Seidinger Ana L, Caminha Isabel P, Mastellaro Maria J, Gabetta Carmen S, Nowill Alexandre E, Pinheiro Vitória R P, Yunes José A
Molecular Biology Laboratory, Centro Infantil Boldrini, Campinas, São Paulo, Brazil.
Medical Genetics Department, Faculty of Medical Sciences, State University of Campinas, Campinas, São Paulo, Brazil.
Mol Genet Genomic Med. 2020 Sep;8(9):e1168. doi: 10.1002/mgg3.1168. Epub 2020 Jun 27.
The p.Arg337His mutation of the TP53 is the most frequent germline missense variant associated with cancer described so far in this gene. It is mainly found in the South and Southeastern regions of Brazil, where it has been associated with a high incidence of pediatric adrenocortical (ACT) and choroid plexus tumors. The frequency and geographic distribution of this mutation is largely unknown, except for the Parana State, where a mean prevalence of 0.27% was reported. In the present study, we developed a high-throughput method for p.Arg337His genotyping, what allowed us to determine the frequency and geographic distribution of this mutation in a cohort from the most populous state in Brazil.
Consecutive samples from 31,612 newborns from São Paulo State were screened for p.Arg337His. The allelic discrimination was done by real-time polymerase chain reaction (PCR) and the presence of haplotype A3 in carriers was examined by using allele-specific oligonucleotide PCR, followed by nested-PCR to detect the SNP rs9894946.
We found 67 (0.21%) samples positive for this mutation. The highest p.Arg337His frequencies were found in the cities close to the boundary between São Paulo and Minas Gerais State. No association could be found between p.Arg337His and gender, ethnicity, premature birth or twinning. Remarkably, a trend was found between the geographic distribution of p.Arg337His carriers and occurrence of ACT.
We presented for the first time the p.Arg337His frequency among individuals unselected for any disease from a subset of the São Paulo State, the most populous in Brazil. The allele discrimination assay we presented here has proven to be a reliable and efficient method for high-throughput genotyping. ACT was found to be a good sentinel cancer to suppose p.Arg337His presence in our region.
TP53基因的p.Arg337His突变是该基因中迄今描述的与癌症相关的最常见的种系错义变异。它主要在巴西南部和东南部地区被发现，在那里它与儿童肾上腺皮质（ACT）和脉络丛肿瘤的高发病率有关。除了巴拉那州报告的平均患病率为0.27%外，这种突变的频率和地理分布在很大程度上尚不清楚。在本研究中，我们开发了一种用于p.Arg337His基因分型的高通量方法，这使我们能够确定该突变在巴西人口最多的州的一个队列中的频率和地理分布。
对来自圣保罗州的31612名新生儿的连续样本进行p.Arg337His筛查。通过实时聚合酶链反应（PCR）进行等位基因鉴别，并使用等位基因特异性寡核苷酸PCR检测携带者中A3单倍型的存在，随后进行巢式PCR以检测SNP rs9894946。
我们发现67个（0.21%）样本对此突变呈阳性。在圣保罗州和米纳斯吉拉斯州边界附近的城市中发现了最高的p.Arg337His频率。在p.Arg337His与性别、种族、早产或双胎之间未发现关联。值得注意的是，在p.Arg337His携带者的地理分布与ACT的发生之间发现了一种趋势。
我们首次呈现了在巴西人口最多的圣保罗州的一个子集中未因任何疾病而被选择的个体中p.Arg337His的频率。我们在此展示的等位基因鉴别分析已被证明是一种用于高通量基因分型的可靠且有效的方法。ACT被发现是推测我们地区存在p.Arg337His的一个良好的哨兵癌症。
