Head and Neck Cancer Susceptibility and Metabolism in Fanconi Anemia.

Abstract

Simple SummaryGermline loss-of-function mutations in any of over 20 known Fanconi anemia (FA) genes cause the disorder FA. The FA pathway plays a key role in the repair of DNA interstrand crosslinks (ICLs) and stabilization of stalled replication fork. Epidemiological studies have shown that persons with FA have a uniquely increased susceptibility to squamous cell carcinomas (SCCs) and increased human papilloma virus (HPV) prevalence. Genomic and transcriptomic studies are informative, but there is a paucity of data regarding metabolic deregulation in FA deficient systems. Metabolism is an essential component of cancer development and has significant impact on therapeutic outcomes. Therefore, a deeper understanding of the metabolic architecture of FA may aid in our understanding of SCC development, and allow for the discovery of metabolism-based diagnostic biomarkers and new therapeutic targets. In this review, we discuss known metabolic consequences of FA pathway loss on cancer pathogenesis, and in particular in normal and transformed keratinocytes—the cells of origin for SCC.Fanconi anemia (FA) is a rare inherited, generally autosomal recessive syndrome, but it displays X-linked or dominant negative inheritance for certain genes. FA is characterized by a deficiency in DNA damage repair that results in bone marrow failure, and in an increased risk for various epithelial tumors, most commonly squamous cell carcinomas of the head and neck (HNSCC) and of the esophagus, anogenital tract and skin. Individuals with FA exhibit increased human papilloma virus (HPV) prevalence. Furthermore, a subset of anogenital squamous cell carcinomas (SCCs) in FA harbor HPV sequences and FA-deficient laboratory models reveal molecular crosstalk between HPV and FA proteins. However, a definitive role for HPV in HNSCC development in the FA patient population is unproven. Cellular metabolism plays an integral role in tissue homeostasis, and metabolic deregulation is a known hallmark of cancer progression that supports uncontrolled proliferation, tumor development and metastatic dissemination. The metabolic consequences of FA deficiency in keratinocytes and associated impact on the development of SCC in the FA population is poorly understood. Herein, we review the current literature on the metabolic consequences of FA deficiency and potential effects of resulting metabolic reprogramming on FA cancer phenotypes.