title: Frequent silencing of fragile histidine triad gene (FHIT) in Burkitt's lymphoma is associated with aberrant hypermethylation.
abstract: The fragile histidine triad (FHIT) gene, a potential tumor-suppressor gene, is frequently inactivated in multiple human cancers. However, the FHIT gene remains largely unexplored in Burkitt's lymphoma (BL). Hence, we assessed whether loss of FHIT expression occurs in BL, and, if so, what is the mechanism of such loss. Lack of protein expression was observed in 50% of BL cell lines. Methylation-specific polymerase chain reaction (MSP) showed that 45% of BL cell lines carried aberrantly methylated FHIT alleles. Sequencing of bisulfite-treated DNA confirmed these data and indicated a very high density of methylation in all methylated alleles. Real-time, quantitative reverse-transcription PCR analysis indicated that attenuation of full-length FHIT transcription was correlated with methylation. Sequencing of transcripts illustrated that aberrant transcription resulting in loss of FHIT exons occurred more commonly in BL containing unmethylated FHIT genes. However, such transcripts often coexisted with full-length FHIT transcripts. Not surprisingly, therefore, loss of FHIT protein in BL correlated with CpG island methylation, rather than with aberrant transcription. FHIT methylation also was detected in 31% (16 of 51) of the primary BLs examined, including 2 samples whose derived cell lines also manifested FHIT hypermethylation. Aberrant methylation can thus occur in vivo. In summary, this report provides evidence that epigenetic modification frequently results in loss of FHIT expression in BL.
authors.affiliation: King Fahd National Centre for Children's Cancer, KFSHRC, Riyadh, Saudi Arabia.
authors.forename: Azhar
authors.initials: A
authors.lastname: Hussain
authors.forename: Marina I
authors.initials: MI
authors.lastname: Gutiérrez
authors.forename: Georgina
authors.initials: G
authors.lastname: Timson
authors.forename: Abdul K
authors.initials: AK
authors.lastname: Siraj
authors.forename: Clara
authors.initials: C
authors.lastname: Deambrogi
authors.forename: Maha
authors.initials: M
authors.lastname: Al-Rasheed
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.forename: Ian
authors.initials: I
authors.lastname: Magrath
authors.forename: Kishor
authors.initials: K
authors.lastname: Bhatia
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000235:genetics* / Q000378:metabolism*; D000483:Alleles; D002051:Burkitt Lymphoma / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D018899:CpG Islands; D019175:DNA Methylation; D005091:Exons; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism*; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D009363:Neoplasm Proteins; D000099170:Bis(5'-adenosyl)triphosphatase