功能性 pri-miR-34b/c rs4938723 和 KRAS 3'UTR rs61764370 单核苷酸多态性：Li-Fraumeni 综合征的新型表型修饰因子？

Functional pri-miR-34b/c rs4938723 and KRAS 3'UTR rs61764370 SNPs: Novel phenotype modifiers in Li-Fraumeni Syndrome?

机构信息

Post-Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil; Genomic Medicine Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Rio Grande do Sul, Brazil; Health School, Universidade do Vale do Rio dos Sinos (UNISINOS), São Leopoldo 93022-750, Brazil.

Genomic Medicine Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Rio Grande do Sul, Brazil.

出版信息

Gene. 2024 Mar 10;898:148069. doi: 10.1016/j.gene.2023.148069. Epub 2023 Dec 7.

DOI:10.1016/j.gene.2023.148069

PMID:38070788

Abstract

PURPOSE

Li-Fraumeni Syndrome (LFS) is a rare cancer predisposing condition caused by germline pathogenic TP53 variants, in which core tumors comprise sarcomas, breast, brain and adrenocortical neoplasms. Clinical manifestations are highly variable in carriers of the Brazilian germline founder variant TP53 p.R337H, possibly due to the influence of modifier genes such as miRNA genes involved in the regulation of the p53 pathway. Herein, we investigated the potential phenotypic effects of two miRNA-related functional SNPs, pri-miR-34b/c rs4938723 and 3'UTR KRAS rs61764370, in a cohort of 273 LFS patients from Southern and Southeastern Brazil.

METHODS

The genotyping of selected SNPs was performed by TaqMan® allelic discrimination and subsequently custom TaqMan® genotyping results were confirmed by Sanger sequencing in all SNP-positive LFS patients.

RESULTS

Although the KRAS SNP showed no effect as a phenotype modulator, the rs4938723 CC genotype was significantly associated with development of LFS non-core tumors (first tumor diagnosis) in p.R337H carriers (p = 0.039). Non-core tumors were also more frequently diagnosed in carriers of germline TP53 DNA binding domain variants harboring the rs4938723 C variant allele. Previous studies described pri-miR-34b/c rs4938723 C as a risk allele for sporadic occurrence of thyroid and prostate cancers (non-core tumors of the LFS spectrum).

CONCLUSION

With this study, we presented additional evidence about the importance of analyzing miRNA genes that could indirectly regulate p53 expression, and, therefore, may modulate the LFS phenotype, such as those of the miR-34 family.

摘要

目的

李-佛美尼综合征（Li-Fraumeni syndrome，LFS）是一种罕见的癌症易感疾病，由种系致病性 TP53 变体引起，其核心肿瘤包括肉瘤、乳腺癌、脑和肾上腺肿瘤。携带巴西种系创始人变体 TP53 p.R337H 的患者临床表现高度多变，这可能是由于调节 p53 途径的 miRNA 基因等修饰基因的影响。在此，我们研究了两个与 miRNA 相关的功能 SNP（pri-miR-34b/c rs4938723 和 3'UTR KRAS rs61764370）在来自巴西南部和东南部的 273 例 LFS 患者中的潜在表型效应。

方法

采用 TaqMan®等位基因鉴别法对选定 SNP 进行基因分型，随后对所有 SNP 阳性 LFS 患者进行 Sanger 测序以确认定制 TaqMan®基因分型结果。

结果

尽管 KRAS SNP 不作为表型调节剂，但 rs4938723 CC 基因型与携带 p.R337H 的 LFS 非核心肿瘤（首次肿瘤诊断）的发生显著相关（p=0.039）。携带 rs4938723 变异等位基因的种系 TP53 DNA 结合域变体的携带者中，非核心肿瘤的诊断也更为频繁。先前的研究描述了 pri-miR-34b/c rs4938723 C 作为散发性甲状腺癌和前列腺癌（LFS 谱的非核心肿瘤）发生的风险等位基因。