Germline TP53 mutation spectrum in Sudanese premenopausal breast cancer patients: correlations with reproductive factors

Abstract

Purpose The role of non-genetic factors as modifiers of TP53 -related hereditary breast cancer (BC) risk is debated. In this regard, little is known about the impact of germline TP53 mutations on BC in sub-Saharan Africa, where the disease often presents in non-contraceptive multiparous premenopausal women with extended history of breastfeeding. Herein, we report the germline TP53 mutations found in a series of 92 Sudanese premenopausal BC patients characterized for reproductive history. Methods The entire TP53 coding sequence, including intron–exon boundaries and UTRs, was analyzed via DHPLC and direct sequencing, and the association of TP53 genotypes with BC risk and with individual lifetime exposures to reproductive factors was investigated with statistical tools. Results The germline TP53 mutation spectrum comprised 20 variants, 15 in the non-coding and 5 in the coding region. The latter included a deleterious missense mutation, c.817C>T (p.Arg273Cys), in a unique patient, and the common and functionally relevant coding polymorphism at amino acid 72 [Pro72Arg (rs1042522)]. The non-coding mutations included c.919+1G>A, a known deleterious splice site mutation, also in a unique patient. Notably, the 2 carriers of deleterious TP53 mutations clustered in the subset of cases with stronger reproductive history relative to childbearing age. When analyzed in comparison to population controls, the codon 72 polymorphism did not reveal associations with BC. Conclusions Our study suggests that the codon 72 Arg>Pro polymorphism is not implicated in premenopausal BC susceptibility, whereas multiparity and breastfeeding might be BC risk factors for carriers of deleterious TP53 mutations. Electronic supplementary material The online version of this article (10.1007/s10549-019-05168-1) contains supplementary material, which is available to authorized users.

Association between Polymorphisms of SNPs Located at the 3’-Untranslated Region of SET8 and Codon 72 of the TP53 with Breast Cancer among Cameroonian Women

“…Armitage trend test. These results are in line with those reported elsewhere in Africa where, whatever the menopausal status, no association was reported between polymorphism at rs1042522 of TP53 and the risk of BC development[19] [48]. However, it is important to point out that the allele frequencies were not in HWE at this locus when the entire population was analyzed.…”

“…Although the CG genotype of TP53 has not been implicated in premenopausal BC susceptibility [48], results (adjusted p-value of 0.002 and an OR of 0.39) of our study revealed its association with a reduced risk of developing BC in premenopausal women. These results contrast those of Cherdyntseva et al [61] reporting that CG genotype seemed to increase the risk of BC in premenopausal Caucasian patients.…”

A Review of Cancer Genetics and Genomics Studies in Africa

“…A mutation in the TP53 gene often accompanies BRCA mutations in breast and ovarian cancers, making the mutations in these DNA repair genes relevant in therapeutic interventions ( 90 , 91 ). The publications on TP53 mutation have focused on its expression in breast cancer and the contribution of its polymorphism, particularly codon 72 to breast cancer ( 28 , 31 , 33 , 36 , 92 – 94 ), as well as to its interaction with MDM2 344T>A polymorphism in response to chemotherapy of breast cancer in Tunisia ( 95 ). Other DNA repair genes that have been studied in Africa include XRCC1 and XPD in Egypt ( 96 , 97 ).…”

TP53 (rs1042522, rs28934571) and TP21 (rs1801270, rs1059234) Polymorphisms and Risk of Breast Cancer among Rural Women of Maharashtra: Findings from a Hospital Based Case- Control Study

“…Similar type of epidemiological studies reported from India for those SNPs and their association with cancer development (Lakshmi et al, 2012;Saikia et al, 2014;Khan et al, 2020) whereas other objected for their association with carcinogenesis in different ethnic population (Pillai and Nasir 2016;Bansal et al, 2016). Various investigations reported some associations of the studied genes with breast cancer development (Ayobi et al, 2018;Diakite et al, 2021) whereas others suggested no association between the polymorphisms either of p21 or p53 genes and the breast carcinogenesis (Habyarimana et al, 2018;Aceto et al, 2019;Zhao et al, 2022). The major attention of this study was to identify the polymorphisms in p53 gene in rural women of Maharashtra and demonstration of their association with risk of BC in studied population.…”