Results from the International FA Registry (IFAR) have revealed that FA patients are highly susceptible to non-hematologic neoplasms [3
]. Squamous cell carcinomas (SCCs) of the anogenital region and head and neck, the latter with an up to 1,400 fold risk over that of the normal population, are the most commonly diagnosed solid tumors in these patients. A recent report on cancer incidence in the German FA Registry also described an extreme risk of head and neck, vulvar, and esophageal SCC [115
]. Cancers of the head and neck can arise throughout the mucosal linings of the entire upper aerodigestive tract, including the oral cavity, oropharynx, nasopharynx, hypopharynx and larynx. HNSCC originates from the normal mucosa [118
], advances through a multistep process and evolves through a sequence of histopathologic stages [119
], which is discussed in detail by Califano et al.
]. Approximately 36,500 new patients are diagnosed yearly with head and neck cancer in the United States [121
]. Head and neck squamous cell carcinomas (HNSCCs) constitute the majority and are the sixth leading cancer worldwide, with prolonged tobacco and alcohol use as principal risk factors for this disease [122
]. In the general population, approximately 25% of these cancers are caused by infection with human papillomavirus (HPV), particularly the HPV16 genotype [119
]. HPV status determines significant biological differences, with HPV positive tumors exhibiting improved response to treatment and prognosis when compared to HPV negative tumors. The prevalence of HPV in FA SCCs, however, remains controversial to date [125
Because only a small number of persons exposed to tobacco, alcohol or HPV ultimately develop cancer, it is believed that an individual must also have an inherent predisposition, which collaborates with these genotoxic exposures for carcinogenesis to occur [128
]. Along with the previously mentioned environmental factors, HNSCC has also been linked to FA, and patients with this BMF syndrome are susceptible to chromosomal instability and the development of SCC [3
]. Cloos et al.
have proposed that there are different levels of DNA safeguarding capability within the general population which play a role in the development of cancer [130
]. Unfortunately, overall treatment outcomes for HNC have not improved in decades and conventional clastogenic therapies have substantial side effects on normal physiological functions such as swallowing, speech and physical appearance. These responses to therapy, together with tumor development, are also predicted to be modified by genetic predispositions, and appear to be greatly amplified in FA patients [131
]. Therefore, while FA tumors are predicted to be exquisitely sensitive to conventional chemotherapy and radiation, the FA individual’s global hyper-sensitivity to DNA damage limits the effectiveness of such therapies, and particularly radiotherapy, dramatically [131
Array based comparative genome hybridization of 21 sporadic oral squamous cell carcinomas revealed de-regulation of a number of FA and FA-associated genes, including BRCA1
]. Two recent publications in Science
utilized whole-exome sequencing approaches in order to screen for genetic mutations in primary head and neck cancers and prior to drug treatment [136
]. Stransky et al.
identified numerous mutations listed in in either FA genes themselves, or more generally in a select subset of genes associated with DNA repair [136
]. The list of genes shown in represents new analyses of the data previously published by Stransky et al
., which reveal that 38 out of the 74 (51%) sequenced tumors harbored one or more somatic mutations in the indicated gene subset. More strikingly, a great majority of these tumors (18/38 tumors; 47%) harbored multiple mutations ranging from 2–7. Among these mutated genes, BRCA2, FANCM
(5 mutations reported), ATR, UBE4A
(4 mutations reported), BRCA1, USP43 and USP44
(3 mutations reported) are most frequent. These recent findings indicate that a subset of primary, therapy-naïve HNSCCs harbor mutations in important DNA repair pathways including FA. Such mutations may contribute functionally to increased tumor growth and/or may modify sensitivity to conventional drug therapies. Of note, mutations in FA-related genes were also identified by Agrawal et al.
], albeit at a lesser frequency. This might be due to a distinct clinical cohort, sample size and/or technical differences.
Somatic mutations of HNSCC patient tumors in a select subset of FA- and DNA-repair associated genes
As stated previously, individuals with FA have an astonishing probability of one in three for developing solid tumors, most commonly HNSCC, by age 48 [2
]. The cumulative risk of developing HNSCC is more than 4% per year, an estimated 700-fold greater risk than in non-FA individuals. In patients that also received bone marrow transplants, this risk increases further by four-fold [138
], likely due to deficiencies in DNA damage repair, and subsequent rises in genomic instability, in epithelial cells of the head and neck region. BMT conditioning regimens are presumed to lead to an increased risk of epithelial cancers through genome instability and clonal selection in epithelial FA compartments. A uniquely high susceptibility to head and neck cancers, however, remains unexplained. Possible factors involved might be extensive tissue destruction and regeneration following the preparative regimen, or a role for oncogenic pathogens including, but not limited, to HPV. FA can affect various organs and individuals generally present with complications such as growth retardation, congenital malformations, learning disability, hyper-pigmentation and an elevated risk of secondary malignancies including HNSCC at a early age [139
In contrast to leukemogenesis, the development of solid tumors in individuals with FA, particularly SCCs of the head and neck (HN) and anogenital tract, is understudied at a molecular level and thus poorly understood. Such tumors occur at an early age in the FA population and with striking aggressiveness. Surgical treatment remains the mainstay, but relapse-free, two-year survival rates are below 50%. Chemotherapy and radiation treatments are associated with high mortality and morbidity due to the patients’ global hypersensitivity to DNA damage. A recent report by Birkeland et al
highlights a particularly high degree of complications from radiotherapy, including mucositis and pancytopenia, and poor overall survival [131
]. Conventional clastogenic treatments are problematic, and new therapies for the clinical management of FA associated SCC are thus urgently needed. Early intervention is the best line of defense, and will be key for increasing the chance of complete surgical resection and survival in this patient population. However, the absence of relevant biomarkers impedes attempts for early detection of tumor cells in individuals with FA. It is important to note that keratinocytes are the cell type of origin for basal cell carcinomas and squamous cell carcinomas; therefore, FA functions in SCC need to be studied in this same cell type.
Sporadic malignancies with inactivated FA pathway components and associated proteins have been identified [140
]. Factors such as hypermethylation, loss of function mutations in FA genes, and increased expression of proteins that influence FA protein functionality and binding interactions have been proposed as mechanisms that disrupt the FA pathway [46
]. Transcriptional BRCA1
repression in the absence of genetic mutations has been reported for sporadic tumors and linked to poor prognosis in patients with breast cancer [143
]. Transcriptional repression of one or several FA genes by an unknown mechanism was also reported for sporadic head and neck SCCs [145
], oral cancers from particularly young patients [146
], and ovarian cancers [42
]. Finally, disruption of transcriptional FA co-regulation may also occur through epigenetic mechanisms, as has been shown with the hypermethylation of FANCF
and at a lower frequency for BRCA1
in cervical, oral, ovarian and lung cancers [45
]. DNA methylation profiling of laryngeal SCC cell lines and primary laryngeal carcinomas revealed very high frequencies of hypomethylation for FANCA
, and hypomethylation for BRCA1
and hypermethylation for BRCA2
]. Together with a recent report that identified a polymorphism in FANCA
associated with cervical cancer progression [149
], it is likely that insights into the role of FA in SCC in the rare FA patient population will advance our understanding of mechanisms and consequences of FA inactivation in a subset of SCC in the general population.