Single nucleotide variation in the TP53 3′ untranslated region in diffuse large B-cell lymphoma treated with rituximab-CHOP: a report from the International DLBCL Rituximab-CHOP Consortium Program

Abstract

Key Points• TP53 39UTR variations demonstrate prognostic value in DLBCL.We identified multiple single nucleotide variants (SNVs) in the TP53 39 untranslated region (39UTR) in tumor specimens from 244 patients with diffuse large B-cell lymphoma (DLBCL). Patients carrying a wild-type TP53 coding sequence (CDS) and 1 or more 39UTR SNVs had a better 5-year survival rate than patients carrying a wild-type CDS and the reference 39UTR, yet there is no statistically significance difference in overall survival (OS). In contrast, 39UTR variation predicted poorer OS for patients with a mutant TP53 CDS. We then sequenced TP53 39UTR in 247 additional DLBCL patients as a validation set. Altogether, we identified 187 novel SNVs; 36 occurred at least twice. Most of the newly identified 39UTR SNVs were located at sites that are complementary to seed sequences of microRNAs (miRNAs) that are predicted or experimentally known to target TP53. Three SNVs disrupt the seed match between miR-125b and the TP53 39UTR, thereby impeding suppression of p53 by this miRNA. In addition, a germline SNV (rs78378222) located in the TP53 polyadenylation signal resulted in downregulation of both p53 messenger RNA and protein levels and reduction of cellular apoptosis. This study is the first to demonstrate the prognostic value of the TP53 39UTR in cancer. (Blood. 2013;121(22):4529-4540)

Noncoding RNAs Regulating p53 and c-Myc Signaling

“…Furthermore, in vivo delivery of a miR-380 antagonist decreases tumor size in an orthotopic mouse model of neuroblastoma. Intriguingly, a recent study has found hundreds of novel somatic mutations in the 3'-UTR of p53 from B-cell lymphoma patients, and the seed match binding sites of 8 out of 11 p53-targeting miRNAs are disrupted by these mutations [ 77 ]. Altogether, these studies demonstrate the physiological importance of miRNAs in suppressing p53 tumor-suppressive function.…”

MicroRNA polymorphisms as markers of risk, prognosis and treatment response in hematological malignancies

“…Furthermore, three nSNVs in the miR-125b binding site were shown to release the negative regulation by miR-125b in vitro in H1299 cells. However, no correlation was found between nSNVs and p53 protein expression in tumor samples, regardless of the presence of mutations in the TP53 CDS but this may be due to the inability of the standard assay of p53 expression in tumors to detect subtle changes in p53 protein levels [60].…”

Absence of the TP53 Poly-A Signal Sequence Variant rs78378222 in Oral, Cervical and Breast Cancers in South India

“…Initially identified in Caucasian population, the variant 'C' allele was associated with an increased risk for prostate cancer, brain cancer and colorectal adenoma but not with colorectal cancer, breast cancer and melanoma (Stacey et al, 2011). Further, the risk allele impaired the proper termination of TP53 resulting in 'cancer promoting' longer mRNA transcripts that hindered p53 expression and its downstream functions in apoptosis (Stacey et al, 2011;Li et al, 2013). Simultaneously it was reported that rs78378222 increased the risk of esophageal cancer in Han Chinese population (Zhou et al, 2012).…”