P53 codon 72 polymorphism is associated with disease progression in adult T‐cell leukaemia/lymphoma

Abstract

Adult T-cell leukaemia/lymphoma (ATL) is associated with the monoclonal integration of human T-lymphotropic virus type I (HTLV-I) proviral DNA into tumour cells, but the incidence of ATL is low (2–5%) among HTLV-I carriers and those who develop the disease usually have a 40- to 60-year latency period from the time of infection to progression to ATL. These phenomena suggest that additional mechanisms are involved in the progression of the disease, such as inactivation of tumour suppressor genes. P53 is one of the most important tumour suppressor genes that is involved in multiple pathways including apoptosis, cellular transcriptional control and cell cycle regulation. A common polymorphism of P53 at codon 72 results in either a variant protein with a proline (Pro) residue (CCC) or an arginine (Arg) amino acid (CGC) (Zhang et al, 2003). Recent studies have found that this polymorphism is associated with susceptibility or progression of several kinds of cancers (Zhang et al, 2003). However, data are not available as to whether this polymorphism plays a role in the pathogenesis of ATL among HTLV-I carriers. Human T-lymphotropic virus type I carriers (n = 81) were identified in the general population in an endemic region for HTLV-I, the Nagasaki district of Japan, after a mass medical and laboratory screening for individuals with anti-HTLV-I serum antibodies. ATL patients (n = 87) were diagnosed at the Department of Haematology, Nagasaki University School of Medicine. HTLV-I negative controls (n = 89) were included in the analysis. All subjects were Japanese. The genotype was performed as previously described (Zhang et al, 2003). Allele frequency of the P53 codon 72 polymorphism was not statistically different between 89 HTLV-I negative controls and 81 healthy HTLV-I carriers (P = 0·677) (Table I). These data suggest that genetic polymorphism in the P53 locus does not play a role in the infection of the HTLV-I. The allele frequency was not statistically different between 87 individuals with ATL and 81 healthy HTLV-I carriers (P = 0·627). These data suggest that this polymorphism does not play a role in the development of ATL among HTLV-I carriers. We previously found that a genetic polymorphism of the tumour necrosis factor gene enhanced susceptibility to ATL among HTLV-I carriers (Tsukasaki et al, 2001). In contrast, polymorphisms at the methylenetetrahydrofolate reductase locus did not alter susceptibility to ATL (Takeuchi et al, 2004). The frequency of the P53 codon 72 genotype in clinically defined subtypes of ATL is shown in Table I. Of note, the frequency of the arginine homozygous allele was higher in acute ATL than in chronic ATL (P = 0·0396). These results suggest that the P53 polymorphism plays an important role in the progression of ATL. Previous studies showed that mutation of the P53 gene in acute ATL was higher than that in chronic ATL (Hatta & Koeffler, 2002). We have previously reported that the frequency of adenomatous polyposis coli (APC) promoter methylation in acute type ATL (57%) was much higher than in chronic type ATL (13%) (P = 0·03) (Yang et al, 2005). Several differences occur among the P53 variants in their ability to bind components of the transcriptional machinery, to activate transcription, to induce apoptosis and to repress the transformation of primary cells (Thomas et al, 1999). Polymorphism of the P53 gene is associated with increased susceptibility to the development of gastric, urinary tract and breast cancers (Zhang et al, 2003). Taken together, P53 may have functional importance in several types of malignancies including ATL, probably by modulating its efficiency as a transcription factor. This work was supported in part by grants from National Institutes of Health, Honara Shapiro Fund, Parker Hughes Trust, Sherly and David Weisberg Foundation, grant-in-aid from the Ministry of Education, Culture Sports, Science and Technology of Japan. H. P. K. is a member of the Jonsson Comprehensive Cancer Center and Molecular Biology Institute of UCLA, and holds the endowed Mark Goodson Chair of Oncology Research at Cedars-Sinai Medical Center/UCLA School of Medicine.