Disruption of the FA/BRCA pathway in bladder cancer

Abstract

Bladder carcinomas frequently show extensive deletions of chromosomes 9p and/or 9q, potentially including the loci of the Fanconi anemia (FA) genes FANCC and FANCG. FA is a rare recessive disease due to defects in anyone of 13 FANC genes manifesting with genetic instability and increased risk of neoplasia. FA cells are hypersensitive towards DNA crosslinking agents such as mitomycin C and cisplatin that are commonly employed in the chemotherapy of bladder cancers. These observations suggest the possibility of disruption of the FA/BRCA DNA repair pathway in bladder tumors. However, mutations in FANCC or FANCG could not be detected in any of 23 bladder carcinoma cell lines and ten surgical tumor specimens by LOH analysis or by FANCD2 immunoblotting assessing proficiency of the pathway. Only a single cell line, BFTC909, proved defective for FANCD2 monoubiquitination and was highly sensitive towards mitomycin C. This increased sensitivity was restored specifically by transfer of the FANCF gene. Sequencing of FANCF in BFTC909 failed to identify mutations, but methylation of cytosine residues in the FANCF promoter region was demonstrated by methylation-specific PCR, HpaII restriction and bisulfite DNA sequencing. Methylation-specific PCR uncovered only a single instance of FANCF promoter hypermethylation in surgical specimens of further 41 bladder carcinomas. These low proportions suggest that in contrast to other types of tumors silencing of FANCF is a rare event in bladder cancer and that an intact FA/BRCA pathway might be advantageous for tumor progression.

Low incidence of methylation of the promoter region of the FANCF gene in Japanese primary breast cancer

“…Since the methylation status of CpG islands in the FANCF gene is important in cisplatin sensitivity in ovarian cancer [13], promoter methylation of FANCF has been investigated in various malignancies [12,[14][15][16][17][18][19]. As a result, there has recently been significant interest in FANCF methylation in breast cancer; there is, however, only one published report regarding breast cancer from a Western country [18].…”

“…Methylation-induced inactivation of FANCF plays an important role in the occurrence of ovarian cancers via disruption of the FA-BRCA pathway [12]. Because the methylation status of CpG islands in the FANCF gene was reported to be an important regulator of cisplatin sensitivity in ovarian cancer [13], FANCF methylation has been investigated in various malignancies [12,[14][15][16][17][18][19]. The frequency of FANCF methylation differs significantly among various malignancies.…”

DNA Repair Capacity and the Risk of Head and Neck Cancer

“…Somatic inactivation of the FA pathway by epigenetic silencing has been observed in several different types of sporadic cancer (Lyakhovich & Surralles, 2006), such as bladder cancer (Neveling et al, 2007), ovarian cancer (Lim et al, 2008), breast cancer (Wu, Shin-ya, & Brosh, 2008) cervical cancer (Narayan et al, 2004) and of course in HNSCC (Marsit et al, 2004;Szaumkessel et al, 2011 ;Wreesmann et al, 2007). Our own study has demonstrated the disruption of DNA methylation of promoter region in FANCA, BRCA1 and BRCA2 in squamous laryngeal carcinoma cell lines and primary tumors (Szaumkessel et al, 2011).…”

Fanconi anaemia: from a monogenic disease to sporadic cancer

“…Different studies have shown that hypermethylation of FANCF is the most frequent epigenetic modifi cation that leads to FA pathway disruption in different cancer types, including AML [21], ovarian cancer [22], cervical cancer [23], head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC) [24], granulosa cell tumours [25], breast cancer [26] and bladder carcinoma [27]. Other studies, however, did not observe FA gene hypermethylation in ovarian tumours [28], HNSCC [29] and AML [30], indicating signifi cant discrepancies in the frequency of this process in sporadic cancer.…”