The rs78378222 prevalence and the copy loss of the protective allele A in the tumor tissue of diffuse large B-cell lymphoma

Abstract

Background Rare single nucleotide polymorphisms (SNPs) are likely to be a crucial genetic factor for human diseases, including cancer. rs78378222 is rare SNP in 3′-untranslated region (UTR) of TP53 gene leading to disturbance of 3′-end mRNA processing. The frequency of rs78378222 varies in several studied populations. The meta-analysis of 34 genome-wide association studies indicated that rs78378222 was significantly associated with an increased risk of cancer overall. Bioinformatic analysis indicates that somatic loss of the protective A allele of rs78378222 occurs in the tumor tissue of some malignant. The goal of the current study is to document the rs78378222 prevalence and evaluate the copy loss status of the protective allele A in the tumor tissue of patients with diffuse large B-cell lymphoma (DLBCL). Methods Total DNA was isolated from FFPE-samples and peripheral blood of patients with DLBCL and comparable in age and sex controls. rs78378222 genotyping was performed by the PCR-RFLP method using restriction endonuclease HindIII. Direct Sanger’s sequencing was used to confirm the presence of C allele of the rs78378222. The search for TP53 gene mutations was carried out by Sanger’s direct sequencing method, according to the IARC protocol. Results The result of genotyping of 136 DNA samples from DLBCL tumor tissue suggested that frequency of the rs78378222 was 11/136 (8.1%). Rare allele C frequency was 11/272 (4.2%). A total of 5/11 DLBCL rs78378222 heterozygous samples had the heterozygosity loss in the TP53 gene. Only one of these cases was combined with TP53 gene mutations which have proven oncogenic potential—p.Arg196Gln, other four cases have not mutations in the coding regions of gene. Conclusions At the stages of DLBCL initiation or progression a loss of the protective allele A of rs78378222 occurs. Further efforts are needed to study possible molecular mechanisms underlying somatic alterations in DLBCL in this region of the TP53 3′-UTR as well as functional studies to illustrate how the presents of rs78378222 may affect tumor progression of lymphoma.

Exploring the frequency of a TP53 polyadenylation signal variant in tumor DNA from patients diagnosed with lung adenocarcinomas, sarcomas and uterine leiomyomas

“…In contrast with our findings in LUAD tumors, recent studies have identified that, regardless of tumor type, rs78378222[C] is more frequent in tumors with no somatic-coding pathogenic TP53 variants, i.e. WT TP53 tumors ( Voropaeva et al ., 2020 ; Zhang et al , 2021 ). The rs78378222[C] minor allele was not associated with lung cancer (not specified distribution of histological types) in a case series from the USA ( Guan et al ., 2013 ),…”

“…The results of the current study must be interpreted in the context of the following limitations: (1) although our overall sample size is more than 800 individuals and a recent study in the Russian population described a very high somatic frequency of rs78378222[C] carriers analyzing only 136 cases of a lymphoma subtype (11/136, 8.1 %) ( Voropaeva et al ., 2020 ), our cancer cohorts actually have a relatively small number of patients for analysis of a rare variant in ULM (n = 41) and SARC (n = 188) study groups; (2) LUAD tumor samples were obtained from a retrospective study and de-identified for use in the current study, hindering the complete clinical characterization of this case series regarding the ethnic ancestry, cancer family history, and histological subtype; (3) the other two positive LUAD cases whose NGS analyses were not performed due to limitations in sample availability could be important for more robust interpretations of LUAD samples with TP53 variants co-occurring with rs78378222[C].…”

“…(2019 ) found a significant association between rs78378222[C] and the risk in soft tissue sarcoma (OR = 3.29, P = 0.0014) in a germline context. In the past years, a limited number of studies have explored the somatic occurrence of this variant in other tumor types ( Li et al ., 2013 ; Wang et al ., 2016 ; Voropaeva et al ., 2020 ; Zhang et al , 2021 ). Importantly, our study described, for the first time, the low somatic prevalence of minor C-allele in LUAD cases.…”

Targeted sequencing for hereditary breast and ovarian cancer in BRCA1/2-negative families reveals complex genetic architecture and phenocopies

“…This variant has been implicated in several studies as a low-penetrance risk factor in LFS and cancer. 52 , 53 , 54 In ClinVar, this variant has been reported in the context of LFS twice (RCV000412103.10) and in the context of hereditary cancer-predisposing syndrome twice (RCV000492363.7). Under both diseases, there is both a benign/likely benign and a VOUS classification.…”

Medical Genetics, Genomics and Bioinformatics Aid in Understanding Molecular Mechanisms of Human Diseases

“…Thus, the current Special Issue on medical genomics shows that bioinformatics tools for the systems analysis of human diseases are in high demand, as could be seen from recently published post-conference papers [28,29]. The outputs of disease model analysis come in the form of sets of genes and protein markers which represent a particular interest to medical practitioners [30]. The guest editors are happy to announce that the next Special Issue topic at MDPI IJMS will be on medical genomics (https://www.mdpi.com/journal/ ijms/special_issues/Medical_Genetics_2021, accessed on 25 August 2021).…”