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Transcriptional silencing of Fanconi anaemia genes and clinical outcome in head and neck cancer.

Gasco, M; Sullivan, A; Smith, P; Farrell, P; Numico, G; Colantonio, I; Merlano, M; (2004) Transcriptional silencing of Fanconi anaemia genes and clinical outcome in head and neck cancer. J Clin Oncol , 22 (14_suppl) 9546-.

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Abstract

9546 Background: Fanconi anaemia (FA) is an autosomal recessive disorder characterised by abnormal response to DNA damage. Both leukemia and solid tumours, including head and neck squamous cell carcinomas (HNSCC), occur at a high rate in FA patients. We have analysed the structure and expression of specific components of the FA pathway in a series of HNSCC and have sought correlation between lesions in the FA pathway and response to chemo-radiotherapy. METHODS: FANC gene structure was analysed by DNA sequencing, and transcriptional silencing using methylation-specific PCR, bisulphite sequencing and immunocytochemistry. The patient cohort comprised 70 individuals with inoperable HNSCC treated with chemo-radiotherapy. RESULTS: No FANC gene mutation was present in any of the 70 cancers. However, aberrant CpG methylation in the transcriptional regulatory elements of FANCC, FANCD2, FANCF, FANCG, FANCL was detected in a high proportion of carcinomas but not normal tissue. Methylation of at least one of these FANC genes was present in 67% of cases. Methylation of two or more FANC genes was detected in 20%. Gene expression was reduced in cases with methylation. Aberrant methylation of specific FANC genes was present in pre-malignant dysplasias, implying that loss of expression is an early event in tumourigenesis. Clinical outcome was strongly influenced by trascriptional silencing of the FANC genes. Complete response (CR) to chemo-radiotherapy was higher in cases with methylation of one or more FANC genes (p= 0.02). Overall survival (OS) and progression-free survival (PFS) were higher in cases with FANC gene methylation (OS p= 0.01), (PFS p=0.03). CONCLUSIONS: Transcriptional silencing of FANC genes occurs commonly in HNSCC and may have clinical utility in predicting the clinical outcome of patients treated with chemo-radiotherapy. No significant financial relationships to disclose.

Type: Article
Title: Transcriptional silencing of Fanconi anaemia genes and clinical outcome in head and neck cancer.
Location: United States
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: http://discovery.ucl.ac.uk/id/eprint/1534908
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