FA Risk for Cancers

Patients with FA are also at a 500-fold increased risk for developing acute myeloid leukemia (AML) and at a nearly 5000-fold increased risk for developing myelodysplastic syndrome (MDS). The incidence of head and neck cancer in this patient population has also been shown to be increased by 500-fold to 700-fold compared with the general population.

Genes Implicated in FA

At least 15 genes have been implicated in FA that are responsible for the various complementation groups (A-C, D1, D2, E-G, I, J, L-P). Mutations in FANCA , FANCC , and FANCG are the most common, involved in 60%, 14%, and 10% of cases, respectively. These FA genes have been identified as cancer susceptibility genes involved in various aspects of DNA repair, DNA stabilization, and modification of downstream proteins. The FA proteins A, B, C, E, F, G, L, and M make up the FA core complex, a nuclear E3 ubiquitin ligase complex that mediates the monoubiquitination of FANCD2 and FANCI after DNA damage. Any mutation or loss of a component of the FA core complex results in failure of monoubiquitination. FANCD1 has since been identified as BRCA2 , FANCG as XRCC9 , FANCJ as BACH1/BRIP1 , FANCN as PALB2 , FANCO as RAD51 C , and FANCP as SLX4 . All mutations in FA genes are inherited in an autosomal recessive manner, with the exception of FANCB , which is an X-linked gene. The FA proteins play an important role in DNA repair, and many of them interact in other DNA repair pathways. Defects in any of these proteins result in increased chromosomal fragility.

Clinical Diagnosis of FA

Most cases of FA are diagnosed between the ages of 6 and 9 years, although some diagnoses may be delayed until adulthood, with malignancies such as HNSCC as the primary clinical manifestation. Diagnosis of FA is made by culturing the patient’s cells with a DNA cross-linking agent, such as diepoxybutane or mitomycin C. Detection of chromosomal fragility or aberrations, in addition to common clinical manifestations, points to a diagnosis of FA. Other diagnostic tools include cell-cycle analysis and the FANCD2 protein monoubiquitination assay. The latter method takes advantage of the fact that monoubiquitination of the FANCD2 protein is normal in other bone marrow failure syndromes. However, this assay is only useful for patients with mutations in the monoubiquitination pathway, including the FA core complex; downstream mutations are not detected. Because of the various shortcomings of these more traditional methods, germline genetic testing may soon become the standard for FA diagnosis in the near future, especially as several clinics now offer this service.

Because of its rarity and variable phenotypic expression, FA may be underdiagnosed. Clinical manifestations of FA resemble other bone marrow failure syndromes, such as dyskeratosis congenital, Shwachman-Diamond syndrome, and Diamond-Blackfan anemia. Furthermore, earlier detection of the disease typically improves outcome, because the hematologic manifestations would otherwise progress with time. Physicians are then also able to provide cancer surveillance and earlier treatment of malignancies. Therefore, it is important to test patients for FA who present at unusually young age with MDS, primary AML, or cancers of the head and neck, cervix, breast, or anogenital tract.

FA Risk for Cancers

Patients with FA are also at a 500-fold increased risk for developing acute myeloid leukemia (AML) and at a nearly 5000-fold increased risk for developing myelodysplastic syndrome (MDS). The incidence of head and neck cancer in this patient population has also been shown to be increased by 500-fold to 700-fold compared with the general population.

Genes Implicated in FA

At least 15 genes have been implicated in FA that are responsible for the various complementation groups (A-C, D1, D2, E-G, I, J, L-P). Mutations in FANCA , FANCC , and FANCG are the most common, involved in 60%, 14%, and 10% of cases, respectively. These FA genes have been identified as cancer susceptibility genes involved in various aspects of DNA repair, DNA stabilization, and modification of downstream proteins. The FA proteins A, B, C, E, F, G, L, and M make up the FA core complex, a nuclear E3 ubiquitin ligase complex that mediates the monoubiquitination of FANCD2 and FANCI after DNA damage. Any mutation or loss of a component of the FA core complex results in failure of monoubiquitination. FANCD1 has since been identified as BRCA2 , FANCG as XRCC9 , FANCJ as BACH1/BRIP1 , FANCN as PALB2 , FANCO as RAD51 C , and FANCP as SLX4 . All mutations in FA genes are inherited in an autosomal recessive manner, with the exception of FANCB , which is an X-linked gene. The FA proteins play an important role in DNA repair, and many of them interact in other DNA repair pathways. Defects in any of these proteins result in increased chromosomal fragility.

