Genetic Predisposition to Cutaneous Squamous Cell Carcinoma

IntroductionUltraviolet (UV) radiation is the most ubiquitous mutagen known and as a direct result the skin is by far the most common site for cancer in Caucasian populations.In United Kingdom, non-melanoma skin cancer (NMSC) is the most frequent occurring cancer registration with over 98,854 cases in 2008, although estimates place it higher due to underreporting (CRUK, 2011a).Approximately three-quarters of NMSC are benign basal cell carcinomas (BCCs), while the remaining quarter consists predominantly of cutaneous squamous cell carcinomas (cSCC).NMSC accounts for 1 in 4 skin cancer deaths, the majority of which is attributed to the more malignant cSCC (Office for National Statistics).The overall prognosis is generally excellent for NMSC with only 491 deaths reported in UK in 2008 (mortality rate of 0.5 per 100,000 population) (CRUK, 2011b).However, those patients presenting with regional metastasis have poor outcome; 5-year survival in this group is 25-50% (Epstein, 1984;Veness et al., 2007).A number of high-risk groups exist such as organ transplant recipients (OTR), patients with recessive dystrophic epidermolysis bullosa (RDEB) and xeroderma pigmentosum (XP), where individuals are predisposed to developing cSCC with considerable morbidity and mortality (Kraemer et al., 1994;Euvrard et al., 2003; Fine et al., 2009).The incidence of cSCC can be up to 250 times higher in OTRs compared to the general population (Hartevelt et al., 1990).Up to 70% of XP patients can develop malignant skin neoplasms (Kraemer et al., 1994).OTRs with metastatic skin cancer (mostly cSCC in regional lymph node basins) have a poor prognosis with 3-year disease specific survival of 56% (Martinez et al., 2003).Comparatively, RDEB patients have a worse prognosis with more than 80% deaths from metastatic disease within 5 years of diagnosis of their first cSCC (Fine et al., 2009).While great strides have been made in understanding the molecular pathogenesis of BCC, where mutations in PTCH1 or SMO result in aberrant patched/hedgehog intracellular signaling (Johnson et al., 1996;Xie et al., 1998;Epstein, 2008), the mechanisms and pathways implicated in cSCC are yet to be fully elucidated.This chapter will discuss what can be learnt from studying inherited diseases that predispose patients to developing cSCC. www.intechopen.comSkin Cancers -Risk Factors, Prevention and Therapy 54 Known molecular mechanisms in cSCC tumourigenesisCancer is a genetic disease that arises as a result of an accumulation of structural and/or functional defects in the DNA double helix.The current paradigm for understanding tumourigenesis is crystallized by Hanahan and Weinberg in their 2000 and 2011 reviews where fundamental events termed "hallmarks of cancer" are required in the multi-step development of human tumours (Hanahan and Weinberg, 2000, 2011).Originally, six hallmarks of cancer were postulated: (i) sustaining proliferative signaling, (ii) evading growth suppressors, (iii) activating invasion and metastasis, (iv) enabling replicative immortality, (v) inducing angiogenesis and (vi) resisting cell death (Hanahan and Weinberg, 2000).A further two "emerging hallmarks" were later added: deregulation of cellular energetics and evasion of immune destruction.At the same time, two "enabling characteristics" which enable the acquisition of the hallmarks of cancer were also described.These are genomic instability and tumour-promoting immune response (Hanahan and Weinberg, 2011).In particular, genomic instability is "enabling" in the sense that it can lead to aberrant expression of key genes that can have an effect on important cellular mechanisms such as apoptosis, DNA repair, and proliferation.Exposure to UV, particularly UV-B, can result in genetic abnormalities, notably mutations in the tumour suppressor TP53 gene, "the guardian of the genome" (Brash et al., 1991;Lane, 1992).Aberrant mutations in this gene have also been observed early on in solar keratoses (Taguchi et al., 1994), Bowen's disease (Campbell et al., 1993) and in ~58% of invasive cSCC (Brash et al., 1991).TP53 mutations are a widespread phenomenon in human tumours and have a unique UV signature (CT dipyrimidine substitution) in skin tumours (Brash et al., 1991).In line with this, germline TP53 mutations in Li-Fraumeni patients can result in an early onset of cancer which includes, but is not limited to, cSCC.Li-Fraumeni, as a cSCC predisposing syndrome will be discussed later in greater detail in this review.Another gene that has been associated with cSCC is the RAS oncogene.RAS was first implicated in the initiation of cSCC when H-ras mutations were found in the benign papillomas of mice treated with the 7,12-dimethylbenz[a]anthracene (Balmain et al., 1984).In laboratories, expression of oncogenic RAS in human keratinocytes was able to recapitulate tumours in mice (Boukamp et al., 1990;Dajee et al., 2003).However the data based on RAS mutations in human cSCC is ambiguous.Various independent studies conducted thus far have revealed heterogeneity in their expression and correlation to cSCC development.In North African XP patients, RAS genes were found to be at least twice as mutated (50%) compared to control tumours (22%) (Daya-Grosjean et al., 1993).In contrast, a separate study found only 1 mutation in 26 cSCCs from XP patients (Sato et al., 1994).Our lab have demonstrated lack of RAS mutations in 10 cSCCs (Pourreyron et al., 2007) while whole exome sequencing have recently identified activating HRAS mutation in only one from 8 cSCC (Durinck et al., 2011).This whole exome sequencing study also identified a high proportion of truncating mutations in NOTCH1 and NOTCH2 genes, an observation also reported in head and neck SCC (Agrawal et al., 2011;Stransky et al., 2011), suggesting that NOTCH may act as a tumour suppressor in a high proportion of SCC.The identification of an increased risk of developing well differentiated cSCC in patients receiving kinase inhibitors, particularly melanoma patients receiving B-RAF inhibitors (Arnault et al.,