DNA methylation regulators, and histone modifiers require oxygen as a substrate, or have metabolic intermediates as cofactors, whose levels are altered during hypoxia. Furthermore, during pathological hypoxia, HIFs’ targets as well as alterations in epigenetic patterns impact several pathways linked to tumorigenesis, such as proliferation and apoptosis, among other hallmarks. Therefore, this review aims to elucidate the intricate relationship between hypoxia and epigenetic mechanisms, and its crucial impact on the acquisition of cancer hallmarks.

Esophageal cancer (EC) is one of the most lethal cancers and a public health concern worldwide, owing to late diagnosis and lack of efficient treatment. Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are main histopathological subtypes of EC that show striking differences in geographical distribution, possibly due to differences in exposure to risk factors and lifestyles. ESCC and EAC are distinct diseases in terms of cell of origin, epidemiology, and molecular architecture of tumor cells. Past efforts aimed at translating potential molecular candidates into clinical practice proved to be challenging, underscoring the need for identifying novel candidates for early diagnosis and therapy of EC. Several major international efforts have brought about important advances in identifying molecular landscapes of ESCC and EAC toward understanding molecular mechanisms and critical molecular events driving the progression and pathological features of the disease. In our review, we summarize recent advances in the areas of genomics and epigenomics of ESCC and EAC, their mutational signatures and immunotherapy. We also discuss implications of recent advances in characterizing the genome and epigenome of EC for the discovery of diagnostic/prognostic biomarkers and development of new targets for personalized treatment and prevention.

The glutathione S-transferase (GST) genes are involved in the metabolism of various carcinogens. Deletion polymorphisms in the genes GSTM1 and GSTT1 and a base transition polymorphism at codon 105 (Ile→Val) in GSTP1 were investigated in relation to breast cancer risk. Tobacco smoking and reproductive factors were examined as potential effect modifiers. Individual data from seven case-control studies were pooled within the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens. To measure the effect of GSTs on breast cancer risk, odds ratios and 95% confidence intervals were computed adjusting for study center and age. The modifying effect was investigated by stratification on variables of smoking habits and reproductive history. A total of 2,048 cases with breast cancer and 1,969 controls were analyzed. The relative odds ratio (95% confidence interval) of breast cancer was 0.98 (0.86–1.12) with the GSTM1 null, 1.11 (0.87–1.41) with the GSTT1 null, 1.01 (0.79–1.28) with GSTP1 heterozygous mutants, and 0.93 (0.62–1.38) with GSTP1 homozygous mutants. Stratification by smoking or reproductive factors did not reveal a modifying effect of these variables, nor was there any association between GSTM1 and age at diagnosis of breast cancer. This is the largest study investigating susceptibility to breast cancer due to polymorphisms in the GST genes. The results conclusively show that single gene GST polymorphisms do not confer a substantial risk of breast cancer to its carriers. Furthermore, GSTs did not interact with smoking or reproductive history to modify cancer risk.

Head and neck squamous cell carcinomas (HNSCCs) represent a heterogeneous group of cancers for which human papilloma virus (HPV) infection is an emerging risk factor. Previous studies showed promoter hypermethylation in HPV(+) oropharyngeal cancers, but only few consistent target genes have been so far described, and the evidence of a functional impact on gene expression is still limited. We performed global and stratified pooled analyses of epigenome-wide data in HNSCCs based on the Illumina HumanMethylation450 bead-array data in order to identify tissue-specific components and common viral epigenetic targets in HPV-associated tumours. We identified novel differentially methylated CpGs and regions associated with viral infection that are independent of the anatomic site. In particular, most hypomethylated regions were characterized by a marked loss of CpG island boundaries, which showed significant correlations with expression of neighbouring genes. Moreover, a subset of only five CpGs in a few hypomethylated regions predicted HPV status with a high level of specificity in different cohorts. Finally, this signature was a better predictor of survival compared with HPV status determined by viral gene expression by RNA sequencing in The Cancer Genome Atlas cohort. We identified a novel epigenetic signature of HPV infection in HNSCCs which is independent of the anatomic site, is functionally correlated with gene expression and may be leveraged for improved stratification of prognosis in HNSCCs.