Clinical Diagnosis of FA

Most cases of FA are diagnosed between the ages of 6 and 9 years, although some diagnoses may be delayed until adulthood, with malignancies such as HNSCC as the primary clinical manifestation. Diagnosis of FA is made by culturing the patient’s cells with a DNA cross-linking agent, such as diepoxybutane or mitomycin C. Detection of chromosomal fragility or aberrations, in addition to common clinical manifestations, points to a diagnosis of FA. Other diagnostic tools include cell-cycle analysis and the FANCD2 protein monoubiquitination assay. The latter method takes advantage of the fact that monoubiquitination of the FANCD2 protein is normal in other bone marrow failure syndromes. However, this assay is only useful for patients with mutations in the monoubiquitination pathway, including the FA core complex; downstream mutations are not detected. Because of the various shortcomings of these more traditional methods, germline genetic testing may soon become the standard for FA diagnosis in the near future, especially as several clinics now offer this service.

Because of its rarity and variable phenotypic expression, FA may be underdiagnosed. Clinical manifestations of FA resemble other bone marrow failure syndromes, such as dyskeratosis congenital, Shwachman-Diamond syndrome, and Diamond-Blackfan anemia. Furthermore, earlier detection of the disease typically improves outcome, because the hematologic manifestations would otherwise progress with time. Physicians are then also able to provide cancer surveillance and earlier treatment of malignancies. Therefore, it is important to test patients for FA who present at unusually young age with MDS, primary AML, or cancers of the head and neck, cervix, breast, or anogenital tract.

FA-associated HNSCC

Patients with FA have a significantly higher risk of developing head and neck cancers, and most occur in the oral cavity. In a study of the International Fanconi Anemia Registry, patients had a 500-fold increase in the incidence of HNSCC, with a cumulative incidence rate of 14% by the age of 40 years. Patients who develop FA-associated HNSCC tend to be female at a 2:1 ratio, with a median age at diagnosis of 31 years. According to the Surveillance Epidemiology and End Results national cancer registry, HNSCC incidence in the general population by age 40 years is only 0.038%, with a median age at presentation of 53 years. However, this increased cumulative incidence in FA is considered an underestimation of risk, as many patients with FA have other complications of the disease earlier in life.

Oral cavity cancers are the most common FA-associated HNSCC, representing 68% of the head and neck cancers diagnosed in patients with FA. Tongue cancer is the most common subsite identified, followed in frequency by tumors in the larynx (11%), oropharynx (11%), and hypopharynx (5%). Similarly, in a review of the literature, Lustig and colleagues found the proportion of tongue carcinomas among FA-associated HNSCC to be 52%. In the general HNSCC population, the proportion of oral cavity cancer among HNSCC is only 27%.

In addition, patients with FA often present with multiple primary tumors. Sixty-three percent of patients with FA who had HNSCC developed multiple malignancies, including 1 patient who developed a total of 4 primary tumors. Locations for a second primary squamous cell carcinoma were distributed equally among anal, cervical, vulvar, and head and neck regions.

Environmental factors, including tobacco and alcohol, play a key role in the development of HNSCC in the general population. Although the use of alcohol and tobacco in a typical population with HNSCC has been reported to be as high as 75% to 85%, only 16% of patients with FA with HNSCC had a history of such factors. Therefore, in young patients with HNSCC without a history of environmental triggers, particularly in those with other hematologic abnormalities, FA should be considered in the diagnosis. In a review of the literature, 22% of patients with FA who developed solid tumors were diagnosed with FA only after discovery of their cancer.

FA and Human Papillomavirus

Because of the affinity of FA-associated squamous cell carcinoma to localize in the body’s mucous membranes, associations between HNSCC and human papillomavirus (HPV) have also been explored, although this link is still considered controversial. In a study by Kutler and colleagues, HPV DNA was detected in 83% of FA HNSCC, compared with only 36% of control non-FA HNSCC, and HPV16 was the type most frequently detected. Spardy and colleagues showed that HPV16 E7 oncoprotein is able to trigger the FA pathway, and expression of HPV16 in FA-deficient cells increases chromosomal instability. However, a study of 21 squamous cell carcinomas primarily from European patients with FA found HPV DNA in only 10% of their tumor samples and none in their HNSCC samples. In further work from this group on 4 cell lines derived from FA HNSCC, no HPV DNA could be detected although mutations in TP53 (as typical for non-FA HNSCC) were found. Kutler and colleagues, on the other hand, detected no TP53 mutations in their samples. Although these 2 groups are in conflict with one another, TP53 can be inactivated by either mutation or the HPV E7 oncoprotein and consequently the carcinogenic processes proposed by each group are both plausible. Thus, the benefits of using prophylactic HPV vaccinations against development of squamous cell carcinoma in patients with FA remain uncertain.