Oncogenic aberrations in the p53 pathway are associated with a high S phase fraction and poor patient survival in b‐cell non‐Hodgkin's lymphoma

Abstract

The implications of aberrations in the p53 pathway for induction of apoptosis and regulation of S phase entry, and for patient survival, were investigated in 83 B-cell NonHodgkin's lymphomas. Eight cases had missense mutations in exons 5, 7, 8 and 9 as revealed by constant denaturant gel electrophoresis and sequencing. Fifteen cases had lost 1 TP53 allele as revealed by fluorescent in situ hybridization and comparative genomic hybridization. Ten cases expressed high levels of p53 as assessed by immunoblotting and immunohistochemistry. S phase fractions were higher, apoptotic fractions were the same and survival times were shorter in all aberration groups compared with the cases with no TP53/p53 aberrations. Since many tumors had more than one TP53/p53 aberration, the tumors were divided into groups with the following characteristics: no TP53/p53 aberrations; loss of one TP53 allele only (9 cases), TP53 point mutation (8 cases), high-level p53 expression and no TP53 mutation (3 cases). Tumors from the 3 latter groups had higher median S phase fractions (5%, 7.6%, and 5%, respectively, p<0.02) than the cases without any aberrations (1.1%), and survival time for these patients was much shorter (relative risks of 5.9, 8.9, and 6.6, respectively, p<0.003). Apoptotic fractions were similar in all these groups (p‫.)90.0؍‬ Multivariate analysis showed that the presence of TP53/p53 aberrations is a strong and independent prognostic parameter in B-cell Non-Hodgkin's lymphoma.

Loss of chromosome 11q21–23.1 and 17p and gain of chromosome 6p are independent prognostic indicators in B-cell non-Hodgkin’s lymphoma

“…There was also good agreement between the CGH results on 17p and the number of TP53 copies (Table 1; see also Stokke et al, 2000). …”

“…Hence, not all four of these aberrations necessarily target genes that are important in the control of cell proliferation. The anti-proliferative activities of wild-type p53 are well documented in the literature (for reviews, see : Sherr, 1996;Levine, 1997), and our previous study showed that a high S phase fraction was characteristic for NHL cases with either mutations in TP53, loss of TP53, or clonal expression of p53 (Stokke et al, 2000).…”

“…Suggested candidates for tumour suppressor genes and protooncogenes at the chromosomal regions which are frequently lost and gained, respectively, include the ATM gene at 11q23.1 (Bullrich et al, 1999;Schaffner et al, 2000), the TP53 gene at 17p13.1 (Stokke et al, 2000), and the BCL-2 gene at 18q21 (Monni et al, 1997). Other tumour suppressor genes and protooncogenes, which are located within the frequently altered regions, include p16INK4a (9p21), RB-1 (13q14), BCL6 (3q27), CCND3 (6p), and c-MYC (8q24).…”

“…The results of numerous reports strongly suggest that the presence Loss of chromosome 11q21-23.1 and 17p and gain of chromosome 6p are independent prognostic indicators in B-cell non-Hodgkin's lymphoma of aberrations in the p53 pathway (i.e. 17p deletions, TP53 mutations, expression of wild-type p53) are adverse prognostic factors in NHL (Sander et al, 1993;Tilly et al, 1994;Dohner et al, 1995;Schoch et al, 1995;Hernandez et al, 1996;Panayiotidis and Kotsi, 1999;Dohner et al, 2000;Stokke et al, 2000; reviewed by Knutsen, 1998). Chromosomal aberrations are important prognostic factors and are used for treatment stratification in acute lymphoblastic leukaemia, including the indication for bone marrow transplantation in first remission (Pui and Evans, 1998).…”

Response of malignant B lymphocytes to ionizing radiation: Gene expression and genotype

“…The expression was measured with antibodies from Oncogene Research Products (San Diego, CA; clone 1801 anti-TP53, clone EA10 anti-CDKN1A), Zymed (San Francisco, CA; clone 33-170 anti-PLK1), DakoCytomation (Glostrup, Denmark; clone 124 anti-BCL2), Pharmingen (now part of Becton Dickinson, San Jose, CA; polyclonal anti-MCL1, clone PMG3-245 anti-RB1), as described previously. 19,20 Lysates of 500,000 cells were loaded per lane. The amount of actin (ACTB; Santa Cruz, Santa Cruz, CA; clone C-2 anti-actin) was determined on the same blots to control for gel loading, cell concentration and protein degradation.…”