Genomic instability underlies the transformation of host cells toward malignancy, promotes development of invasion and metastasis and shapes the response of established cancer to treatment. In this review, we discuss recent advances in our understanding of genomic stability in squamous cell carcinoma of the head and neck (HNSCC), with an emphasis on DNA repair pathways. HNSCC is characterized by distinct profiles in genome stability between similarly staged cancers that are reflected in risk, treatment response and outcomes. Defective DNA repair generates chromosomal derangement that can cause subsequent alterations in gene expression, and is a hallmark of progression toward carcinoma. Variable functionality of an increasing spectrum of repair gene polymorphisms is associated with increased cancer risk, while aetiological factors such as human papillomavirus, tobacco and alcohol induce significantly different behaviour in induced malignancy, underpinned by differences in genomic stability. Targeted inhibition of signalling receptors has proven to be a clinically-validated therapy, and protein expression of other DNA repair and signalling molecules associated with cancer behaviour could potentially provide a more refined clinical model for prognosis and treatment prediction. Development and expansion of current genomic stability models is furthering our understanding of HNSCC pathophysiology and uncovering new, promising treatment strategies. 1. Introduction Carcinogenesis and evolution of the cancer genome are driven by genomic instability. We review here advances in our understanding of the pathways that preserve genome integrity that have improved insight into cancer behaviour, prediction, prognosis, and personalised therapy. Traditional anticancer therapy has exploited the inherent genomic instability of malignancy; however, this mutagenic pressure also promotes the emergence of treatment resistance, invasion, and metastasis (Figure 1). Squamous cell carcinoma of the head and neck (HNSCC) is the sixth most-common cancer in the developed world [1, 2] and represents a therapeutically-challenging, behaviourally-heterogenous category of disease. Genomic instability is a defining characteristic of HNSCC [3]. Subregional differences in patterns in risk, treatment response, and prognosis in HNSCC are underpinned by aetiological factors that affect genomic stability in different ways. In HNSCC, the principal subsites of the upper aerodigestive tract are oral cavity (including tongue, floor of mouth, and buccal surface), nasopharynx, oropharynx (including
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